Publications by authors named "Martin Mihm"

222 Publications

Epibulbar Proliferative Fasciitis, a Variant of Nodular Fasciitis: A Differential Diagnosis of Conditions With Focal or Diffuse Myxoid Stromas.

Ophthalmic Plast Reconstr Surg 2021 Jan 19. Epub 2021 Jan 19.

David G. Cogan Laboratory of Ophthalmic Pathology, Department of Ophthalmology, Massachusetts Eye and Ear/Harvard Medical School Department of Dermatopathology, Brigham and Women's Hospital, Boston, Massachusetts, U.S.A.

Purpose: To describe the clinical and pathologic features of a case of epibulbar proliferative fasciitis and to compare it with other focal or diffuse myxoid lesions.

Methods: A clinical, histopathologic, and immunohistochemical analysis was performed. The clinical history, photographic documentation, history, and referred slides were reanalyzed. Additional immunohistochemical stains were performed at our institution.

Results: A 68-year-old woman developed over a week a brightly vascularized and focally hemorrhagic placoid lesion on the temporal side of the OS. She had had earlier augmentation breast surgery that had been mistakenly initially reported to us to be for breast carcinoma. Hematoxylin- and eosin-stained reactions revealed microscopically a spindle cell lesion with an intact nonkeratinizing epithelium and a background myxoid stroma with prominent capillaries and a light dispersion of small T-cell lymphocytes. Most striking among the spindle cells were some widely separated large atypical cells. The atypical cells were cytokeratin positive, but an expansive panel of immunohistochemical stains for breast carcinoma was negative. The lesion was diagnosed as proliferative fasciitis and has not recurred after 1-year follow up.

Conclusion: A rapidly evolving conjunctival lesion is unlikely to be a primary or metastatic carcinoma. In the current case, the large ganglioform or rhabdomyoblast-like cells displayed diffuse cytokeratin positivity, still consistent with a mesenchymal or connective tissue cell lineage. Cytokeratin expression has been a finding previously reported in connective tissue tumors and in lymphoma cells. While the current lesion clinically resembles a conventional nodular fasciitis, the presence of the large atypical cells can lead to the misdiagnosis of a sarcoma, which typically displays a much higher Ki-67 proliferation index in comparison with nodular/proliferative fasciitis.
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http://dx.doi.org/10.1097/IOP.0000000000001872DOI Listing
January 2021

Molecular analysis of primary melanoma T cells identifies patients at risk for metastatic recurrence.

Nat Cancer 2020 Feb 20;1(2):197-209. Epub 2020 Jan 20.

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

Primary melanomas >1 mm thickness are potentially curable by resection, but can recur metastatically. We assessed the prognostic value of T cell fraction (TCFr) and repertoire T cell clonality, measured by high-throughput-sequencing of the T cell receptor beta chain (TRB) in T2-T4 primary melanomas (n=199). TCFr accurately predicted progression-free survival (PFS) and was independent of thickness, ulceration, mitotic rate, or age. TCFr was second only to tumor thickness in its predictive value, using a gradient boosted model. For accurate PFS prediction, adding TCFr to tumor thickness was superior to adding any other histopathological variable. Furthermore, a TCFr >20% was protective regardless of tumor ulceration status, mitotic rate or presence of nodal disease. TCFr is a quantitative molecular assessment that predicts metastatic recurrence in primary melanoma patients whose disease has been resected surgically. This study suggests that a successful T cell-mediated antitumor response can be present in primary melanomas.
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http://dx.doi.org/10.1038/s43018-019-0019-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725220PMC
February 2020

Purpuric plaques in a patient with breast cancer.

JAAD Case Rep 2020 Dec 20;6(12):1228-1230. Epub 2020 Sep 20.

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

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http://dx.doi.org/10.1016/j.jdcr.2020.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701037PMC
December 2020

Nodular primary cutaneous melanoma is associated with PD-L1 expression.

Eur J Dermatol 2020 Aug;30(4):352-357

Division of Clinical Immunology and Allergy, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 8 andar, 05403-900, São Paulo SP, Brazil.

Background: In previous studies, patients with Stage III melanomas expressing PD-L1 in more than 5% of their neoplastic cells had improved recurrence-free survival with anti-PD1 adjuvant therapy.

Objectives: We examined PD-L1 expression as a possible biomarker of primary cutaneous melanomas in the vertical growth phase.

Materials And Methods: This was a retrospective study including 66 patients with invasive primary cutaneous melanomas. We assessed patient clinical and histopathological data and performed immunohistochemical assays with melanoma specimens from the patients to evaluate PD-L1, PD-1, CD3, CD8 and FoxP3 expression.

Results: We observed PD-L1 expression in 21% (14/66) of our samples, and this expression correlated with increased melanoma thickness (p = 0.002) and nodular-type melanoma (p = 0.001). After adjusting for tumor thickness using a logistic regression test, the association of PD-L1 with nodular-type melanoma persisted. Nodular-type melanoma was 6.48 times more likely to be positive for PD-L1 than other histological types (p = 0.014; 95% CI: 1.46-28.82). As expected, PD-L1 expression correlated with the number of PD-1-expressing cells in the tumor-infiltrating lymphocyte population (p = 0.04). No correlation with PD-L1 was observed for age, sex, tumor site, skin phototype, ulceration status, sentinel lymph node status, metastasis development or survival. Regarding the immune profile of the tumor-infiltrating lymphocytes of PD-L1-positive and -negative groups, no significant differences were observed in the numbers of CD3 + , CD8 + FoxP3-, CD8-FoxP3+ and CD8 + FoxP3+ cells by immunohistochemistry.

Conclusion: Nodular-type melanoma is associated with PD-L1 expression and may be a suitable candidate for adjuvant therapy of primary melanomas treated with immunotherapy.
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http://dx.doi.org/10.1684/ejd.2020.3846DOI Listing
August 2020

Peripheral host T cells survive hematopoietic stem cell transplantation and promote graft-versus-host disease.

J Clin Invest 2020 09;130(9):4624-4636

Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT). Donor T cells are key mediators in pathogenesis, but a contribution from host T cells has not been explored, as conditioning regimens are believed to deplete host T cells. To evaluate a potential role for host T cells in GVHD, the origin of skin and blood T cells was assessed prospectively in patients after HSCT in the absence of GVHD. While blood contained primarily donor-derived T cells, most T cells in the skin were host derived. We next examined patient skin, colon, and blood during acute GVHD. Host T cells were present in all skin and colon acute GVHD specimens studied, yet were largely absent in blood. We observed acute skin GVHD in the presence of 100% host T cells. Analysis demonstrated that a subset of host T cells in peripheral tissues were proliferating (Ki67+) and producing the proinflammatory cytokines IFN-γ and IL-17 in situ. Comparatively, the majority of antigen-presenting cells (APCs) in tissue in acute GVHD were donor derived, and donor-derived APCs were observed directly adjacent to host T cells. A humanized mouse model demonstrated that host skin-resident T cells could be activated by donor monocytes to generate a GVHD-like dermatitis. Thus, host tissue-resident T cells may play a previously unappreciated pathogenic role in acute GVHD.
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http://dx.doi.org/10.1172/JCI129965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456221PMC
September 2020

The role of skin biopsy in diagnosis and management of calciphylaxis: a retrospective analysis.

J Am Acad Dermatol 2020 May 29. Epub 2020 May 29.

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

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http://dx.doi.org/10.1016/j.jaad.2020.05.101DOI Listing
May 2020

Topographical Evaluation of Penile Lichen Sclerosus Reveals a Lymphocytic Depleted Variant, Preferentially Associated With Neoplasia: A Report of 200 Cases.

Int J Surg Pathol 2020 Aug 22;28(5):468-476. Epub 2020 Jan 22.

Instituto de Patología e Investigación, Asunción, Paraguay.

Since the seminal study of Hart and Helwig in 1975, there are few detailed pathological studies of lichen sclerosus (LS). The aims of this study were to provide a detailed histopathological description of penile LS, as well as to explore its relationship with penile intraepithelial neoplasia (PeIN) or invasive carcinoma. We evaluated 200 patients and designed a topographical approach for the histological evaluation focusing in alterations of the following anatomical layers: squamous epithelium, lamina propria, dartos, and corpus spongiosum. We documented the quantity and topographical location of stromal lymphocytes. The prevalent lesions found were epithelial hyperplasia, atrophy, PeIN, basal cell vacuolization, lamina propria sclerosis, and variable patterns of lymphocytic infiltration. Various unique patterns of stromal sclerosis were described: perivascular, globular, linear, and solid fibrosis/hyalinization; any of them were found to be diagnostic for LS. The variation in the topography and density of lymphocytes was determinant for the identification of LS morphological variants: lichenoid, band-like, lymphocytic depleted, and mixed. A major finding was the identification of the variant designated as lymphocytic depleted LS, which we considered as the morphological prototype of LS associated with penile neoplasia. The detailed description of this complex lesion presented in this study may help pathologists in practice to identify and better define LS. The identification of the special variants suggests a role of the stromal lymphocytes in the process of carcinogenesis. Confirmation of the observations with more studies is necessary to determine the significance of these findings.
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http://dx.doi.org/10.1177/1066896920901333DOI Listing
August 2020

Photochemical Tissue Passivation Prevents Contracture of Full Thickness Wounds in Mice.

Lasers Surg Med 2019 12 6;51(10):910-919. Epub 2019 Jul 6.

Division of Plastic and Recontructive Surgery, Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts, 02114.

Background And Objectives: Wound contracture formation from excessive myofibroblast activity can result in debilitating morbidities. There are currently no treatments to prevent contracture. Photochemical tissue passivation (PTP), an established, safe, and user-friendly treatment modality, crosslinks collagen by a light-activated process, thus modulating the wound healing response and scarring. We hypothesised that PTP treatment would reinforce wounds by blunting the fibrotic response thus limiting contracture.

Study Design/materials And Methods: Full-thickness, 1 cm × 1 cm excisional wounds were created on the dorsum of 32 C57BL/6 mice. Treated wounds were painted with photosensitizing dye and exposed to visible light. Wounds were serially photographed over 6 weeks to measure wound contracture. At 7, 14, 21, and 42 days after wound creation, mice were euthanized and wounds were harvested for histologic review by a dermatopathologist.

Results: By Day 7, control wounds had significantly more contracture than those treated with PTP (33.0 ± 17.1% and 19.3 ± 9.0%, respectively; P = 0.011). PTP-treated wounds maintained approximately 20% less contracture than controls from Day 14 and on (P < 0.05). By Day 42, wounds had contracted by 86.9 ± 5.5% in controls and 64.2 ± 3.2% in PTP-treated wounds (P < 0.03). Histologically, PTP wounds had earlier growth and development of dermal collagen, neovascularization, and development of skin appendages, compared with control wounds.

Conclusions: PTP significantly limits contracture of full-thickness wounds and improves wound healing. PTP-treated wounds histologically demonstrate more mature structural organization than untreated wounds and closely resemble native skin. PTP treatment may be applicable not only for excisional wounds, but also for wounds with a high incidence of contracture and associated morbidity. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.23128DOI Listing
December 2019

The Pathogenesis of Port Wine Stain and Sturge Weber Syndrome: Complex Interactions between Genetic Alterations and Aberrant MAPK and PI3K Activation.

Int J Mol Sci 2019 May 7;20(9). Epub 2019 May 7.

Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA.

Port wine stain (PWS) is a congenital vascular malformation involving human skin. Approximately 15-20% of children a facial PWS involving the ophthalmic (V1) trigeminal dermatome are at risk for Sturge Weber syndrome (SWS), a neurocutaneous disorder with vascular malformations in the cerebral cortex on the same side of the facial PWS lesions. Recently, evidence has surfaced that advanced our understanding of the pathogenesis of PWS/SWS, including discoveries of somatic genetic mutations (, ), MAPK and PI3K aberrant activations, and molecular phenotypes of PWS endothelial cells. In this review, we summarize current knowledge on the etiology and pathology of PWS/SWS based on evidence that the activation of MAPK and/or PI3K contributes to the malformations, as well as potential futuristic treatment approaches targeting these aberrantly dysregulated signaling pathways. Current data support that: (1) PWS is a multifactorial malformation involving the entire physiological structure of human skin; (2) PWS should be pathoanatomically re-defined as "a malformation resulting from differentiation-impaired endothelial cells with a progressive dilatation of immature venule-like vasculatures"; (3) dysregulation of vascular MAPK and/or PI3K signaling during human embryonic development plays a part in the pathogenesis and progression of PWS/SWS; and (4) sporadic low frequency somatic mutations, such as , , work as team players but not as a lone wolf, contributing to the development of vascular phenotypes. We also address many crucial questions yet to be answered in the future research investigations.
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http://dx.doi.org/10.3390/ijms20092243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539103PMC
May 2019

Atypical Cellular Blue Nevus of the Foot: A Case Report.

Dermatopathology (Basel) 2019 Jan-Mar;6(1):20-22. Epub 2019 Mar 5.

Department of Dermatology, Geneva University Hospitals, Geneva, Switzerland.

Blue nevus is a congenital and acquired melanocytic proliferation that includes different histological types. The atypical cellular type has been rarely described and it classically has a benign course. However, because of its intermediate features between common blue nevus and malignant blue nevus, long-term clinical follow-up is required. Here we report the case of a 28-year-old woman who presented with an atypical cellular blue nevus on the right foot.
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http://dx.doi.org/10.1159/000496752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489059PMC
March 2019

Continuous Spatial Sequences of Lichen Sclerosus, Penile Intraepithelial Neoplasia, and Invasive Carcinomas: A Study of 109 Cases.

Int J Surg Pathol 2019 Aug 7;27(5):477-482. Epub 2019 Jan 7.

1 Instituto de Patología e Investigación, Asunción, Paraguay.

Lichen sclerosus (LSc) with penile cancer is found in about two thirds of specimens. It has been hypothesized that LSc represents a precancerous condition. To qualify as such, in addition to cytological atypia and similarity with the invasive tumor, a spatial correlation between LSc and neoplastic lesions needs to be demonstrated. The purpose of this study was to evaluate such a spatial relationship. Circumcision (28 cases) and penectomy (81 cases) specimens were evaluated. All cases had LSc, penile intraepithelial neoplasia (PeIN), and/or invasive squamous cell carcinomas. We examined LSc in relation to invasive carcinoma, PeIN, and normal epithelia. Invasive squamous cell carcinomas, classified according to the World Health Organization criteria as non-human papillomavirus (HPV)-related and HPV-related PeIN, were present in 100 cases. Non-HPV-related (differentiated) PeIN was the most common subtype associated with LSc (89%). There were 5 spatial patterns identified: (1) LSc adjacent to PeIN (23%), (2) LSc adjacent and comprising PeIN (42%), (3) LSc next to and within invasive carcinomas (8%), (4) LSc throughout the sequence PeIN-invasive carcinoma (24%), and (5) LSc was separate (with normal tissue between the lesions) from PeIN and/or invasive carcinomas in a minority of cases (3%). LSc within the cancer was not previously described. In this series, we found 35 cases with LSc within invasive carcinomas. The striking continuous spatial relationship among LSc, PeIN, and/or invasive carcinoma as shown in this study may be a necessary (but not sufficient) condition for the hypothesis postulating LSc as a penile precancerous lesion.
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http://dx.doi.org/10.1177/1066896918820960DOI Listing
August 2019

Membrane trafficking and exocytosis are upregulated in port wine stain blood vessels.

Histol Histopathol 2019 May 10;34(5):479-490. Epub 2018 Oct 10.

Department of Surgery, Beckman Laser Institute and Medical Clinic, University of California, Irvine, California, USA.

Introduction: Port wine stain (PWS) is characterized as a progressive dilatation of immature venule-like vasculatures which result from differentiation-impaired endothelial cells. In this study, we aimed to identify the major biological pathways accounting for the pathogenesis of PWS.

Methods: Sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) was used to identify differentially expressed proteins in PWS lesions, followed by confirmative studies with immunohistochemistry, immunoblot and transmission electron microscopy (TEM).

Results: 107 out of 299 identified proteins showed differential expressions in PWS lesions as compared to normal skin, mainly involving the functions of biosynthesis, membrane trafficking, cytoskeleton and cell adhesion/migration. The confirmative studies showed that expressions of membrane trafficking/exocytosis related proteins such as VAT1, IQGAP1, HSC70, clathrin, perlecan, spectrin α1 and GDIR1 were significantly increased in PWS blood vessels as compared to normal ones; while collagen subtypes 6A1 and 6A3 were decreased in PWS skin. Furthermore, TEM studies showed there is a significant upregulation of extracellular vesicle exocytosis from PWS blood vessels as compared to control.

Conclusions: The biological process of membrane trafficking and exocytosis is enhanced in PWS blood vessels. Our results imply that the extracellular vesicles released by lesional endothelial cells may act as potential intercellular signaling mediators to contribute to the pathogenesis of PWS.
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http://dx.doi.org/10.14670/HH-18-051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594380PMC
May 2019

A 53-Year-Old Male with Relapsed Diffuse Large B-Cell Lymphoma on Chemotherapy with a New Leg Lesion.

Dermatopathology (Basel) 2017 Jan-Dec;4(1-4):31-35. Epub 2017 Nov 16.

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

Patients with underlying malignancy who develop new skin findings while acutely ill often require skin biopsy for histologic evaluation and/or culture to reach a diagnosis. Here, we present the case of a 53-year-old male with relapsed diffuse large B-cell lymphoma on chemotherapy who developed new skin lesions on the leg. On exam, there were 2 nickel-sized, erythematous to violaceous round plaques with central necrotic cores on the right lower leg with relatively nonspecific clinical features for which the initial differential diagnosis was broad. Consensus on a diagnosis was reached upon histologic evaluation of his skin biopsy in the context of his clinical setting. This diagnosis led to a change in treatment plan, with subsequent clinical improvement.
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http://dx.doi.org/10.1159/000481307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803737PMC
November 2017

A 12-Month-Old Healthy Girl with a New Oral Ulcer and Chronic Diaper Rash.

Dermatopathology (Basel) 2017 Jan-Dec;4(1-4):24-30. Epub 2017 Nov 16.

Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA.

A 12-month-old healthy girl presented with a chronic diaper rash. Physical examination demonstrated crusting of the scalp, erythematous papules with surrounding petechiae on the lower abdomen, and an intraoral palatal ulcer. Further imaging demonstrated bone involvement. Histopathologic examination of involved skin and the intraoral ulcer demonstrated epithelioid histiocytes with "coffee bean-shaped" nuclei, staining positive for CD1a and langerin by immunohistochemistry, consistent with Langerhans cell histiocytosis (LCH). LCH is a disease entity of unknown etiology characterized by histiocytic proliferation that most commonly presents in young children. The cutaneous findings of LCH include a seborrheic dermatitis-like and/or red-brown papular eruption. Intraoral examination is crucial as oral mucosal and maxillofacial skeletal disease can also be seen in LCH. When a child presents with a recalcitrant seborrheic dermatitis-like eruption or chronic diaper rash, the clinician should be alerted to the possibility of LCH. Timely recognition and diagnosis of LCH is important for oncologic referral, evaluation, and treatment.
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http://dx.doi.org/10.1159/000481308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803736PMC
November 2017

A 71-Year-Old Female with Myocardial Infarction and Long-Standing Ulcers on the Thigh.

Dermatopathology (Basel) 2017 Jan-Dec;4(1-4):18-23. Epub 2017 Nov 16.

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

Calciphylaxis is most commonly encountered in patients with end-stage renal disease; however, it is increasingly observed in nonuremic patients as well. It is important to consider and diagnose nonuremic calciphylaxis early, as prompt treatment and mitigation of associated risk factors is essential to improve long-term outcomes for these patients. Here, we present the case of a 71-year-old woman with atrial fibrillation on warfarin, but without renal disease, who presented with two long-standing ulcers on her thigh and was diagnosed with the aid of biopsy with calciphylaxis. We review the existing literature on the subject and offer this case as a representative report of a clinicopathologic correlation for this disorder.
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http://dx.doi.org/10.1159/000481727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803738PMC
November 2017

Histological features and outcome of inverted type-A melanocytic nevi.

J Cutan Pathol 2018 Apr 13;45(4):254-262. Epub 2018 Feb 13.

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

The presence of enlarged epithelioid/spindled nests located deep in the reticular dermis of a biphasic melanocytic neoplasm can mimic melanoma arising in a pre-existing nevus, causing over-interpretation of malignancy. We aimed to define the clinicopathologic significance of epithelioid/spindled nests in melanocytic nevi. Retrospectively using clinical and histologic information, we characterized 121 patients with a single lesion showing epithelioid/spindled melanocytes in the reticular dermis or subcutaneous fat, surrounded by melanophages, sometimes blending in with the adnexa. The majority of nevi occurred in women in the ages of 10 to 39 years, where the most frequent presentation was a changing mole. While 78% of the lesions displayed an anatomic (Clark's) level of IV-V, there was no ulceration, significant regression or inflammation. Up to 2 mitoses were found in only 12% of the cases, not correlating with the severity of cytological atypia. No recurrence or metastasis occurred during 45.5 months (mean) of clinical follow up in 26 patients. Notwithstanding the deep dermal extension, these findings suggest a benign histopathology and clinical outcome. Having compared the overlapping histopathology and clinical features between deep penetrating/clonal nevus and combined nevus, we posit that "inverted type-A nevus" might be considered a variant of the two.
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http://dx.doi.org/10.1111/cup.13106DOI Listing
April 2018

Vaccination with autologous myeloblasts admixed with GM-K562 cells in patients with advanced MDS or AML after allogeneic HSCT.

Blood Adv 2017 Nov 14;1(24):2269-2279. Epub 2017 Nov 14.

Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA.

We report a clinical trial testing vaccination of autologous myeloblasts admixed with granulocyte-macrophage colony-stimulating factor secreting K562 cells after allogeneic hematopoietic stem cell transplantation (HSCT). Patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with ≥5% marrow blasts underwent myeloblast collection before HSCT. At approximately day +30, 6 vaccines composed of irradiated autologous myeloblasts mixed with GM-K562 were administered. Tacrolimus-based graft-versus-host disease (GVHD) prophylaxis was not tapered until vaccine completion (∼day 100). Thirty-three patients with AML (25) and MDS (8) enrolled, 16 (48%) had ≥5% marrow blasts at transplantation. The most common vaccine toxicity was injection site reactions. One patient developed severe eosinophilia and died of eosinophilic myocarditis. With a median follow-up of 67 months, cumulative incidence of grade 2-4 acute and chronic GVHD were 24% and 33%, respectively. Relapse and nonrelapse mortality were 48% and 9%, respectively. Progression-free survival (PFS) and overall survival (OS) at 5 years were 39% and 39%. Vaccinated patients who were transplanted with active disease (≥5% marrow blasts) had similar OS and PFS at 5 years compared with vaccinated patients transplanted with <5% marrow blasts (OS, 44% vs 35%, respectively, = .81; PFS, 44% vs 35%, respectively, = .34). Postvaccination antibody responses to angiopoietin-2 was associated with superior OS (hazard ratio [HR], 0.43; = .031) and PFS (HR, 0.5; = .036). Patients transplanted with active disease had more frequent angiopoeitin-2 antibody responses (62.5% vs 20%, = .029) than those transplanted in remission. GM-K562/leukemia cell vaccination induces biologic activity, even in patients transplanted with active MDS/AML. This study is registered at www.clinicaltrials.gov as #NCT 00809250.
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http://dx.doi.org/10.1182/bloodadvances.2017009084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737123PMC
November 2017

New insights into naevoid melanomas: a clinicopathological reassessment.

Histopathology 2017 Dec 2;71(6):943-950. Epub 2017 Oct 2.

Members of EORTC Melanoma Group Pathology Working Group, Florence, Italy.

Aims: Because the term 'naevoid melanoma' has variable clinical and pathological interpretations, we aimed to clarify the features of melanomas referred to as naevoid.

Methods And Results: A review was undertaken of 102 melanomas diagnosed histopathologically as naevoid melanomas and ascertained by European Organization for Research and Treatment of Cancer Melanoma Group Subcommittee pathologists from their records. We found these could be classified morphologically into three groups. Thirteen melanomas were overlying genuine naevi and were therefore excluded. Of the 89 melanomas considered to be naevoid, 11 presented clinically as exophytic papillomatous nodules with little junctional component and composed of small atypical cells showing numerous mitoses and no change with depth; we termed these 'papillomatous naevoid' melanomas. The other 78 were flat or only slightly raised, and had a superficial spreading melanoma-like component with maturation to a small cell, but still an atypical, dermal component; we termed these 'maturing naevoid' melanomas. We showed that papillomatous and maturing naevoid melanomas also have differing immunochemical profiles. Preliminary clinical follow-up suggested different outcomes for these two naevoid melanoma types.

Conclusions: Melanomas that have been classified as naevoid melanomas comprise two types with distinct clinical, histopathological and immunohistochemical features that may also be prognostically significant.
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http://dx.doi.org/10.1111/his.13317DOI Listing
December 2017

The correlation of the standard 5 probe FISH assay with melanocytic tumors of uncertain malignant potential.

Ann Diagn Pathol 2017 Jun 10;28:30-36. Epub 2016 Nov 10.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. Electronic address:

Background: FISH has recently emerged as a technique to better assess the malignant potential of histologically ambiguous melanocytic lesions. However, the usefulness of FISH has not been conclusively established. The purpose of this study was to further explore the diagnostic value of FISH in distinguishing the borderline melanocytic tumor (BMT) from melanoma.

Method: 73 cases with BMT were analyzed retrospectively from a dermatopathology database between 2010-2015. FISH studies were conducted in each case using probes targeting 5 loci including CCND1 on 11q13, RREB1 on 6p25, MYB on 6q23, CDKN2A on 9p21, and CEP 6 control probe for chromosome 6.

Results: The study was composed of 50 females and 23 males with an age range of 1-73 and a mean age of 35years. Of the 6 cases in the superficial atypical Spitz tumor (AST) category, 2 had indeterminate results due to polyploidy. In the conventional atypical Spitz tumor cases, FISH was positive in 3 of 15 cases. Of the 27 cases in the borderline nevoid tumor (BNM) category, 3 showed positive FISH and 3 were equivocal due to the possibility of polyploidy. 3 of 13 cases of the borderline tumor of deep penetrating nevus variant (B-DPN) were positive for FISH. Neither of the 2 pigmented epithelioid melanocytoma (PEM) cases had positive FISH result. Of the 4 cases in the superficial atypical dermoepidermal nevomelanocytic proliferation group, only 1 met the FISH diagnostic criteria for melanoma. None of the 6 borderline tumors with overlapping features met FISH criteria diagnostic of melanoma. Clinical follow up was available on 55 patients. None of the patients had recurrence nor died of the disease. Lymph node biopsy was performed on five patients without evidence of metastasis.

Conclusion: Despite the benefits of FISH, it is limited by the fact that melanomas are not genetically identical whereby certain genetic abnormalities are only seen in specific subtypes. Additionally, FISH only targets specific chromosomes resulting in limitations in sensitivity and specificity. Although FISH has proven to be highly sensitive and specific in distinguishing unequivocally benign from malignant lesions, in cases of histopathological ambiguity, these parameters cannot be assessed with great confidence because the histopathological diagnosis (gold standard) is not without uncertainty. The 4-probe set (excluding 9p21) consistently showed chromosomal aberrations throughout all groups, but only 10 of the 73 total cases (13%) met the diagnostic criteria for melanoma. Moreover, it would be wise to establish new cytogenetic reference values that incorporate these borderline lesions in an effort to better assess the possibility of malignant behavior and or define a cytogenetic profile supportive of its categorization as an indeterminate proliferation. Polyploidy is another inherent limitation, which leads to false positives due to the absolute signal counts incorrectly reflecting relative imbalances in the tumor genome.
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http://dx.doi.org/10.1016/j.anndiagpath.2016.11.001DOI Listing
June 2017

5-Hydroxymethylcytosine is a nuclear biomarker to assess biological potential in histologically ambiguous heavily pigmented melanocytic neoplasms.

J Cutan Pathol 2017 Mar 6;44(3):249-255. Epub 2017 Feb 6.

Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: 5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker detectable through immunohistochemistry (IHC) that has been shown to distinguish benign nevi from melanoma with high sensitivity and specificity. The purpose of the study was to explore its diagnostic utility in a subset of histologically challenging, heavily pigmented cutaneous melanocytic neoplasms.

Methods: 5-hmC IHC was performed on 54 heavily pigmented melanocytic tumors. Semi-quantitative analysis of immunoreactivity was correlated with clinical, pathologic and follow-up data.

Results: Benign melanocytic neoplasms (4 of 4 blue nevi with epithelioid change; 12 of 12 combined nevi; 5 of 5 deep penetrating nevi, DPN) exhibited strong 5-hmC nuclear reactivity. Eight heavily pigmented blue nevus-like melanomas and 7 of 8 pigmented epithelioid melanocytomas (PEM) showed significant 5-hmC loss. Five of 7 atypical DPN cases and 8 of 10 melanocytic tumors of uncertain malignant potential (MELTUMP) showed low to intermediate 5-hmC immunoreactivity. These differences were statistically significant (P-value <.0001).

Conclusions: Loss of 5-hmC may be helpful in differentiating benign, diagnostically challenging, heavily pigmented melanocytic tumors from those with malignant potential. The intermediate to low 5-hmC immunoreactivity in atypical DPNs, PEMs and so-called MELTUMP categories further underscores the need to consider these neoplasms as having some potential for lethal biological behavior.
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http://dx.doi.org/10.1111/cup.12880DOI Listing
March 2017

Skin regeneration with all accessory organs following ablation with irreversible electroporation.

J Tissue Eng Regen Med 2018 01 23;12(1):98-113. Epub 2017 May 23.

Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, and the Shriners Burns Hospital, Boston, MA, 02114, USA.

Skin scar formation is a complex process that results in the formation of dense extracellular matrix (ECM) without normal skin appendages such as hair and glands. The absence of a scarless healing model in adult mammals prevents the development of successful therapies. We show that irreversible electroporation of skin drives its regeneration with all accessory organs in normal adult rats. Pulsed electric fields at 500 V, with 70 μs pulse duration and 1000 pulses delivered at 3 Hz, applied through two electrodes separated by 2 mm lead to massive cell death. However, the ECM architecture of the skin was preserved. Six months after the ablation, the epidermis, sebaceous glands, panniculus carnosus, hair follicles, microvasculature and arrector pili muscle were altogether re-formed in the entire ablated area. These results suggest a key role of the ECM architecture in the differentiation, migration and signalling of cells during scarless wound healing. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/term.2374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555830PMC
January 2018

Lethal melanoma in children: a clinicopathological study of 12 cases.

Pathology 2016 Dec 27;48(7):705-711. Epub 2016 Oct 27.

Dermatology Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

Melanoma in children is rare, representing 3% of paediatric malignancies and <1% of all melanomas. Very few detailed descriptions of bona fide lethal childhood melanomas exist in the literature. We performed a retrospective clinicopathological review of 12 paediatric (≤16 years) melanoma patients who died of metastatic disease, including detailed assessment of architectural and cytomorphological features. There were nine prepubertal patients (median age 7 years old) and three postpubertal cases (median age 15 years old). The patients died on average 45.7 months after diagnosis with the prepubertal subcohort showing a relatively longer time from diagnosis to death. The tumours were bulky (average tumour thickness=10mm), showed brisk mitotic activity (average mitotic count per mm=7), and were formed by large expansile nodules with sheet-like growth pattern and infiltrative borders in the majority of cases (83%). Cytologically, large grossly pleomorphic epithelioid cells with massive eosinophilic macronucleoli were present in most cases (75%). In this cohort, we did not identify specific features of melanoma that were unique to children. Although melanomas are extremely rarely encountered in childhood, the above-cited unequivocal malignant features should prompt an outright diagnosis of melanoma even in a paediatric patient.
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http://dx.doi.org/10.1016/j.pathol.2016.08.008DOI Listing
December 2016

Preventing Scars after Injury with Partial Irreversible Electroporation.

J Invest Dermatol 2016 11 5;136(11):2297-2304. Epub 2016 Jul 5.

Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, and the Shriners Burns Hospital, Boston, Massachusetts, USA; Department of Biomedical Engineering, Rutgers University, Piscataway, NJ.

Preventing the formation of hypertrophic scars, especially those that are a result of major trauma or burns, would have enormous impact in the fields of regenerative and trauma medicine. In this report, we introduce a noninvasive method to prevent scarring based on nonthermal partial irreversible electroporation. Contact burn injuries in rats were treated with varying treatment parameters to optimize the treatment protocol. Scar surface area and structural properties of the scar were assessed with histology and non-invasive, longitudinal imaging with polarization-sensitive optical coherence tomography. We found that partial irreversible electroporation using 200 pulses of 250 V and 70 μs duration, delivered at 3 Hz every 20 days during a total of five therapy sessions after the initial burn injury, resulted in a 57.9% reduction of the scar area compared with untreated scars and structural features approaching those of normal skin. Unlike humans, rats do not develop hypertrophic scars. Therefore, the use of a rat animal model is the limiting factor of this work.
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http://dx.doi.org/10.1016/j.jid.2016.06.620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516938PMC
November 2016

Endocrine Mucin-Producing Sweat Gland Carcinoma: An Uncommon Presentation.

Semin Ophthalmol 2017 15;32(4):511-513. Epub 2016 Jul 15.

d Eye & Ear Institute , Pittsburgh , PA , USA.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare, often underrecognized, low-grade sweat gland carcinoma of the skin of the eyelid. To date, only 20 cases of this carcinoma have been reported, most frequently in Caucasian females with an average age of 70 years. Although the diagnosis is primarily made with immunohistochemical stain, compared to endocrine ductal carcinoma in situ, clinical detection serves as a potentially curative treatment. Further, its benign appearance clinically makes this tumor often misdiagnosed and undertreated. This disease commonly presents in Caucasian women of advanced age, aiding in the diagnosis of this tumor, which presents an even more critical diagnosis in a patient with a rare presentation. In the available literature, we could find no case of EMPSGC in younger African American women. The following case is the first case presented in the literature. Here, we present a case of an atypical presentation of the tumor in a young African American female, as well as a review of literature on the pathophysiology, clinical presentation, and treatment of EMPSGC.
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http://dx.doi.org/10.3109/08820538.2015.1115085DOI Listing
October 2017

Evaluation of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) classification scheme for diagnosis of cutaneous melanocytic neoplasms: Results from the International Melanoma Pathology Study Group.

J Am Acad Dermatol 2016 Aug 14;75(2):356-63. Epub 2016 May 14.

Department of Pathology, Institut Curie and Faculty of Medicine, University of Paris Descartes, Paris, France.

Background: Pathologists use diverse terminology when interpreting melanocytic neoplasms, potentially compromising quality of care.

Objective: We sought to evaluate the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) scheme, a 5-category classification system for melanocytic lesions.

Methods: Participants (n = 16) of the 2013 International Melanoma Pathology Study Group Workshop provided independent case-level diagnoses and treatment suggestions for 48 melanocytic lesions. Individual diagnoses (including, when necessary, least and most severe diagnoses) were mapped to corresponding MPATH-Dx classes. Interrater agreement and correlation between MPATH-Dx categorization and treatment suggestions were evaluated.

Results: Most participants were board-certified dermatopathologists (n = 15), age 50 years or older (n = 12), male (n = 9), based in the United States (n = 11), and primary academic faculty (n = 14). Overall, participants generated 634 case-level diagnoses with treatment suggestions. Mean weighted kappa coefficients for diagnostic agreement after MPATH-Dx mapping (assuming least and most severe diagnoses, when necessary) were 0.70 (95% confidence interval 0.68-0.71) and 0.72 (95% confidence interval 0.71-0.73), respectively, whereas correlation between MPATH-Dx categorization and treatment suggestions was 0.91.

Limitations: This was a small sample size of experienced pathologists in a testing situation.

Conclusion: Varying diagnostic nomenclature can be classified into a concise hierarchy using the MPATH-Dx scheme. Further research is needed to determine whether this classification system can facilitate diagnostic concordance in general pathology practice and improve patient care.
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http://dx.doi.org/10.1016/j.jaad.2016.04.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958559PMC
August 2016

Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy.

Pathology 2016 Feb 16;48(2):177-87. Epub 2016 Jan 16.

Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA. Electronic address:

The field of systemic cancer therapy for metastatic disease has entered an exciting era with the advent of novel immunomodulatory strategies targeting immune checkpoints. At the heart of these promising efforts are the tumour-infiltrating lymphocytes (TILs). As the reports demonstrating efficacy of modulating TIL effector function in patients with advanced stage cancer continue to accrue, it has become essential to better understand TIL immunobiology in order to further improve clinical outcome. In addition to providing an overview of the current immunotherapies available for metastatic melanoma, this review will briefly introduce the history and classification of TILs. Moreover, we will dissect the multifaceted roles of TILs in tumour-specific immunity and melanoma immune escape. The significance of TILs in melanoma prognosis and cancer immunotherapy will also be discussed, with a particular focus on their potential utility as biomarkers of patient response. The goal of personalised medicine appears to be in realistic sight, as new immunomodulatory techniques and technological innovations continue to advance the field of cancer immunotherapy. In light of recent studies highlighting the possible utility of TILs in determining therapeutic outcome, further characterisation of TIL phenotype and function has the potential to help translate individualised care into current medical practice.
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http://dx.doi.org/10.1016/j.pathol.2015.12.006DOI Listing
February 2016

Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy.

Pathology 2016 Feb 18;48(2):113-31. Epub 2016 Jan 18.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, United States.

Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas common acquired naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET. In Spitz naevi, which lack significant histological atypia, all of these mitogenic driver aberrations trigger rapid cell proliferation, but after an initial growth phase, various tumour suppressive mechanisms stably block further growth. In some tumours, additional genomic aberrations may abrogate various tumour suppressive mechanisms, such as cell-cycle arrest, telomere shortening, or DNA damage response. The melanocytes then start to grow in a less organised fashion and may spread to regional lymph nodes, and are termed atypical Spitz tumours. Upon acquisition of even more aberrations, which often activate additional oncogenic pathways or alter cell differentiation, the neoplastic cells become entirely malignant and may colonise and take over distant organs (spitzoid melanoma). The sequential acquisition of genomic aberrations suggests that Spitz tumours represent a continuous biological spectrum, rather than a dichotomy of benign versus malignant, and that tumours with ambiguous histological features (atypical Spitz tumours) might be best classified as low-grade melanocytic tumours. The number of genetic aberrations usually correlates with the degree of histological atypia and explains why existing ancillary genetic techniques, such as array comparative genomic hybridisation (CGH) or fluorescence in situ hybridisation (FISH), are usually capable of accurately classifying histologically benign and malignant Spitz tumours, but are not very helpful in the diagnosis of ambiguous melanocytic lesions. Nevertheless, we expect that progress in our understanding of tumour progression will refine the classification of spitzoid melanocytic tumours in the near future. By integrating clinical, pathological, and genetic criteria, distinct tumour subsets will be defined within the heterogeneous group of Spitz tumours, which will eventually lead to improvements in diagnosis, prognosis and therapy.
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http://dx.doi.org/10.1016/j.pathol.2015.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817351PMC
February 2016

Advances in melanoma: revolutionary progress delivering improved patient management and outcomes.

Pathology 2016 Feb 14;48(2):105-7. Epub 2016 Jan 14.

Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

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http://dx.doi.org/10.1016/j.pathol.2015.12.011DOI Listing
February 2016

Decreased tumor-infiltrating lymphocytes in nodular melanomas compared with matched superficial spreading melanomas.

Melanoma Res 2016 10;26(5):524-7

aHarvard Medical School bMihm Cutaneous Pathology Consultative Service cProgram in Dermatopathology, Department of Pathology dDepartment of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts eDepartment of Biostatistics, Tulane University, New Orleans, Louisiana, USA.

Melanoma causes over 9000 deaths annually in the USA. Among its subtypes, nodular melanoma leads to a disproportionate number of fatalities compared with superficial spreading melanoma, the most common subtype. Recent breakthroughs in melanoma research have indicated a strong connection between melanoma virulence and the immune system. We hypothesize that the aggression of nodular melanoma may, in part, be because of decreased recognition by the immune system, as represented by a decreased presence of tumor-infiltrating lymphocytes (TILs), compared with its superficial spreading counterpart. Indeed, TILs on a primary melanoma have been used as a marker for immune response and have prognostic value for survival and sentinel lymph node status. After matching melanoma cases by age, sex, and Breslow thickness, we found significantly fewer TILs in nodular melanomas than in superficial spreading melanomas. This association was prominent in thin (≤2 mm) melanomas and was no longer significant in thick (>2 mm) melanomas. In addition, this difference in TILs was only present in men and not in women. Our finding suggests that nodular melanomas are more frequently associated with absent TILs, providing an avenue for further investigation into differences in immunogenicity of the primary melanoma and whether they underlie the unique virulence of nodular melanoma.
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http://dx.doi.org/10.1097/CMR.0000000000000253DOI Listing
October 2016

Vaccination with Irradiated Autologous Tumor Cells Mixed with Irradiated GM-K562 Cells Stimulates Antitumor Immunity and T Lymphocyte Activation in Patients with Recurrent Malignant Glioma.

Clin Cancer Res 2016 06 12;22(12):2885-96. Epub 2016 Feb 12.

Harvard Medical School, Boston, Massachusetts. Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts. Cancer Vaccine Center, Dana Farber Cancer Institute, Boston, Massachusetts.

Purpose: Recurrent malignant glioma carries a dismal prognosis, and novel therapies are needed. We examined the feasibility and safety of vaccination with irradiated autologous glioma cells mixed with irradiated GM-K562 cells in patients undergoing craniotomy for recurrent malignant glioma.

Experimental Design: We initiated a phase I study examining the safety of 2 doses of GM-K562 cells mixed with autologous cells. Primary endpoints were feasibility and safety. Feasibility was defined as the ability for 60% of enrolled subjects to initiate vaccination. Dose-limiting toxicity was assessed via a 3+3 dose-escalation format, examining irradiated tumor cells mixed with 5 × 10(6) GM-K562 cells or 1 × 10(7) GM-K562 cells. Eligibility required a priori indication for resection of a recurrent high-grade glioma. We measured biological activity by measuring delayed type hypersensitivity (DTH) responses, humoral immunity against tumor-associated antigens, and T-lymphocyte activation.

Results: Eleven patients were enrolled. Sufficient numbers of autologous tumor cells were harvested in 10 patients, all of whom went on to receive vaccine. There were no dose-limiting toxicities. Vaccination strengthened DTH responses to irradiated autologous tumor cells in most patients, and vigorous humoral responses to tumor-associated angiogenic cytokines were seen as well. T-lymphocyte activation was seen with significantly increased expression of CTLA-4, PD-1, 4-1BB, and OX40 by CD4(+) cells and PD-1 and 4-1BB by CD8(+) cells. Activation was coupled with vaccine-associated increase in the frequency of regulatory CD4(+) T lymphocytes.

Conclusions: Vaccination with irradiated autologous tumor cells mixed with GM-K562 cells is feasible, well tolerated, and active in patients with recurrent malignant glioma. Clin Cancer Res; 22(12); 2885-96. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911283PMC
June 2016