Exploring the relation between TGF-β pathway activity and response to checkpoint inhibition in patients with metastatic melanoma.

Introduction: Immune checkpoint inhibition (ICI) is highly effective for the treatment of melanoma, but intrinsic resistance is present in a subgroup of patients. TGF-β pathway activity may play a role in this resistance by preventing T-cells from entering the tumor microenvironment, causing immune escape. We investigated the association of TGF-β signal transduction pathway activity with resistance to ICI treatment in advanced melanoma.

Weakly Supervised Classification of Mohs Surgical Sections Using Artificial Intelligence.

Basal cell carcinoma (BCC) is the most frequently diagnosed form of skin cancer, and its incidence continues to rise, particularly among older individuals. This trend puts a significant strain on health care systems, especially in terms of histopathologic diagnostics required for Mohs micrographic surgery (MMS), which is used to treat BCC in sensitive locations to minimize tissue loss. This study aims to address the challenges in BCC detection within MMS whole-slide images by developing and evaluating a deep learning model that bridges weakly supervised learning with interpretable segmentation-based methods through attention maps.

Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome.

Mutations in proteasome β-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome β2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash.

Detection and subtyping of basal cell carcinoma in whole-slide histopathology using weakly-supervised learning.

The frequency of basal cell carcinoma (BCC) cases is putting an increasing strain on dermatopathologists. BCC is the most common type of skin cancer, and its incidence is increasing rapidly worldwide. AI can play a significant role in reducing the time and effort required for BCC diagnostics and thus improve the overall efficiency of the process.

Read the clonotype: Next-generation sequencing-based lymphocyte clonality analysis and perspectives for application in pathology.

Clonality assessment using the unique rearrangements of immunoglobulin (IG) and T-cell receptor (TR) genes in lymphocytes is a widely applied supplementary test for the diagnosis of B-cell and T-cell lymphoma. To enable a more sensitive detection and a more precise comparison of clones compared with conventional clonality analysis based on fragment analysis, the EuroClonality NGS Working Group developed and validated a next-generation sequencing (NGS)-based clonality assay for detection of the IG heavy and kappa light chain and TR gene rearrangements for formalin-fixed and paraffin-embedded tissues. We outline the features and advantages of NGS-based clonality detection and discuss potential applications for NGS-based clonality testing in pathology, including site specific lymphoproliferations, immunodeficiency and autoimmune disease and primary and relapsed lymphomas.

Paired primary and metastatic lesions of patients with ipilimumab-treated melanoma: high variation in lymphocyte infiltration and HLA-ABC expression whereas tumor mutational load is similar and correlates with clinical outcome.

Background: Immune checkpoint inhibitors (ICI) can lead to long-term responses in patients with metastatic melanoma. Still many patients with melanoma are intrinsically resistant or acquire secondary resistance. Previous studies have used primary or metastatic tumor tissue for biomarker assessment.

Atypical fibroxanthoma and pleomorphic dermal sarcoma: Is superficial infiltration in subcutaneous tissue acceptable in AFX?

Background: Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are rare cutaneous neoplasms forming a spectrum. Case reports with recurrences and metastasis have been published despite the current view that AFX is benign. The aim of this study was to identify clinical and histopathological features that predict tumor recurrence.

Predictors of surgical treatment burden, outcomes, and overall survival in older adults with basal cell carcinoma: Results from the prospective, multicenter BATOA cohort.

Background: Incorporating patient-related factors associated with treatment outcomes could improve personalized care in older patients with basal cell carcinoma (BCC).

Objective: To evaluate and identify predictors of treatment burden, treatment outcomes, and overall survival in patients aged ≥70 years, surgically treated for BCC in the head and neck area.

Methods: The data from the prospective, multicenter Basal Cell Carcinoma Treatment in Older Adults (BATOA) cohort study were extracted to evaluate the experienced treatment burden (visual analog scale, 0-10 cm; lower scores indicating higher treatment burden), treatment outcomes, and mortality.

Merkel Cell Carcinoma: New Trends.

Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin mainly seen in the elderly. Its incidence is rising due to ageing of the population, increased sun exposure, and the use of immunosuppressive medication. Additionally, with the availability of specific immunohistochemical markers, MCC is easier to recognize.

Identification of a coordinated CD8 and CD4 T cell response directed against mismatched HLA Class I causing severe acute graft-versus-host disease.

After HLA class I-mismatched stem cell transplantation, allo-HLA-directed CD8 T cell responses can be activated without the help of CD4 T cells if memory CD8 T cells cross-reactive against the allo-HLA class I are present or if naïve CD8 T cells are administered during inflammatory conditions. However, in the absence of inflammatory conditions, cooperation between CD4 and CD8 T cells likely is required for an effective primary CD8 T cell response directed against allo-HLA class I. In this study we investigated whether a coordinated response of CD8 and CD4 T cells could be demonstrated in an HLA class I-directed immune response in a patient who developed severe graft-versus-host disease (GVHD) after the administration HLA-A2-mismatched donor lymphocyte infusion in the absence of inflammatory conditions.

Allo-HLA-reactive T cells inducing graft-versus-host disease are single peptide specific.

T-cell alloreactivity directed against non-self-HLA molecules has been assumed to be less peptide specific than conventional T-cell reactivity. A large variation in degree of peptide specificity has previously been reported, including single peptide specificity, polyspecificity, and peptide degeneracy. Peptide polyspecificity was illustrated using synthetic peptide-loaded target cells, but in the absence of confirmation against endogenously processed peptides this may represent low-avidity T-cell reactivity.

PRAME-specific Allo-HLA-restricted T cells with potent antitumor reactivity useful for therapeutic T-cell receptor gene transfer.

Purpose: In human leukocyte antigen (HLA)-matched stem cell transplantation (SCT), it has been shown that beneficial immune response mediating graft-versus-tumor (GVT) responses can be separated from graft-versus-host disease (GVHD) immune responses. In this study, we investigated whether it would be possible to dissect the beneficial immune response of allo-HLA-reactive T cells with potent antitumor reactivity from GVHD-inducing T cells present in the detrimental immune response after HLA-mismatched SCT.

Experimental Design: The presence of specific tumor-reactive T cells in the allo-HLA repertoire was analyzed at the time of severe GVHD after HLA-mismatched SCT, using tetramers composed of different tumor-associated antigens (TAA).

Mixed T cell receptor dimers harbor potentially harmful neoreactivity.

Adoptive transfer of T cell receptor (TCR)-transduced T cells may be an attractive strategy to target both hematological malignancies and solid tumors. By introducing a TCR, large numbers of T cells with defined antigen (Ag) specificity can be obtained. However, by introduction of a TCR, mixed TCR dimers can be formed.

Allo-HLA reactivity of virus-specific memory T cells is common.

Graft-versus-host disease and graft rejection are major complications of allogeneic HLA-mismatched stem cell transplantation or organ transplantation that are caused by alloreactive T cells. Because a range of acute viral infections have been linked to initiating these complications, we hypothesized that the cross-reactive potential of virus-specific memory T cells to allogeneic (allo) HLA molecules may be able to mediate these complications. To analyze the allo-HLA reactivity, T cells specific for Epstein-Barr virus, cytomegalovirus, varicella zoster virus, and influenza virus were tested against a panel of HLA-typed target cells, and target cells transduced with single HLA molecules.

A direct beta-catenin-independent interaction between androgen receptor and T cell factor 4.

T cell factor (Tcf) proteins bind beta-catenin and are downstream effectors of Wnt/beta-catenin signals. A recently demonstrated interaction between beta-catenin and the androgen receptor (AR) ligand binding domain has suggested that AR may be a Tcf-independent Wnt/beta-catenin effector. This study demonstrates that there is a direct interaction between the AR DNA binding domain (DBD) and Tcf4.