TTK inhibitor OSU13 promotes immunotherapy responses by activating tumor STING.

TTK (MPS1) spindle assembly checkpoint kinase is an emerging cancer target. This preclinical study explored the anti-tumor mechanism of TTK inhibitor OSU13 to define a strategy for clinical development. We observed prominent anti-tumor activity of OSU13 in melanoma, colon, and breast cancer cells, melanoma patient-derived organoids, and mice bearing colon tumors associated with G2 cell cycle arrest, senescence, and apoptosis. OSU13-treated cells displayed DNA damage and micronuclei that triggered the cytosolic DNA-sensing cGAS-STING pathway. STING was required for the induction of several proteins involved in T cell recruitment and activity. Tumors from OSU13-treated mice showed an increased proportion of T and NK cells and evidence of PD-1/PD-L1 immune checkpoint activation. Combining a low-toxicity dose of OSU13 with anti-PD1 checkpoint blockade resulted in prominent STING- and CD8 T cell-dependent tumor inhibition and improved survival. These findings provide a rationale for utilizing TTK inhibitors in combination with immunotherapy in STING-proficient tumors.

Impact of Cutaneous Squamous Cell Carcinoma Histologic Features on Percent Interrater Agreement Regarding Tumor Differentiation.

BACKGROUND: Poor differentiation predicts adverse outcomes in cutaneous squamous cell carcinoma (CSCC), but there is no standardized, reliable grading system. OBJECTIVE: To explore which histologic features have the greatest impact on CSCC differentiation interrater agreement. MATERIALS AND METHODS: In a prior study, 40 raters graded differentiation for 45 squamous cell carcinomas, and percent interrater agreements were calculated. Cases graded as well/moderately differentiated with 100% agreement (10), those graded as poorly differentiated with ≥80% agreement (5), and those that received a variety of grades with ≤60% agreement (7) were pulled for the current study. Three raters graded individual histologic features for each case, and percent interrater agreements were calculated using both the well/moderately/poorly differentiated grading system and a dichotomized system. RESULTS: The percent interrater agreements were 34.8% for mitoses, 53% for pleomorphism, 59.1% for keratinization, 66.7% for cellular cohesion/intercellular bridges, and 78.8% for tumor edges. Percent agreements improved with dichotomous grading; the largest improvement was seen within the group of cases that had been graded as well/moderately differentiated with 100% agreement in the prior study. CONCLUSION: Future squamous cell carcinoma differentiation grading systems would benefit from eliminating mitotic rate, clearly defining how to grade other features, and dichotomous grading.

Myeloid neoplasm with histiocytosis and spleen tyrosine kinase fusion responds to fostamatinib.

Not available.

Advancements in the treatment of mycosis fungoides and Sézary syndrome: monoclonal antibodies, immunotherapies, and Janus kinase inhibitors.

Mycosis fungoides (MF) and Sézary syndrome (SS) are forms of cutaneous T cell lymphoma (CTCL) that pose significant challenges in their clinical management, particularly in refractory and advanced-stage disease. With the emergence of novel therapeutic modalities however, there are increasing opportunities to exploit the current understanding of pathophysiologic mechanisms of MF/SS for treatment. This review summarizes recent advances in the treatment of MF/SS, with a focus on monoclonal antibodies, immunotherapies, and Janus kinase (JAK) inhibitors, including ongoing clinical trials.

Low-Grade Hidradenocarcinoma of the Foot With Metastasis to a Lymph Node.

ABSTRACT: Hidradenocarcinoma (HAC) is a rare adnexal tumor associated with the potential for locoregional recurrence and systemic metastasis. The clinical appearance of HAC is nonspecific, frequently presenting as a solitary firm subcutaneous nodule or plaque on the head and neck region or distal extremities. These tumors show histomorphologic heterogeneity, as they can be low and high grade. Distinguishing HAC from hidradenoma, especially the low-grade variant of HAC, can be challenging as both tumors can show histologic overlapping features. In this article, we describe a case of a 33-year-old patient presenting with a low-grade HAC of the plantar foot who was subsequently found to have lymph node metastasis.

Randomized Mechlorethamine/Chlormethine Induced Dermatitis Assessment Study (MIDAS) Establishes Benefit of Topical Triamcinolone 0.1% Ointment Cotreatment in Mycosis Fungoides.

INTRODUCTION: Treatment of early-stage mycosis fungoides (MF) requires safe, skin-directed therapies. Medication side effects can lead to underutilization of effective therapies. The objective of this study was to assess the use of topical triamcinolone 0.1% ointment as a means of reducing contact dermatitis associated with topical mechlorethamine/chlormethine gel for the treatment of MF. METHODS: This prospective, randomized, open-label study evaluated 28 adults with mycosis fungoides who were eligible for treatment with topical mechlorethamine/chlormethine gel from December 17, 2017 to December 23, 2020. Patients were treated for 4 months with clinical follow-up through 12 months. Patients had half of their lesions also treated with topical triamcinolone 0.1% ointment (while the other half were treated with mechlorethamine/chlormethine alone). The study was self-controlled with separate lesions in the same patient receiving each treatment arm. Treatment arms were determined by the flip of a coin. RESULTS: Twenty-eight patients enrolled (17 men (61%) and 11 women (39%)). Demographics included 25 White, 2 African Americans, and 1 Asian patient. Twenty-five completed the 12-month follow-up. Triamcinolone 0.1% ointment led to increased tolerability of mechlorethamine/chlormethine gel but did not change the efficacy of mechlorethamine/chlormethine. There was a statistically significant 50% decrease in dermatitis (SCORD score) at month 2 in the triamcinolone-treated arm. CONCLUSIONS: Topical triamcinolone ointment is a helpful adjuvant therapy when treating patients with topical mechlorethamine/chlormethine gel. It diminishes inflammation and does not reduce efficacy. The peak incidence of dermatitis in the study occurred in the second and third months. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03380026.

Talimogene laherparepvec pseudolymphomatous reaction mimicking metastatic melanoma.

Talimogene laherparepvec (TVEC) is a genetically modified herpes simplex virus-1 approved as an intralesional oncolytic immunotherapy for the treatment of advanced melanoma. Cutaneous reactions at the site of injection may mimic recurrent or progressive melanoma; histopathological findings have included chronic granulomatous dermatitis, neutrophilic dermatitis, lymphocytic dermatitis, and pigment incontinence. We report a 39-year-old male with metastatic stage IIIc melanoma treated with TVEC with clinical regression of melanoma lesions that later developed pink nodules at sites of prior injection. Histopathology demonstrated a nodular mononuclear infiltrate that stained strongly and diffusely with CD45 and CD20 with a surrounding rim of CD3-positive T-cells. Immunoglobulin gene rearrangement was negative for a clonal B-cell population. To our knowledge, this is the first report of a pseudolymphomatous reaction mimicking recurrent melanoma after TVEC therapy.

Nonpancreatic Pancreatic Panniculitis: An Incidental Finding in Individuals without Pancreatic Disease? A Case Series and Review of the Literature.

Pancreatic panniculitis occurs in up to three percent of all patients with pancreatic disease. This cutaneous eruption, as implied by the name, is almost exclusively encountered in the context of pancreatic disorders, such as pancreatitis or pancreatic carcinoma. We report three cases in which histopathologic examination demonstrated hallmarks of pancreatic panniculitis occurring in patients without any history or evidence of pancreatic disorder. These nonpancreatic pancreatic panniculitis eruptions might be underreported in the literature.

Anogenital syringocystadenocarcinoma papilliferum in situ or anaplastic extramammary Paget disease? A unifying concept and review of the literature.

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy that typically involves the genital skin and can be primary or associated with an underlying internal malignancy. The typical histopathological appearance of EMPD consists of single or small aggregates of cells with abundant pale cytoplasm and large pleomorphic nuclei, known as Paget cells, scattered throughout the epidermis. We report a case of anogenital EMPD occurring in a 53-year-old man with unusual histopathologic findings of marked epidermal acanthosis, acantholysis, intraepidermal glandular differentiation, and prominent plasma cell-rich fibrovascular cores. These features were entirely confined to the epidermis and adnexa with no evidence of dermal invasion or underlying systemic disease. We review and summarize the literature for atypical features noted in EMPD and summarize similar findings previously described under a variety of descriptions including anaplastic EMPD, anogenital syringocystadenocarcinoma papilliferum in situ (SCACPIS), SCACPIS-like changes in EMPD, and EMPD mimicking acantholytic squamous cell carcinoma in situ. We propose that these features represent a single entity and be considered under a unifying diagnosis to facilitate recognition of this entity.

GATA-3 expression in a de-differentiated chondrosarcoma with cutaneous iatrogenic implantation: a diagnostic pitfall with important clinical implications.

De-differentiated chondrosarcoma (DDCS) is an extremely aggressive tumor of the bone characterized by a high-grade, non-chondroid sarcoma adjacent to a low- or intermediate-grade chondrosarcoma. Adequate tumor sampling demonstrating the biphasic features is necessary to make an accurate diagnosis. The diagnosis may be challenging as histopathology may mimic other neoplasms. We present a case of a 76-year-old woman with a history of breast cancer who presented with a pathologic non-displaced fracture. A bone biopsy demonstrated a high-grade neoplasm composed of pleomorphic spindled and epithelioid cells with focal expression of AE1/3 and GATA3, most likely consistent with metastatic breast carcinoma. After a difficult clinical course, the tumor was resected demonstrating a similar morphology to her prior biopsy, as well as an area of a low-grade cartilaginous neoplasm consistent with chondrosarcoma. The biphasic tumor alongside a low-grade chondrosarcoma allowed for a diagnosis of DDCS. Several days after her procedure, the patient developed violaceous nodules overlying and surrounding the surgical site. Skin biopsy demonstrated a malignant epithelioid neoplasm with identical histomorphologic features identical to her prior bone resection. Given the location of the skin lesions directly within the surgical site right after resection, the clinical-pathological picture was that of sarcomatosis cutis by iatrogenic cutaneous implantation.