Deficient mismatch repair system (dMMR)/microsatellite instability (MSI) is found in about 5% of ... more Deficient mismatch repair system (dMMR)/microsatellite instability (MSI) is found in about 5% of metastatic colorectal cancers (mCRCs) with a major therapeutic impact for immune checkpoint inhibitor (ICI) use. We conducted a multicentre study including all consecutive patients with a dMMR/MSI mCRC. MSI status was determined using the Pentaplex panel and expression of the four MMR proteins was evaluated by immunohistochemistry (IHC). The primary endpoint was the rate of discordance of dMMR/MSI status between primary tumours and paired metastases. We included 99 patients with a dMMR/MSI primary CRC and 117 paired metastases. Only four discrepancies (3.4%) with a dMMR/MSI primary CRC and a pMMR/MSS metastasis were initially identified and reviewed by expert pathologists and molecular biologists. Two cases were false discrepancies due to human or technical errors. One discordant case could not be confirmed due to the low level of tumour cells. The last case had a confirmed discrepancy w...
PURPOSE To prospectively assess the impact of expert pathological review of skin adnexal carcinom... more PURPOSE To prospectively assess the impact of expert pathological review of skin adnexal carcinoma diagnosis in France. METHODS From 2014 to 2019, 2573 samples from patients with newly diagnosed or suspected skin adnexal carcinomas were reviewed prospectively by expert pathologists through the national CARADERM (CAncers RAres DERMatologiques) network. Changes in diagnosis between referral and expert review were analysed regarding their potential impact on patient care or prognosis. RESULTS The samples comprised 2205 newly diagnosed adnexal carcinomas, 129 benign adnexal tumours, 136 basal cell carcinomas, 74 squamous cell carcinomas, six cutaneous metastases and 13 other malignancies. There were 930 (42%) sweat gland carcinomas, of which porocarcinoma (261; 11.8%), microcystic adnexal carcinoma (125; 5.7%) and hidradenocarcinoma (109; 4.9%) were the most frequent subtypes; 778 (35%) hair follicle carcinomas, 238 (11%) sebaceous carcinomas and 212 (10%) extramammary Paget diseases/mammary-like anogenital gland adenocarcinomas. A diagnostic change between referral and expert review occurred in 503 (21.3%) patients, significantly higher for cases sent with a provisional diagnosis seeking an expert second opinion (45.7%) than for cases sent with a formal diagnosis (2.8%) (p < .0001). Sweat gland carcinomas were more prone to diagnostic discrepancies than other tumours (p < .0001), including 1.8% of patients with sweat gland carcinoma subtype misclassification with predicted clinical impact. Changes between benign and malignant conditions occurred in 117 samples (5% of patients). CONCLUSION The study provides a unique description of the distribution of skin adnexal carcinomas and highlights the importance of expert review for these rare cancers. Optimal clinical management was impacted in a significant proportion of patients.
Subcorneal pustular dermatosis (SPD), also known as Sneddon-Wilkinson disease, is a skin conditio... more Subcorneal pustular dermatosis (SPD), also known as Sneddon-Wilkinson disease, is a skin condition for which treatments are poorly codified. Anti-tumor necrosis factor alpha (TNFα) efficacy has been reported in multidrug-resistant SPD, as in our two cases. In the first case, an 83-year-old woman was monitored for SPD, associated with monoclonal IgA gammopathy. After multiple-line treatment failure, infliximab (5mg/kg) led to clinical improvement, noted few days following the first injection, and with complete remission at one month. At 12 months, the patient relapsed and concomitant serum anti-TNFα antibodies were found. A switch to adalimumab led to complete remission in three months with a follow-up of six months. In the second case, a 62-year-old woman was monitored for SPD associated with monoclonal IgA gammopathy recalcitrant to different lines of treatment. Treatment with adalimumab (40mg every two weeks) in combination with dapsone led to significant improvement after two inj...
Incidence of brain metastases has increased in patients with colorectal cancer (CRC) as their sur... more Incidence of brain metastases has increased in patients with colorectal cancer (CRC) as their survival has improved. CD3 T-cells and, lately, DGMate (DiGital tuMor pArameTErs) score, have been identified as prognostic factors in locally advanced CRC. Until now, there is no data concerning the prognostic value of these markers in patients with CRC-derived brain metastases. All consecutive patients with CRC-derived brain metastases diagnosed between 2000 and 2017 were retrospectively included. Staining for CD3, CD8, PD-1, PD-L1 and DGMate analyses were performed using tissue micro-array from primary tumors and, if available, brain metastases. All in all, 83 patients were included with 80 primary tumor samples and 37 brain metastases samples available. CD3 and CD8 T-cell infiltration was higher in primary tumors compared to brain metastases. We observed a significant higher DGMate score in rectal tumors compared to colon tumors (p=0.03). We also noted a trend of higher CD3 T-cell infil...
Conjunctival melanoma (CM) iss a rare and aggressive tumour that is increasing in frequency. The ... more Conjunctival melanoma (CM) iss a rare and aggressive tumour that is increasing in frequency. The prognostic value of PD-L1 expression, alone or in combination with CD8 and PD-1 expression and the BRAF and NRAS status, has not been determined in CM to date. We evaluated the expression of PD-L1, CD8, PD-1 in CM and investigated whether there was an association between the expression of these markers and the BRAF and NRAS molecular profile as well as some clinico-pathological criteria. A total of sixty-five CM were assessed for PD-L1, PD-1, and CD8 expression by immunohistochemistry (IHC) and for BRAF and NRAS genomic alterations using molecular biology techniques and anti-BRAF and anti-NRAS antibodies. PD-L1 expression in tumour cells (TC) was very low or absent but detected in tumour-infiltrating immune cells (IC). A correlation was observed between the expression of PD-L1, CD8, and PD-1 in IC. No correlation between PD-L1 expression (in tumour and/or immune cells) and BRAF or NRAS m...
Background: In most countries, participation in colorectal cancer (CRC) screening programs with t... more Background: In most countries, participation in colorectal cancer (CRC) screening programs with the immunological fecal occult blood test (iFOBT) is low. Mutations of RAS and BRAF occur early in colorectal carcinogenesis and “liquid biopsy” allows detection of mutated circulating tumor DNA (ctDNA). This prospective study aims to evaluate the performance of RAS and BRAF-mutated ctDNA in detecting CRC and advanced adenomas (AA). Methods: One hundred and thirty patients who underwent colonoscopy for suspicion of colorectal lesion were included and divided into four groups: 20 CRC, 39 AA, 31 non-advanced adenoma and/or hyperplastic polyp(s) (NAA) and 40 with no lesion. Mutated ctDNA was analyzed by droplet digital PCR. Results: ctDNA was detected in 45.0% of CRC, in 2.6% of AA and none of the NAA and “no-lesion” groups. All patients with stage II to IV mutated CRC had detectable ctDNA (n = 8/8). Among the mutated AA, only one patient had detectable ctDNA (4.3%), maybe due to limited tec...
Introduction La vasculopathie collagenique cutanee (VCC) est une microangiopathie rare de physiop... more Introduction La vasculopathie collagenique cutanee (VCC) est une microangiopathie rare de physiopathologie mal elucidee, decrite en 2000. Son traitement est mal codifie. Nous rapportons une nouvelle observation de VCC diagnostique chez une patiente ayant une comorbidite auto-immune, totalement regressive apres 2 seances de laser vasculaire. Observations Une femme de 60 ans aux antecedents dysimmunitaires (lupus cutane, polyarthrite rhumatoide et syndrome de Gougerot) consultait pour de larges plaques telangiectasiques acquises des membres et du decollete, evoluant de facon ascendante depuis 6 ans. Son traitement comportait hydroxychloroquine, flecaine et metoprolol. Ses maladies auto-immunes etaient controlees. La biopsie cutanee montrait un aspect typique de VCC. Un blanchiment quasi complet des lesions etaient observe apres 2 seances de laser. La premiere seance etait realisee en mode LCP au niveau d’un bras droit (595 nm, 6,5 J/cm2, 2ms, 10 mm) et en mode multiplex (PDL 7,5-9 J/cm2–YAG 40-50) au niveau du bras gauche. La deuxieme seance etait realisee 4 mois plus tard en mode LCP aux niveaux des 2 bras. Discussion Nous rapportons une nouvelle observation de VCC chez une patiente ayant une comorbidite auto-immune. Cette affection rare pourrait etre la consequence d’une anomalie genetique, d’un facteur environnemental, metabolique ou infectieux. Des atteintes repetees des cellules endotheliales, avec micro-occlusion vasculaire entraineraient une hyperplasie endotheliale, une duplication de la membrane basale avec integration de fibrine dans la paroi des vaisseaux et production excessive de collagene IV. A notre connaissance 42 cas de VCC ont ete decrits : une majorite de femmes (29F/13H), d’âge moyen 59,4 ans, avec une duree d’evolution avant le diagnostic de 8,4 ans en moyenne. Il est interessant de constater une proportion importante de patients ayant une maladie auto-immune associee (11,9 %) ce qui pose la question d’un eventuel role de l’auto-immunite dans la physiopathologie de cette affection. Le traitement de VCC n’est pas codifie. Seulement 2 cas decrits ont ete traites par laser : le premier en mode LCP (585 nm, 8 J/cm2, 2ms, 7 mm) d’efficacite moyenne, et le second, par 7 seances de laser vasculaire en mode multiplex PDL (595 nm, 8,5 J/cm2,10 ms,7 mm)+ YAG (1,064 nm, 55j/cm2, 15ms) avec une bonne efficacite. Contrairement aux autres cas decrits, nous avons observe une meilleure efficacite du laser LCP par rapport au mode multiplex, puisque le LCP a permis un blanchiment presque total des la premiere seance. Conclusion Nous rapportons une nouvelle observation de vasculopathie collagenique cutanee rapidement amelioree par un laser vasculaire. La coexistence de VCC et des maladies dysimmunitaires chez notre patiente pose la question d’un role eventuel de l’auto-immunite dans le declenchement des lesions.
EJD, vol. 28, n◦ 2, March-April 2018 tion 234, we found that the side chain of Pro234 contacts Le... more EJD, vol. 28, n◦ 2, March-April 2018 tion 234, we found that the side chain of Pro234 contacts Leu237 via a hydrogen bond, while the side chain of the mutated Ser234 leads to hydrogen bonds with Leu237, His230 and Val238 (figure 1F). Therefore, Pro234Ser mutation may reduce the stability of the protein, particularly the proline-rich region. Based on FoldX conformational stability analysis, the free energy of unfolding ( G) for wild-type PNPLA1 (612.733 kcal/mol) was lower than that for the mutant PNPLA1 (615.687 kcal/mol), also indicating the structural instability of the mutant PNPLA1. Western blotting demonstrated that the expression of mutant PNPLA1 was reduced by about 50% in the patients’ skin (figure 1G), consistent with the prediction of structural instability of the mutant PNPLA1 based on conformational analyses. In 2012, Grall et al. first identified two mutations (p.Glu131* and p.Ala59Val) in two ARCI families [1]. Subsequently, more mutations were reported in ARCI families [2, 3]. Most of the mutations locate to the conserved patatin domain of PNPLA1 [2, 3]. The missense mutation p.Pro234Ser that we identified is located outside of the patatin domain. Recent studies show that PNPLA1 is a transacylase, essential for the generation of the skin barrier lipid -O-acylceramide [4,5]. Lipids are integral parts of CE. PNPLA1 deficiency may disturb the formation of the lamellar body at a later stage of epidermal differentiation, when involucrin, envoplakin, and periplakin normally form a scaffold on the inner plasma membrane for CE assembly. Other structural proteins are subsequently crosslinked to the scaffold by transglutaminases, followed by loricrin, small proline-rich proteins, and lipids, to complete the CE [6]. Defects in CE scaffold result in abnormal barrier function, such as that observed in TGM1-deficient ARCI [7] and loricrin keratoderma [8]. Therefore, our findings allow us to speculate that the p.Pro234Ser mutant PNPLA1 causes a decrease and dysfunction of PNPLA1 in skin, affects the integrity of the CE, and impairs skin barrier function. This novel mutation in PNPLA1 expands the spectrum of mutations and genetic heterogeneity of ARCI. In addition, our two ARCI patients also suffered from Leber congenital amaurosis due to a homozygous nonsense mutation in LCA5, which encodes lebercilin [9]. Leber congenital amaurosis is a rare inheritable retinal dystrophy with early onset and severe symptoms, which was incidentally accompanied by ACR1 in the offspring of this consanguineous family.
Background: Colorectal cancers (CRC) with brain metastases (BM) are scarcely described. The main ... more Background: Colorectal cancers (CRC) with brain metastases (BM) are scarcely described. The main objective of this study was to determine the molecular profile of CRC with BM. Methods: We included 82 CRC patients with BM. KRAS, NRAS, BRAF and mismatch repair (MMR) status were investigated on primary tumors (n = 82) and BM (n = 38). ALK, ROS1, cMET, HER-2, PD-1, PD-L1, CD3 and CD8 status were evaluated by immunohistochemistry, and when recommended, by fluorescence in situ hybridization. Results: In primary tumors, KRAS, NRAS and BRAF mutations were observed in 56%, 6%, and 6% of cases, respectively. No ROS1, ALK and cMET rearrangement was detected. Only one tumor presented HER-2 amplification. Molecular profiles were mostly concordant between BM and paired primary tumors, except for 9% of discordances for RAS mutation. CD3, CD8, PD-1 and PD-L1 expressions presented some discordance between primary tumors and BM. In multivariate analysis, multiple BM, lung metastases and PD-L1+ tumor ...
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, Jan 12, 2018
The diagnosis of a uterine smooth muscle lesion is, in the majority of cases, straightforward. Ho... more The diagnosis of a uterine smooth muscle lesion is, in the majority of cases, straightforward. However, in a small number of cases, the morphological criteria used in such lesions cannot differentiate with certainty a benign from a malignant lesion and a diagnosis of smooth muscle tumor with uncertain malignant potential (STUMP) is made. Uterine leiomyosarcomas are often easy to diagnose but it is difficult or even impossible to identify a prognostic factor at the moment of the diagnosis with the exception of the stage. We hypothesize, for uterine smooth muscle lesions, that there is a gradient of genomic complexity that correlates to outcome. We first tested this hypothesis on STUMP lesions in a previous study and demonstrated that this 'gray category' could be split according to genomic index into two groups. A benign group, with a low to moderate alteration rate without recurrence and a malignant group, with a highly rearranged profile akin to uterine leiomyosarcomas. Her...
Deficient mismatch repair system (dMMR)/microsatellite instability (MSI) is found in about 5% of ... more Deficient mismatch repair system (dMMR)/microsatellite instability (MSI) is found in about 5% of metastatic colorectal cancers (mCRCs) with a major therapeutic impact for immune checkpoint inhibitor (ICI) use. We conducted a multicentre study including all consecutive patients with a dMMR/MSI mCRC. MSI status was determined using the Pentaplex panel and expression of the four MMR proteins was evaluated by immunohistochemistry (IHC). The primary endpoint was the rate of discordance of dMMR/MSI status between primary tumours and paired metastases. We included 99 patients with a dMMR/MSI primary CRC and 117 paired metastases. Only four discrepancies (3.4%) with a dMMR/MSI primary CRC and a pMMR/MSS metastasis were initially identified and reviewed by expert pathologists and molecular biologists. Two cases were false discrepancies due to human or technical errors. One discordant case could not be confirmed due to the low level of tumour cells. The last case had a confirmed discrepancy w...
PURPOSE To prospectively assess the impact of expert pathological review of skin adnexal carcinom... more PURPOSE To prospectively assess the impact of expert pathological review of skin adnexal carcinoma diagnosis in France. METHODS From 2014 to 2019, 2573 samples from patients with newly diagnosed or suspected skin adnexal carcinomas were reviewed prospectively by expert pathologists through the national CARADERM (CAncers RAres DERMatologiques) network. Changes in diagnosis between referral and expert review were analysed regarding their potential impact on patient care or prognosis. RESULTS The samples comprised 2205 newly diagnosed adnexal carcinomas, 129 benign adnexal tumours, 136 basal cell carcinomas, 74 squamous cell carcinomas, six cutaneous metastases and 13 other malignancies. There were 930 (42%) sweat gland carcinomas, of which porocarcinoma (261; 11.8%), microcystic adnexal carcinoma (125; 5.7%) and hidradenocarcinoma (109; 4.9%) were the most frequent subtypes; 778 (35%) hair follicle carcinomas, 238 (11%) sebaceous carcinomas and 212 (10%) extramammary Paget diseases/mammary-like anogenital gland adenocarcinomas. A diagnostic change between referral and expert review occurred in 503 (21.3%) patients, significantly higher for cases sent with a provisional diagnosis seeking an expert second opinion (45.7%) than for cases sent with a formal diagnosis (2.8%) (p < .0001). Sweat gland carcinomas were more prone to diagnostic discrepancies than other tumours (p < .0001), including 1.8% of patients with sweat gland carcinoma subtype misclassification with predicted clinical impact. Changes between benign and malignant conditions occurred in 117 samples (5% of patients). CONCLUSION The study provides a unique description of the distribution of skin adnexal carcinomas and highlights the importance of expert review for these rare cancers. Optimal clinical management was impacted in a significant proportion of patients.
Subcorneal pustular dermatosis (SPD), also known as Sneddon-Wilkinson disease, is a skin conditio... more Subcorneal pustular dermatosis (SPD), also known as Sneddon-Wilkinson disease, is a skin condition for which treatments are poorly codified. Anti-tumor necrosis factor alpha (TNFα) efficacy has been reported in multidrug-resistant SPD, as in our two cases. In the first case, an 83-year-old woman was monitored for SPD, associated with monoclonal IgA gammopathy. After multiple-line treatment failure, infliximab (5mg/kg) led to clinical improvement, noted few days following the first injection, and with complete remission at one month. At 12 months, the patient relapsed and concomitant serum anti-TNFα antibodies were found. A switch to adalimumab led to complete remission in three months with a follow-up of six months. In the second case, a 62-year-old woman was monitored for SPD associated with monoclonal IgA gammopathy recalcitrant to different lines of treatment. Treatment with adalimumab (40mg every two weeks) in combination with dapsone led to significant improvement after two inj...
Incidence of brain metastases has increased in patients with colorectal cancer (CRC) as their sur... more Incidence of brain metastases has increased in patients with colorectal cancer (CRC) as their survival has improved. CD3 T-cells and, lately, DGMate (DiGital tuMor pArameTErs) score, have been identified as prognostic factors in locally advanced CRC. Until now, there is no data concerning the prognostic value of these markers in patients with CRC-derived brain metastases. All consecutive patients with CRC-derived brain metastases diagnosed between 2000 and 2017 were retrospectively included. Staining for CD3, CD8, PD-1, PD-L1 and DGMate analyses were performed using tissue micro-array from primary tumors and, if available, brain metastases. All in all, 83 patients were included with 80 primary tumor samples and 37 brain metastases samples available. CD3 and CD8 T-cell infiltration was higher in primary tumors compared to brain metastases. We observed a significant higher DGMate score in rectal tumors compared to colon tumors (p=0.03). We also noted a trend of higher CD3 T-cell infil...
Conjunctival melanoma (CM) iss a rare and aggressive tumour that is increasing in frequency. The ... more Conjunctival melanoma (CM) iss a rare and aggressive tumour that is increasing in frequency. The prognostic value of PD-L1 expression, alone or in combination with CD8 and PD-1 expression and the BRAF and NRAS status, has not been determined in CM to date. We evaluated the expression of PD-L1, CD8, PD-1 in CM and investigated whether there was an association between the expression of these markers and the BRAF and NRAS molecular profile as well as some clinico-pathological criteria. A total of sixty-five CM were assessed for PD-L1, PD-1, and CD8 expression by immunohistochemistry (IHC) and for BRAF and NRAS genomic alterations using molecular biology techniques and anti-BRAF and anti-NRAS antibodies. PD-L1 expression in tumour cells (TC) was very low or absent but detected in tumour-infiltrating immune cells (IC). A correlation was observed between the expression of PD-L1, CD8, and PD-1 in IC. No correlation between PD-L1 expression (in tumour and/or immune cells) and BRAF or NRAS m...
Background: In most countries, participation in colorectal cancer (CRC) screening programs with t... more Background: In most countries, participation in colorectal cancer (CRC) screening programs with the immunological fecal occult blood test (iFOBT) is low. Mutations of RAS and BRAF occur early in colorectal carcinogenesis and “liquid biopsy” allows detection of mutated circulating tumor DNA (ctDNA). This prospective study aims to evaluate the performance of RAS and BRAF-mutated ctDNA in detecting CRC and advanced adenomas (AA). Methods: One hundred and thirty patients who underwent colonoscopy for suspicion of colorectal lesion were included and divided into four groups: 20 CRC, 39 AA, 31 non-advanced adenoma and/or hyperplastic polyp(s) (NAA) and 40 with no lesion. Mutated ctDNA was analyzed by droplet digital PCR. Results: ctDNA was detected in 45.0% of CRC, in 2.6% of AA and none of the NAA and “no-lesion” groups. All patients with stage II to IV mutated CRC had detectable ctDNA (n = 8/8). Among the mutated AA, only one patient had detectable ctDNA (4.3%), maybe due to limited tec...
Introduction La vasculopathie collagenique cutanee (VCC) est une microangiopathie rare de physiop... more Introduction La vasculopathie collagenique cutanee (VCC) est une microangiopathie rare de physiopathologie mal elucidee, decrite en 2000. Son traitement est mal codifie. Nous rapportons une nouvelle observation de VCC diagnostique chez une patiente ayant une comorbidite auto-immune, totalement regressive apres 2 seances de laser vasculaire. Observations Une femme de 60 ans aux antecedents dysimmunitaires (lupus cutane, polyarthrite rhumatoide et syndrome de Gougerot) consultait pour de larges plaques telangiectasiques acquises des membres et du decollete, evoluant de facon ascendante depuis 6 ans. Son traitement comportait hydroxychloroquine, flecaine et metoprolol. Ses maladies auto-immunes etaient controlees. La biopsie cutanee montrait un aspect typique de VCC. Un blanchiment quasi complet des lesions etaient observe apres 2 seances de laser. La premiere seance etait realisee en mode LCP au niveau d’un bras droit (595 nm, 6,5 J/cm2, 2ms, 10 mm) et en mode multiplex (PDL 7,5-9 J/cm2–YAG 40-50) au niveau du bras gauche. La deuxieme seance etait realisee 4 mois plus tard en mode LCP aux niveaux des 2 bras. Discussion Nous rapportons une nouvelle observation de VCC chez une patiente ayant une comorbidite auto-immune. Cette affection rare pourrait etre la consequence d’une anomalie genetique, d’un facteur environnemental, metabolique ou infectieux. Des atteintes repetees des cellules endotheliales, avec micro-occlusion vasculaire entraineraient une hyperplasie endotheliale, une duplication de la membrane basale avec integration de fibrine dans la paroi des vaisseaux et production excessive de collagene IV. A notre connaissance 42 cas de VCC ont ete decrits : une majorite de femmes (29F/13H), d’âge moyen 59,4 ans, avec une duree d’evolution avant le diagnostic de 8,4 ans en moyenne. Il est interessant de constater une proportion importante de patients ayant une maladie auto-immune associee (11,9 %) ce qui pose la question d’un eventuel role de l’auto-immunite dans la physiopathologie de cette affection. Le traitement de VCC n’est pas codifie. Seulement 2 cas decrits ont ete traites par laser : le premier en mode LCP (585 nm, 8 J/cm2, 2ms, 7 mm) d’efficacite moyenne, et le second, par 7 seances de laser vasculaire en mode multiplex PDL (595 nm, 8,5 J/cm2,10 ms,7 mm)+ YAG (1,064 nm, 55j/cm2, 15ms) avec une bonne efficacite. Contrairement aux autres cas decrits, nous avons observe une meilleure efficacite du laser LCP par rapport au mode multiplex, puisque le LCP a permis un blanchiment presque total des la premiere seance. Conclusion Nous rapportons une nouvelle observation de vasculopathie collagenique cutanee rapidement amelioree par un laser vasculaire. La coexistence de VCC et des maladies dysimmunitaires chez notre patiente pose la question d’un role eventuel de l’auto-immunite dans le declenchement des lesions.
EJD, vol. 28, n◦ 2, March-April 2018 tion 234, we found that the side chain of Pro234 contacts Le... more EJD, vol. 28, n◦ 2, March-April 2018 tion 234, we found that the side chain of Pro234 contacts Leu237 via a hydrogen bond, while the side chain of the mutated Ser234 leads to hydrogen bonds with Leu237, His230 and Val238 (figure 1F). Therefore, Pro234Ser mutation may reduce the stability of the protein, particularly the proline-rich region. Based on FoldX conformational stability analysis, the free energy of unfolding ( G) for wild-type PNPLA1 (612.733 kcal/mol) was lower than that for the mutant PNPLA1 (615.687 kcal/mol), also indicating the structural instability of the mutant PNPLA1. Western blotting demonstrated that the expression of mutant PNPLA1 was reduced by about 50% in the patients’ skin (figure 1G), consistent with the prediction of structural instability of the mutant PNPLA1 based on conformational analyses. In 2012, Grall et al. first identified two mutations (p.Glu131* and p.Ala59Val) in two ARCI families [1]. Subsequently, more mutations were reported in ARCI families [2, 3]. Most of the mutations locate to the conserved patatin domain of PNPLA1 [2, 3]. The missense mutation p.Pro234Ser that we identified is located outside of the patatin domain. Recent studies show that PNPLA1 is a transacylase, essential for the generation of the skin barrier lipid -O-acylceramide [4,5]. Lipids are integral parts of CE. PNPLA1 deficiency may disturb the formation of the lamellar body at a later stage of epidermal differentiation, when involucrin, envoplakin, and periplakin normally form a scaffold on the inner plasma membrane for CE assembly. Other structural proteins are subsequently crosslinked to the scaffold by transglutaminases, followed by loricrin, small proline-rich proteins, and lipids, to complete the CE [6]. Defects in CE scaffold result in abnormal barrier function, such as that observed in TGM1-deficient ARCI [7] and loricrin keratoderma [8]. Therefore, our findings allow us to speculate that the p.Pro234Ser mutant PNPLA1 causes a decrease and dysfunction of PNPLA1 in skin, affects the integrity of the CE, and impairs skin barrier function. This novel mutation in PNPLA1 expands the spectrum of mutations and genetic heterogeneity of ARCI. In addition, our two ARCI patients also suffered from Leber congenital amaurosis due to a homozygous nonsense mutation in LCA5, which encodes lebercilin [9]. Leber congenital amaurosis is a rare inheritable retinal dystrophy with early onset and severe symptoms, which was incidentally accompanied by ACR1 in the offspring of this consanguineous family.
Background: Colorectal cancers (CRC) with brain metastases (BM) are scarcely described. The main ... more Background: Colorectal cancers (CRC) with brain metastases (BM) are scarcely described. The main objective of this study was to determine the molecular profile of CRC with BM. Methods: We included 82 CRC patients with BM. KRAS, NRAS, BRAF and mismatch repair (MMR) status were investigated on primary tumors (n = 82) and BM (n = 38). ALK, ROS1, cMET, HER-2, PD-1, PD-L1, CD3 and CD8 status were evaluated by immunohistochemistry, and when recommended, by fluorescence in situ hybridization. Results: In primary tumors, KRAS, NRAS and BRAF mutations were observed in 56%, 6%, and 6% of cases, respectively. No ROS1, ALK and cMET rearrangement was detected. Only one tumor presented HER-2 amplification. Molecular profiles were mostly concordant between BM and paired primary tumors, except for 9% of discordances for RAS mutation. CD3, CD8, PD-1 and PD-L1 expressions presented some discordance between primary tumors and BM. In multivariate analysis, multiple BM, lung metastases and PD-L1+ tumor ...
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, Jan 12, 2018
The diagnosis of a uterine smooth muscle lesion is, in the majority of cases, straightforward. Ho... more The diagnosis of a uterine smooth muscle lesion is, in the majority of cases, straightforward. However, in a small number of cases, the morphological criteria used in such lesions cannot differentiate with certainty a benign from a malignant lesion and a diagnosis of smooth muscle tumor with uncertain malignant potential (STUMP) is made. Uterine leiomyosarcomas are often easy to diagnose but it is difficult or even impossible to identify a prognostic factor at the moment of the diagnosis with the exception of the stage. We hypothesize, for uterine smooth muscle lesions, that there is a gradient of genomic complexity that correlates to outcome. We first tested this hypothesis on STUMP lesions in a previous study and demonstrated that this 'gray category' could be split according to genomic index into two groups. A benign group, with a low to moderate alteration rate without recurrence and a malignant group, with a highly rearranged profile akin to uterine leiomyosarcomas. Her...
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Papers by Eric Frouin