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Primary intraosseous xanthomas of the jaws (PIXJ) are rare and predominantly affect the posterior mandible (86%) of normolipemic patients, with a mean age of 30 years and no gender predilection. Clinically, PIXJ exhibit indolent biologic behavior; curettage is considered treatment of choice. Only 36 PIXJ have been reported. Apoptosis-related hyaline globules (HGs), also known as "thanatosomes", have not been previously reported in PIXJ. Cases diagnosed as xanthoma of bone were retrieved. Six cases fulfilling currently accepted criteria were identified and their clinicopathologic and immunohistochemical properties are presented herein. Mean age for PIXJ was 21.8 years (range = 12-33) and F:M ratio = 2:1. All cases presented as well-demarcated, unilocular or multilocular radiolucencies. Microscopically, PIXJ featured sheets of lipid-laden macrophages with eosinophilic or foamy cytoplasm. A secondary fibroblastic population lacking storiform pattern was evident in two cases. Adipocytes (3/6), peripheral neurovascular bundles (1/6), bone fragments (3/6) and dystrophic calcifications (3/6) were observed enclosed by the xanthoma cells. Notably, one case exhibited numerous, spherical, eosinophilic HGs containing apoptotic nuclei. PIXJ were consistently CD68(+) and negative for CD1α and S100. CD45 decorated lymphocytes and the membrane of foamy histiocytes. Xanthoma cells stained for lysozyme and plasma proteins including alpha-1 antitrypsin (AAT), IgG and IgA in one probed case. HGs were lysozyme(+), AAT(+), IgG(+), IgA(+), PAS(+) and diastase-resistant, and fuchsinophilic with Masson's trichrome. PIXJ represent infrequent, solitary, mandibular lesions with a predilection for the second and third decade of life. Thanatosomes associated with cell injury and death can be present in PIXJ.

Aims Primary head/neck mucosal melanomas (MMs) are rare and exhibit aggressive biologic behaviour and elevated mutational loads. The molecular mechanisms responsible for high genomic instability observed in head/neck MMs remain elusive. The DNA cytosine deaminase APOBEC3B (A3B) constitutes a major endogenous source of mutation in human cancer. A3B‐related mutations are identified through C‐to‐T/−G base substitutions in 5′‐TCA/T motifs. Herein, we present immunohistochemical and genomic data supportive of a role for A3B in head/neck MMs. Methods and results A3B protein levels were assessed in oral ( n = 13) and sinonasal ( n = 13) melanomas, and oral melanocytic nevi ( n = 13) by immunohistochemistry using a custom rabbit α‐A3B mAb (5210‐87‐13). Heterogeneous, selective‐to‐diffuse, nuclear only, A3B immunopositivity was observed in 12 of 13 (92.3%) oral melanomas (H‐score range = 9–72, median = 40) and 8 of 13 (62%) sinonasal melanomas (H‐score range = 1–110, median = 24). Two cases negative for A3B showed prominent cytoplasmic staining consistent with A3G. A3B protein levels were significantly higher in oral and sinonasal MMs than intraoral melanocytic nevi ( P < 0.0001 and P = 0.0022, respectively), which were A3B‐negative (H‐score range = 1–8, median = 4). A3B levels, however, did not differ significantly between oral and sinonasal tumours ( P > 0.99). NGS performed in 10 sinonasal MMs revealed missense NRAS mutations in 50% of the studied cases and one each KIT and HRAS mutations. Publicly available whole‐genome sequencing (WGS) data disclosed that the number of C‐to‐T mutations and APOBEC3 enrichment score were markedly elevated in head/neck MMs ( n = 2). Conclusion The above data strongly indicate a possible role for the mutagenic enzyme A3B in head/neck melanomagenesis, but not benign melanocytic neoplasms.

Human Papilloma Virus (HPV) infection is associated with the development of Cervical cancer. Therapeutic resistance and recurrence remain the major obstacle to successful treatment of cervical cancer patients. Recently, a novel pro-drug Minnelide, derived from the diterpenoid triepoxide, triptolide, was found to be very effective against several human cancers in experimental animal models. The goal of the present study is to determine the effect of triptolide (in vitro) or Minnelide (in vivo) on HPV positive cervical cancer cells. Triptolide inhibited the proliferation of human cervical cancer cell lines, Ca Ski, SiHa, Me-180, and C-33a with an IC50 of 50 - 100 nM. Furthermore, triptolide inhibited the expression of viral oncoproteins E6 and E7 transcripts significantly. Consequently, p53, tumor suppressor protein levels were increased in the treated cells which led to increased apoptosis and reduced proliferation. Subsequently, we determined the effect of Minnelide on cervical cancer growth in athymic, nude mice. Tumor (SiHa and CaSki) bearing mice were treated with either 0.2 or 0.4 ug/kg doses of Minnelide. These studies showed that Minnelide inhibited tumor growth by about 70 % when compared to control group of mice and improved survival significantly. In a parallel study, combination treatment with carboplatin and Minnelide showed more than additive inhibition of tumor growth. In summary, Minnelide treatment reduced the transcript levels of HPV oncoproteins and inhibited cellular proliferation by upregulating p53. Our studies further demonstrate that Minnelide can be used either as a monotherapy or in combination with platinum drugs to inhibit the growth of cervical cancers. Citation Format: Vivek Ramakrishnan, Bhuwan Giri, Urvashi Hooda, Peter Wilkinson, Christopher deHaydu, Janneth Oleas, Sabita Roy, Sundaram Ramakrishnan, Ashok Saluja. Effect of Minnelide, a prodrug, on cervical cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5879.

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