Publications by authors named "Mai Hoang"

191 Publications

Prognostic Roles of , , , and Mutations in Mucosal Melanomas.

Cells 2021 Aug 27;10(9). Epub 2021 Aug 27.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Background: The prognostic value of commonly recurrent mutations remains unclear in mucosal melanomas.

Methods: Clinicopathologic parameters of 214 cases of mucosal melanomas diagnosed in 1989-2020 in several clinical institutions were analyzed. , , , and mutational analyses by Sanger sequencing and next generation sequencing-based assay were performed in a subset of cases.

Results: Of the triple (, , )-negative cases, , and are detected mainly in sinonasal, vulvovaginal and anorectal melanomas, respectively. , , , and mutations are detected in 19% (37/198), 22% (44/197), 12% (25/201), 16% (22/138) and 15% (20/133) of cases, respectively. In univariate analyses, advanced stage ( = 0.016), 65 years or older ( = 0.048) and presence of ulceration ( = 0.027) are significantly correlated with worse overall survival (OS), respectively. mutation significantly correlates with worse OS ( = 0.028) and worse melanoma-specific survival (MSS) ( = 0.03) for all cases of mucosal melanomas. In multivariate analyses, mutation remains as an independent predictor of worse OS ( = 0.036) and worse MSS ( = 0.024).

Conclusion: mutation is a predictor of worse survival, independent of stage in mucosal melanomas. The significance of frequently mutated in mucosal melanomas remains unclear.
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http://dx.doi.org/10.3390/cells10092216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468625PMC
August 2021

Deep Herpes.

Am J Surg Pathol 2021 10;45(10):1357-1363

Pathology Service, Massachusetts General Hospital and Harvard Medical School, Boston.

Herpes viruses are known for infecting epithelial cells and manifesting as vesicles. However, herpes viruses can also infect stromal cells. While established in the ocular setting, cutaneous stromal herpes (deep herpes) is previously unreported and may evade clinical and microscopic detection. We searched for skin biopsies with herpes stromal disease. Clinical information was retrieved via electronic medical records and pathology records system. Hematoxylin and eosin slides, immunohistochemical staining, and polymerase chain reaction detection of viral DNA was performed. We identified 12 specimens from 10 patients with cutaneous stromal herpes simplex virus 1/2 (n=7) or varicella-zoster virus infection (n=5). The most common site involved was the buttocks/perianal region (n=6). Ulceration was a frequent dermatologic finding (n=8). Pyoderma gangrenosum was clinically suspected in 6 specimens (50%). Eight patients (80%) were immunosuppressed. Biopsies frequently demonstrated a dense dermal mixed inflammatory infiltrate with subcutaneous extension and enlarged cells with viral cytopathic changes confirmed by herpes simplex virus 1/2 or varicella-zoster virus immunohistochemistry (n=10) or polymerase chain reaction (n=2). Most specimens (67%) lacked evidence of characteristic epidermal keratinocyte infection. This study presents the first known report of the ability of herpes virus to infect deep stromal cells of the dermis. We raise awareness of cutaneous stromal herpes in patients presenting with atypical clinical lesions, particularly while immunocompromised. Establishing the correct diagnosis is critical for initiating therapy.
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http://dx.doi.org/10.1097/PAS.0000000000001733DOI Listing
October 2021

Skin biopsy in the diagnosis of intravascular lymphoma: a retrospective diagnostic accuracy study.

J Am Acad Dermatol 2021 Jul 24. Epub 2021 Jul 24.

Massachusetts General Hospital, Dermatology Department - Boston, Massachusetts, United States of America. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2021.07.024DOI Listing
July 2021

Prognostic Role of Tumoral PD-L1 and IDO1 Expression, and Intratumoral CD8+ and FoxP3+ Lymphocyte Infiltrates in 132 Primary Cutaneous Merkel Cell Carcinomas.

Int J Mol Sci 2021 May 23;22(11). Epub 2021 May 23.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

The association of immune markers and clinicopathologic features and patient outcome has not been extensively studied in Merkel cell carcinoma (MCC). We correlated tumoral PD-L1 and IDO1 expression, and intratumoral CD8+ and FoxP3+ lymphocytes count with clinicopathologic variables, Merkel cell polyomavirus (MCPyV) status, and patient outcomes in a series of 132 MCC. By univariate analyses, tumoral PD-L1 expression >1% and combined tumoral PD-L1 >1% and high intratumoral FoxP3+ lymphocyte count correlated with improved overall survival (OS) ( = 0.016, 0.0072), MCC-specific survival (MSS) ( = 0.019, 0.017), and progression-free survival (PFS) ( = 0.043, 0.004, respectively). High intratumoral CD8+ and FoxP3+ lymphocyte count correlated with longer MSS ( = 0.036) and improved PFS ( = 0.047), respectively. Ulceration correlated with worse OS and worse MSS. Age, male gender, and higher stage (3 and 4) significantly correlated with worse survival. MCPyV positivity correlated with immune response. By multivariate analyses, only ulceration and age remained as independent predictors of worse OS; gender and stage remained for shorter PFS. Tumoral PD-L1 expression and increased density of intratumoral CD8+ lymphocytes and FoxP+ lymphocytes may represent favorable prognosticators in a subset of MCCs. Tumoral PD-L1 expression correlated with intratumoral CD8+ and FoxP3+ lymphocytes, which is supportive of an adaptive immune response.
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http://dx.doi.org/10.3390/ijms22115489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197111PMC
May 2021

Microwave-Assisted Automated Glycan Assembly.

J Am Chem Soc 2021 Jun 1;143(23):8893-8901. Epub 2021 Jun 1.

Department of Biomolecular Systems, Max-Planck-Institute of Colloids and Interfaces, 14476 Potsdam, Germany.

Automated synthesis of DNA, RNA, and peptides provides quickly and reliably important tools for biomedical research. Automated glycan assembly (AGA) is significantly more challenging, as highly branched carbohydrates require strict regio- and stereocontrol during synthesis. A new AGA synthesizer enables rapid temperature adjustment from -40 to +100 °C to control glycosylations at low temperature and accelerates capping, protecting group removal, and glycan modifications using elevated temperatures. Thereby, the temporary protecting group portfolio is extended from two to four orthogonal groups that give rise to oligosaccharides with up to four branches. In addition, sulfated glycans and unprotected glycans can be prepared. The new design reduces the typical coupling cycles from 100 to 60 min while expanding the range of accessible glycans. The instrument drastically shortens and generalizes the synthesis of carbohydrates for use in biomedical and material science.
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http://dx.doi.org/10.1021/jacs.1c03851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213053PMC
June 2021

A luminescent ATCUN peptide variant with enhanced properties for copper(II) sensing in biological media.

J Inorg Biochem 2021 Aug 30;221:111478. Epub 2021 Apr 30.

Institut de Chimie, UMR 7177, CNRS, Université de Strasbourg, 4 Rue Blaise Pascal, 67000 Strasbourg, France. Electronic address:

The measurement of labile Cu in biological samples is fundamental for understanding Cu metabolism and has been emerging as a promising diagnostic marker for Cu-related pathologies such as Wilson's and Alzheimer's diseases. The use of fluorescent chelators may be useful to circumvent separation steps employed by current methods. For this purpose, we recently designed a selective and suited-affinity turn-off luminescent probe based on a peptide bearing the Cu-binding Xxx-Zzz-His (Amino-Terminal Cu- and Ni-binding, ATCUN) motif and a Tb-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) complex. Here, we present an analogue probe bearing the ATCUN motif variant Xxx-His-His. This probe showed much faster response in biologically-relevant media and higher stability than the previous motif at low pH. These features could be beneficial to the measurement of dynamic Cu fluctuations and the application in slightly acidic media, such as urine.
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http://dx.doi.org/10.1016/j.jinorgbio.2021.111478DOI Listing
August 2021

Evolution of delayed resistance to immunotherapy in a melanoma responder.

Nat Med 2021 06 3;27(6):985-992. Epub 2021 May 3.

Department of Pathology, Harvard Medical School, Brigham and Woman's Hospital, Boston, MA, USA.

Despite initial responses, most melanoma patients develop resistance to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor-immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course.
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http://dx.doi.org/10.1038/s41591-021-01331-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474080PMC
June 2021

Merkel Cell Carcinoma of Unknown Primary: Immunohistochemical and Molecular Analyses Reveal Distinct UV-Signature/MCPyV-Negative and High Immunogenicity/MCPyV-Positive Profiles.

Cancers (Basel) 2021 Mar 31;13(7). Epub 2021 Mar 31.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Background: Merkel cell carcinomas of unknown primary (MCC-UPs) are defined as deep-seated tumors without an associated cutaneous tumor. Although the distinction has important clinical implications, it remains unclear whether these tumors represent primary tumors of lymph nodes or metastatic cutaneous primaries.

Methods: We compared the immunohistochemical profiles of four groups of MCCs (Merkel cell polyomavirus (MCPyV)-positive UP, MCPyV-negative UP, MCPyV-positive known primary (KP), and MCPyV-negative KP) using B-cell and pre-B-cell markers, cell cycle regulating proteins, follicular stem cell markers, and immune markers, and performed next generation and Sanger sequencing.

Results: Virus-positive and virus-negative MCC-UPs exhibited an immunoprofile similar to virus-positive and virus-negative primary cutaneous MCCs, respectively. MCC-UP tumors (both virus-positive and -negative) were immunogenic with similar or even higher tumoral PD-L1 expression and intratumoral CD8 and FoxP3 infiltrates in comparison to MCPyV-positive cutaneous tumors. In addition, similar to primary cutaneous MCCs, MCPyV-negative MCC-UPs exhibited UV signatures and frequent high tumor mutational burdens, whereas few molecular alterations were noted in MCPyV-positive MCC-UPs.

Conclusions: Our results showed distinct UV-signatures in MCPyV-negative tumors and high immunogenicity in MCPyV-positive tumors. Although additional studies are warranted for the MCPyV-positive cases, our findings are supportive of a cutaneous metastatic origin for MCPyV-negative MCC-UP tumors.
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http://dx.doi.org/10.3390/cancers13071621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037250PMC
March 2021

Co-Encapsulation of Lycopene and Resveratrol in Polymeric Nanoparticles: Morphology and Lycopene Stability.

J Nanosci Nanotechnol 2021 05;21(5):3156-3164

Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi, 100000, Vietnam.

Lycopene and resveratrol are well-known for their high bioactivity, anti-inflammatory effects, and strong antioxidant properties. The combination of lycopene and resveratrol was synergistic in the potentializing immunity of the mammal body. In this study, the scalable co-encapsulation of lycopene and resveratrol into polymeric nanoparticles was performed using lycopene extracted from ripe gac fruit. These nanoparticles exhibited excellent water dispersion and spherical morphology with average particle diameters of 66.102 nm. The particle size was proportional to the lycopene/resveratrol ratio. The combinative use of lecithin and Tween® as surfactants and the use of a polylactide-polyethylene glycol copolymer as an encapsulation agent generated well-defined lycopene/resveratrol nanoparticles although the total content of these active compounds reached 12%. The stability of lycopene was enhanced when combined with resveratrol and antioxidants such as vitamin E and butylated hydroxytoluene. After 3 months of storage at -16 °C, the lycopene content in the lycopene/resveratrol nanopowder remained at ∼95%.
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http://dx.doi.org/10.1166/jnn.2021.19146DOI Listing
May 2021

Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses.

Sci Transl Med 2021 02;13(581)

Experimental Cancer Genetics, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.

Although immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein-1 (PD-1), can deliver durable antitumor effects, most patients with cancer fail to respond. Recent studies suggest that ICI efficacy correlates with a higher load of tumor-specific neoantigens and development of vitiligo in patients with melanoma. Here, we report that patients with low melanoma neoantigen burdens who responded to ICI had tumors with higher expression of pigmentation-related genes. Moreover, expansion of peripheral blood CD8 T cell populations specific for melanocyte antigens was observed only in patients who responded to anti-PD-1 therapy, suggesting that ICI can promote breakdown of tolerance toward tumor-lineage self-antigens. In a mouse model of poorly immunogenic melanomas, spreading of epitope recognition toward wild-type melanocyte antigens was associated with markedly improved anti-PD-1 efficacy in two independent approaches: introduction of neoantigens by ultraviolet (UV) B radiation mutagenesis or the therapeutic combination of ablative fractional photothermolysis plus imiquimod. Complete responses against UV mutation-bearing tumors after anti-PD-1 resulted in protection from subsequent engraftment of melanomas lacking any shared neoantigens, as well as pancreatic adenocarcinomas forcibly overexpressing melanocyte-lineage antigens. Our data demonstrate that somatic mutations are sufficient to provoke strong antitumor responses after checkpoint blockade, but long-term responses are not restricted to these putative neoantigens. Epitope spreading toward T cell recognition of wild-type tumor-lineage self-antigens represents a common pathway for successful response to ICI, which can be evoked in neoantigen-deficient tumors by combination therapy with ablative fractional photothermolysis and imiquimod.
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http://dx.doi.org/10.1126/scitranslmed.abd8636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130008PMC
February 2021

Purpuric ulcers associated with COVID-19: A case series.

JAAD Case Rep 2021 May 3;11:13-19. Epub 2021 Feb 3.

Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.jdcr.2021.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857020PMC
May 2021

Distinction Between Hypertrophic Lichen Planus and Squamous Cell Carcinoma Requires Clinicopathologic Correlation in Difficult Cases.

Am J Dermatopathol 2021 May;43(5):349-355

Department of Pathology, Massachusetts General Hospital, Boston, MA.

Abstract: Distinguishing hypertrophic lichen planus (HLP) and squamous cell carcinoma (SCC) can be diagnostically challenging because of overlapping clinical and histopathological features. This study characterizes histopathological features in HLP and SCC, assessing their utility in diagnosing atypical squamous proliferations. We compared 12 histopathological features of 15 HLP and 11 SCC biopsies from the lower extremities. We then reviewed 16 cases that were diagnosed as atypical squamous proliferations with differential diagnoses of HLP versus SCC. Clinical follow-up allowed for retrospective categorization of these difficult cases as HLP or SCC. HLP showed significant differences in hyperorthokeratosis (P = 0.04), wedge-shaped hypergranulosis (P = 0.0033), and irregular psoriasiform hyperplasia (P = 0.004), whereas parakeratosis (P = 0.001), solar elastosis (P = 0.001), deep extension (P = 0.02), and perforating elastic fibers (P = 0.0001) were significant for SCC. A scoring system based on these significant differences was devised to aid the classification of difficult cases. 56% of the difficult cases received an "indeterminate" score. A score favoring HLP had a sensitivity of 44% and a specificity of 71%. Although significant differences were identified between cases of definitive HLP and SCC, these histopathological features were unable to distinguish difficult cases, highlighting the need for clinicopathological correlation in patients with atypical squamous proliferations of the lower extremities. Many difficult cases had histologic features that could not be evaluated because of the superficial nature of the biopsy. Therefore, obtaining a deep wedge or punch biopsy may facilitate a diagnosis in cases with a differential diagnosis of HLP and SCC.
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http://dx.doi.org/10.1097/DAD.0000000000001776DOI Listing
May 2021

Large nuclear size correlated with better overall survival, Merkel cell polyomavirus positivity, and terminal deoxynucleotidyl transferase expression in Merkel cell carcinoma.

J Am Acad Dermatol 2021 Feb 11;84(2):550-552. Epub 2020 Dec 11.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.05.125DOI Listing
February 2021

Case 33-2020: A 55-Year-Old Man with Abdominal Pain, Joint Swelling, and Skin Lesions.

N Engl J Med 2020 Oct;383(17):1664-1671

From the Departments of Dermatology (M.R.Y.), Radiology (L.A.R.), Surgery (P.J.F.), and Pathology (M.P.H.), Massachusetts General Hospital, and the Departments of Dermatology (M.R.Y.), Radiology (L.A.R.), Surgery (P.J.F.), and Pathology (M.P.H.), Harvard Medical School - both in Boston.

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http://dx.doi.org/10.1056/NEJMcpc1916257DOI Listing
October 2020

Metastasizing basal cell carcinoma: A clinicopathologic and immunohistochemical study of 22 cases.

J Cutan Pathol 2021 Mar 5;48(3):374-383. Epub 2020 Nov 5.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Basal cell carcinomas metastasize rarely, and there have been limited studies of potential drivers for this metastasis. Epithelial-mesenchymal transition (EMT) may play a role, although this has not been investigated in detail. We reviewed clinicopathologic features of 22 patients with metastasizing basal cell carcinoma (MBCC). Immunohistochemical markers of EMT, including CD44, E-cadherin, claudin, smooth muscle actin, beta-catenin, Twist1, and Oct 3/4, were evaluated on 10 MBCC (primary and metastases) and 18 non-metastasizing BCC. Primary sites included the head and neck, trunk, and extremity, while metastatic sites included lymph nodes, lung, bone, and soft tissue. Of 19 cases with follow-up, the range of follow-up after diagnosis of metastasis was 5 to 248 months (median: 50 months). Two cases were of unknown primary, nine metastases were diagnosed concurrently with primary tumors, and remaining cases showed a median latency between diagnosis of primary and metastatic tumors of 27.5 months (range: 3-81 months). Median survival was 66 months. Compared to non-metastasizing BCC, MBCC demonstrated reduced CD44 expression (primary [P = .0036], metastatic [P = .011]) and increased Twist1 expression (primary, P = .0017). MBCC shows variably aggressive behavior, and reduced CD44 and increased Twist1 expression may indicate significant EMT in metastasizing tumors and signify a metastatic phenotype.
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http://dx.doi.org/10.1111/cup.13888DOI Listing
March 2021

Morphologic Diversity of Merkel Cell Carcinoma.

Am J Dermatopathol 2020 Sep;42(9):629-640

Professor of Pathology, Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, MA.

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine carcinoma of unknown origin. We performed a retrospective histologic review of primary cutaneous MCCs diagnosed from 1997 to 2018 in several clinical institutions and literature review to determine the frequency of various unusual morphologic appearances of MCC. Of the 136 primary MCCs identified, intraepidermal carcinoma or epidermotropism was noted in 11/136 (8%) cases. An association with pilar cyst in 1/136 (0.7%) case, with actinic keratosis in 2/136 (1.5%) cases, with either invasive or in situ squamous cell carcinoma (SCC) in 14/136 (10%) cases, with poroma in 1/136 (0.7%), and with basal cell carcinoma in 1/136 (0.7%) case was noted. Trabecular pattern and rosettes were noted in 7/136 (5%) and 3/136 (2%) cases, respectively. There was one case of metastatic MCC in a lymph node with chronic lymphocytic leukemia and one rare case of metastatic MCC and SCC in a lymph node. Although uncommon, differentiation toward other cell lineage can be observed in both primary and metastatic MCCs. The tumor can assume a variety of histologic appearances including association with SCC, basal cell carcinoma, melanocytic neoplasm, and follicular cyst; as well as exhibit glandular, sarcomatous, and mesenchymal differentiation. This diversity of morphologic appearance of MCC reflects the complexity of its underlying pathogenesis.
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http://dx.doi.org/10.1097/DAD.0000000000001548DOI Listing
September 2020

Granuloma Formation Secondary to Surreptitiously Placed Silicone.

Dermatol Surg 2021 06;47(6):849-851

Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1097/DSS.0000000000002630DOI Listing
June 2021

Molecular Alterations in Vaginal Melanomas: Report of 4 Cases and Literature Review.

Am J Dermatopathol 2021 Jan;43(1):45-48

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Abstract: Melanomas of the female gynecological tract comprise approximately 18% of mucosal melanomas, a rare subtype of melanoma. Within the female genital tract, 70% of primary melanomas of the gynecological tract are from the vulva with the remainder occurring in the vagina and rarely, in the cervix. We investigate molecular alterations by next-generation sequencing-based molecular tests targeting 99 cancer genes and translocation/fusion assays in 4 and 3 vaginal melanomas, respectively. The ages of the 4 patients range from 65 to 90 years. Postmenopausal bleeding was the most common presenting symptom. Tumor size ranged from 0.5 to 6.6 cm. KIT L576P mutation was documented in case 1, whereas TP53 mutation was seen in cases 2 and 3 (L130F and Y163C). Case 2 also harbored NF2 E204Q and ATRX D1719H mutations. A number of gene copy alterations were noted in case 4, which included GNA11 loss, MYC gain, RET loss, SMO loss, SUFU loss, and TSC2 loss. No gene fusion was detected in any of the 3 tested cases. In conclusion, in addition to KIT, TP53, and ATRX mutations, which have been previously reported, our cases harbor NF2 mutation and multiple gene copy alterations that have not previously been documented in vaginal melanomas. These findings highlight the potential role of targeted therapy in this rare melanoma subtype.
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http://dx.doi.org/10.1097/DAD.0000000000001759DOI Listing
January 2021

Programmed cell death ligand-1 and cytotoxic T cell infiltrates in metastatic cutaneous squamous cell carcinoma of the head and neck.

Head Neck 2020 11 1;42(11):3226-3234. Epub 2020 Aug 1.

Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.

Background: Metastatic cutaneous squamous cell carcinoma (cSCC) carries a poor prognosis. Increased numbers of CD8+ cytotoxic T cells are associated with a favorable prognosis and programmed cell death receptor-1 is a suppressor of the CD8+ cytotoxic T cell response. We aim to define their expression in metastatic cutaneous squamous cell carcinoma.

Methods: Cytotoxic T cell infiltrates and tumoral PD-L1 expression in lymph node metastases from patients with cSCC of the head and neck were analyzed.

Results: High tumoral PD-L1 expression, intratumoral and peritumoral CD8+ cell density in metastases were significantly associated with poor primary tumor differentiation. Low PD-L1 expression, intratumoral and peritumoral CD8+ density were associated with lower grade primary tumor differentiation. Low PD-L1 expression correlated with disease progression.

Conclusions: Increased expression of PD-L1 correlates with increased CD8+ cell density. Increased expression of PD-L1 in poorly differentiated tumors may be more likely to benefit from anti PD-1/PD-L1 therapy.
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http://dx.doi.org/10.1002/hed.26370DOI Listing
November 2020

Up-Regulation of PARP1 Expression Significantly Correlated with Poor Survival in Mucosal Melanomas.

Cells 2020 05 5;9(5). Epub 2020 May 5.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Introduction: Mucosal melanoma is rare and associated with poorer prognosis in comparison to conventional melanoma subtypes. Little is known about the prognostic significance as well as possible associations between PARP1 and immunologic response in mucosal melanoma.

Methods: PARP1, PD-L1 and IDO1 immunostains were performed on 192 mucosal melanomas including 86 vulvar, 89 sinonasal, and 17 anorectal melanomas.

Results: By Kaplan-Meier analyses, high PARP1 expression correlated with worse overall and melanoma-specific survival (log-rank values = 0.026 and 0.047, respectively). Tumors with combined PARP1 and IDO1 high expression correlated with worse overall and melanoma-specific survival ( = 0.015, 0.0034 respectively). By multivariate analyses, high PARP1 expression remained a predictor of worse survival independent of stage. By Fisher's exact test, high PARP1 expression correlated with highly mitogenic tumors ( = 0.02). High tumoral PD-L1 and IDO1 expression were associated with ulcerated primary tumors ( = 0.019, 0.0019, respectively). By linear regression analyses, correlations between PARP1 expression versus IDO1 expression ( = 0.0001) and mitotic index ( = 0.0052) were observed.

Conclusion: Increased expression of PARP1 is an independent negative prognostic marker in mucosal melanomas. The association between PARP1 and IDO1 and their combined adverse prognostic role raise the potential of combined therapy in mucosal melanoma.
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http://dx.doi.org/10.3390/cells9051135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290913PMC
May 2020

Discrimination of β-1,4- and β-1,3-Linkages in Native Oligosaccharides via Charge Transfer Dissociation Mass Spectrometry.

J Am Soc Mass Spectrom 2020 Jun 4;31(6):1249-1259. Epub 2020 May 4.

INRAE, UR BIA, F-44316 Nantes, France.

The connection between monosaccharides influences the structure, solubility, and biological function of carbohydrates. Although tandem mass spectrometry (MS/MS) often enables the compositional identification of carbohydrates, traditional MS/MS fragmentation methods fail to generate abundant cross-ring fragments of intrachain monosaccharides that could reveal carbohydrate connectivity. We examined the potential of helium-charge transfer dissociation (He-CTD) as a method of MS/MS to decipher the connectivity of β-1,4- and β-1,3-linked oligosaccharides. In contrast to collision-induced dissociation (CID), He-CTD of isolated oligosaccharide precursors produced both glycosidic and cross-ring cleavages of each monosaccharide. The radical-driven dissociation in He-CTD induced single cleavage events, without consecutive fragmentations, which facilitated structural interpretation. He-CTD of various standards up to a degree of polymerization of 7 showed that β-1,4- and β-1,3-linked carbohydrates can be distinguished based on diagnostic A fragment ions that are characteristic for β-1,4-linkages. Overall, fragment ion spectra from He-CTD contained sufficient information to infer the connectivity specifically for each glycosidic bond. When testing He-CTD to resolve the order of β-1,4- and β-1,3-linkages in mixed-linked oligosaccharide standards, He-CTD spectra sometimes provided less confident assignment of connectivity. Ion mobility spectrometry-mass spectrometry (IMS-MS) of the standards indicated that ambiguity in the He-CTD spectra was caused by isobaric impurities in the mixed-linked oligosaccharides. Radical-driven dissociation induced by He-CTD can thus expand MS/MS to carbohydrate linkage analysis, as demonstrated by the comprehensive fragment ion spectra on native oligosaccharides. The determination of connectivity in true unknowns would benefit from the separation of isobaric precursors, through UPLC or IMS, before linkage determination via He-CTD.
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http://dx.doi.org/10.1021/jasms.0c00087DOI Listing
June 2020

Perineural and Vascular Invasion in an Endocrine Mucin-Producing Sweat Gland Carcinoma of the Ear with Associated Mucinous Carcinoma.

Dermatopathology (Basel) 2019 Oct-Dec;6(4):271-274. Epub 2020 Feb 27.

Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a low-grade, indolent tumor found almost exclusively on the eyelids that may histologically mimic metastatic breast carcinoma. To our knowledge, we present the first case of EMPSGC located on the external ear, and the first case with histologic evidence of vascular and perineural invasion. Due to the aggressive potential of this lesion, wide local excision and adjuvant radiation therapy were performed to help reduce the risk of recurrence.
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http://dx.doi.org/10.1159/000503767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098345PMC
February 2020

TdT Expression Is a Marker of Better Survival in Merkel Cell Carcinoma, and Expression of B-Cell Markers Is Associated With Merkel Cell Polyomavirus.

Am J Clin Pathol 2020 06;154(1):38-47

Department of Pathology, Center of Oncology, M. Sklodowska-Curie Memorial Institute, Krakow, Poland.

Objectives: Merkel cell carcinoma is a rare but very aggressive cutaneous tumor. We evaluated the prognostic potential of B-cell markers (terminal deoxynucleotidyl transferase [TdT], PAX5, CD117), follicular stem cell markers (CK15, CK19), p63, p53, RB, and Merkel cell polyomavirus (MCPyV; CM2B4) in 136 primary cutaneous Merkel cell carcinomas.

Methods: Clinical, histopathologic, and immunohistochemical analyses were performed. The results were correlated with patient outcomes by Fisher exact test, log-rank tests, and Cox multivariate models.

Results: By Fisher exact test, although TdT significantly correlated with both lack of progression (P = .0087) and alive status (P = .0056), MCPyV status correlated only with alive status (P = .031). In univariate analyses, TdT, MCPyV, and RB significantly correlated with improved overall survival, whereas p63 and CK15 correlated with worse overall survival. However, in multivariate analyses, only TdT expression remained as an independent predictor of improved overall survival, Merkel cell carcinoma-specific survival, and progression-free survival. By linear regression analyses, significant correlations between MCPyV vs TdT, PAX5, and CD117 were observed.

Conclusions: TdT expression is a potential marker of better survival in Merkel cell carcinoma. Expression of B-cell markers is associated with MCPyV, suggesting that clonal viral integration might play a role in the expression of these markers.
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http://dx.doi.org/10.1093/ajcp/aqaa017DOI Listing
June 2020

Synthetic biohybrid peptidoglycan oligomers enable pan-bacteria-specific labeling and imaging: and .

Chem Sci 2020 Feb 26;11(12):3171-3179. Epub 2020 Feb 26.

School of Physical and Mathematical Sciences, Nanyang Technological University 21 Nanyang Link Singapore 637371 Singapore

Peptidoglycan is the core component of the bacterial cell wall, which makes it an attractive target for the development of bacterial targeting agents. Intercepting its enzymatic assembly with synthetic substrates allows for labeling and engineering of live bacterial cells. Over the past two decades, small-molecule-based labeling agents, such as antibiotics, d-amino acids or monosaccharides have been developed for probing biological processes in bacteria. Herein, peptidoglycan oligomers, substrates for transglycosylation, are prepared for the first time using a top-down approach, which starts from chitosan as a cheap feedstock. A high efficiency of labeling has been observed in all bacterial strains tested using micromolar substrates. In contrast, uptake into mammalian cells was barely observable. Additional mechanistic studies support a hypothesis of bacteria-specific metabolic labeling rather than non-specific binding to the bacterial surface. Eventually, its practicality in bacterial targeting capability is demonstrated in resistant strain detection and infection models.
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http://dx.doi.org/10.1039/c9sc06345eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157403PMC
February 2020

Prognostic implications of normal or minimal urinary findings on long-term renal impairment in adults with Henoch-Schönlein purpura.

J Am Acad Dermatol 2020 Jun 24;82(6):1393-1399. Epub 2019 Dec 24.

Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts.

Background: Renal involvement in adult Henoch-Schönlein purpura is a major cause of morbidity and can lead to significant long-term renal impairment. The prognostic significance of normal or minimal urinary abnormalities at diagnosis is unknown.

Objective: To assess the risk of long-term renal impairment in patients with Henoch-Schönlein purpura who present with normal or minimal urinary abnormalities.

Methods: Retrospective cohort study of adult Henoch-Schönlein purpura patients presenting with normal urinalysis results, microscopic hematuria, or low-grade proteinuria. Patients were followed for development of long-term renal impairment, with adjusting for comorbidities.

Results: Forty-seven patients were included, with median follow-up 73.9 months (interquartile range 35 to 98 months). Thirty-nine patients (83.0%) had abnormal urinalysis results, of whom 15 (38.5%) progressed to long-term renal impairment. In contrast, 8 patients (17%) had normal urinalysis results, of whom only 1 (12.5%) developed long-term renal impairment (adjusted hazard ratio 10.58; 95% confidence interval 1.18-94.73). Renal events occurred at a median 36.1 months (interquartile range 17.1 to 61 months) from diagnosis, earlier in patients with comorbidities compared with those with none, and in a constant event rate over time.

Limitations: Small sample size.

Conclusions: Microscopic hematuria and low-grade proteinuria at Henoch-Schönlein purpura diagnosis is a poor prognostic sign for the development of long-term renal impairment. This population should be targeted for prolonged surveillance.
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http://dx.doi.org/10.1016/j.jaad.2019.12.037DOI Listing
June 2020

Measuring Phagocytosis of Aspergillus fumigatus Conidia by Human Leukocytes using Flow Cytometry.

J Vis Exp 2019 12 7(154). Epub 2019 Dec 7.

Infections in Hematology and Oncology, Leibniz Institute for Infection Biology and Natural Product Research; Department for Hematology and Medical Oncology, Jena University Hospital.

Invasive pulmonary infection by the mold Aspergillus fumigatus poses a great threat to immunocompromised patients. Inhaled fungal conidia (spores) are cleared from the human lung alveoli by being phagocytosed by innate monocytes and/or neutrophils. This protocol offers a fast and reliable measurement of phagocytosis by flow cytometry using fluorescein isothiocyanate (FITC)-labeled conidia for co-incubation with human leukocytes and subsequent counterstaining with an anti-FITC antibody to allow discrimination of internalized and cell-adherent conidia. Major advantages of this protocol are its rapidness, the possibility to combine the assay with cytometric analysis of other cell markers of interest, the simultaneous analysis of monocytes and neutrophils from a single sample and its applicability to other cell wall-bearing fungi or bacteria. Determination of percentages of phagocytosing leukocytes provides a means to microbiologists for evaluating virulence of a pathogen or for comparing pathogen wildtypes and mutants as well as to immunologists for investigating human leukocyte capabilities to combat pathogens.
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http://dx.doi.org/10.3791/60397DOI Listing
December 2019

A 63-Year-Old Male with AIDS and Diffuse Violaceous Plaques.

Dermatopathology (Basel) 2019 Jul-Sep;6(3):195-200. Epub 2019 Sep 11.

Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Hyperkeratotic Kaposi's sarcoma (KS) is a rare clinicopathologic variant of AIDS-related KS that typically presents with chronic lymphedema and diffuse hyperkeratotic plaques of the lower extremities. Histopathologically, this variant is defined by epidermal hyperplasia, thickened lymphatic walls, and increased numbers of dermal fibroblasts and vascular spaces. Herein, we report the case of a 63-year-old HIV-positive male who presented with this rare hyperkeratotic variant of AIDS-related KS.
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http://dx.doi.org/10.1159/000502371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787420PMC
September 2019

Resolution of folliculitis decalvans with medical honey.

Dermatol Online J 2019 Aug 15;25(8). Epub 2019 Aug 15.

Department of Dermatology, Massachusetts General Hospital, Boston, MA.

Folliculitis decalvans is a rare scarring alopecia that presents with indurated, tender pustules and papules on the vertex and occipital scalp. Although systemic antibiotics with activity against Staphylococcus species provide some symptomatic improvement, folliculitis decalvans remains a significant management challenge and often exhibits a relapsing-and-remitting course. In this report, we posit the potential utility of medical grade honey as a safe and cost-effective adjuvant therapy in the treatment of folliculitis decalvans. We describe a patient with painful, boggy scalp pustules who achieved clearance of his scalp lesions with the addition of Manuka honey. To our knowledge, this report is the first to demonstrate the clinical use of honey in the management of folliculitis decalvans and may lend support to the role of Staphylococcus in the pathogenesis of this disease.
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August 2019

Skin biopsy in the diagnosis of intravascular lymphoma: A retrospective diagnostic accuracy study.

J Am Acad Dermatol 2021 Sep 18;85(3):665-670. Epub 2019 Sep 18.

Harvard Medical School, Boston, Massachusetts; Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background: The yield of skin biopsies in the evaluation of intravascular lymphoma (IVL) is largely unknown in Western patients. Most data supporting this test come from Asian populations, in which both prevalence and disease presentation seem to differ.

Objective: To determine the yield and diagnostic properties of skin biopsy in the evaluation of IVL.

Methods: We reviewed skin biopsy pathology reports of 50 patients being evaluated for IVL to calculate the diagnostic yield of this test. An additional 6 patients, who underwent skin biopsies after the diagnosis of IVL was made by other means, were included to calculate the sensitivity and specificity of our index test.

Results: Skin biopsy samples were positive for 5 of the 50 patients being investigated for IVL. Sensitivity was 50% and specificity was 100%.

Limitations: Only pathology reports containing IVL as an indication for the biopsy were retrieved. This might have excluded patients in whom the disease was considered but was not deemed likely enough to be listed as the indication for the test, inflating our estimative of skin biopsy yield.

Conclusion: A relatively high diagnostic yield was found in the evaluation of IVL among patients with a diverse presentation in a Western hospital.
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http://dx.doi.org/10.1016/j.jaad.2019.09.015DOI Listing
September 2021
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