Xanthomatized Neutrophilic Dermatosis in a Patient With Myelodysplastic Syndrome.

We present an original case report of a 58-year-old man with a history of histiocytoid Sweet and myelodysplastic syndrome who presented with a new onset of tender plaques on his oral commissures. A biopsy revealed a dense dermal neutrophilic infiltrate, leukocytoclasis without frank vasculitis, and, most notably, the presence of many xanthomatized cells. Clinical presentation and histologic features were most consistent with an acute neutrophilic dermatosis, which we believe to be a xanthomized variant of Sweet syndrome. Recent cases have described patients with similar clinical features and neutrophilic dermatosis in the setting of a normolipemic xanthomatosis. These cases were ultimately diagnosed as neutrophilic xanthoma, suggesting a possible histologic overlap between neutrophilic xanthoma and Sweet syndrome. Given these findings, we propose xanthomatized Sweet syndrome as a new histologic variant.

Mucin in the dermis: a case of tender tumors.

We present an original case report of a 45-year-old woman with a five-month history of sporadic, tender, nodules present on the right upper abdomen, bilateral dorsal wrists, right upper arm, and left flank. Biopsy revealed a mild perivascular infiltrate, increased dermal mucin, and no significant increase in fibroblasts. Presentation and histology were most consistent with nodular lichen myxedematosus (NLM), a rare primary mucinosis. Only four previous cases are reported in the literature to our knowledge. Management of NLM and other subtypes of lichen myxedematosus is not well described. Our patient failed systemic steroids and was unable to tolerate hydroxychloroquine, but subsequently improved with oral methotrexate. This suggests that methotrexate may be of benefit for NLM.

Two-step procedure for evaluating experimentally induced DNA damage: Texas Red and Comet assays.

The technique of Texas Red immunostaining for cellular γH2AX identifies by fluorescence microscopy DNA undergoing active remodeling or repair. To fully characterize γH2AX foci, the technique of alkaline single cell electrophoresis (Comet) assay quantifiably resolves DNA double-strand breaks from other types of DNA damage. When used together, these two techniques may provide evidence for radiochemotherapy-induced DNA damage.

Inhibition of Poly(ADP-Ribose) Polymerase Enhances Radiochemosensitivity in Cancers Proficient in DNA Double-Strand Break Repair.

Pharmacologic inhibitors of poly(ADP-ribose) polymerase (PARP) putatively enhance radiation toxicity in cancer cells. Although there is considerable information on the molecular interactions of PARP and BRCA1- and BRCA2-deficient cancers, very little is known of the PARP inhibition effect upon cancers proficient in DNA double-strand break repair after ionizing radiation or after stalled replication forks. In this work, we investigate whether PARP inhibition by ABT-888 (veliparib) augments death-provoking effects of ionizing radiation, or of the topoisomerase I poison topotecan, within uterine cervix cancers cells harboring an unfettered, overactive ribonucleotide reductase facilitating DNA double-strand break repair and contrast these findings with ovarian cancer cells whose regulation of ribonucleotide reductase is relatively intact. Cell lethality of a radiation-ABT-888 combination is radiation and drug dose dependent. Data particularly highlight an enhanced topotecan-ABT-888 cytotoxicity, and corresponds to an increased number of unrepaired DNA double-strand breaks. Overall, our findings support enhanced radiochemotherapy toxicity in cancers proficient in DNA double-strand break repair when PARP is inhibited by ABT-888.

dNTP Supply Gene Expression Patterns after P53 Loss.

Loss of the transcription factor p53 implies mRNA losses of target genes such as the p53R2 subunit of human ribonucleotide reductase (RNR). We hypothesized that other genes in the dNTP supply system would compensate for such p53R2 losses and looked for this in our own data and in data of the Gene Expression Omnibus (GEO). We found that the de novo dNTP supply system compensates for p53R2 losses with increases in RNR subunit R1, R2, or both. We also found compensatory increases in cytosolic deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1) and in mitochondrial deoxyguanosine kinase (dGK), all of the salvage dNTP supply system; in contrast, the remaining mitochondrial salvage enzyme thymidine kinase 2 (TK2) decreased with p53 loss. Thus, TK2 may be more dedicated to meeting mitochondrial dNTP demands than dGK which may be more obligated to assist cytosolic dNTP supply in meeting nuclear DNA dNTP demands.

Deoxynucleoside salvage facilitates DNA repair during ribonucleotide reductase blockade in human cervical cancers.

Cells generate 2'-deoxyribonucleoside triphosphates (dNTPs) for both replication and repair of damaged DNA predominantly through de novo reduction of intracellular ribonucleotides by ribonucleotide reductase (RNR). Cells can also salvage deoxynucleosides by deoxycytidine kinase/thymidine kinase 1 in the cytosol or by deoxyguanosine kinase/thymidine kinase 2 in mitochondria. In this study we investigated whether the salvage dNTP supply pathway facilitates DNA damage repair, promoting cell survival, when pharmacological inhibition of RNR by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC no. 663249) impairs the de novo pathway. Human cervical cancer cells were subjected to radiation with or without 3-AP under medium deoxynucleoside concentrations of 0, 0.05, 0.5 and 5.0 µM. Efficacy of DNA damage repair was assessed by γ-H2AX flow cytometry and focus counts, by single cell electrophoresis (Comet assay), and by caspase 3 cleavage assay as a marker of treatment-induced apoptosis. Cell survival was assessed by colony formation. We found that deoxyribonucleotide salvage facilitates DNA repair during RNR inhibition by 3-AP and that salvage reduces the radiochemosensitivity of human cervical cancer cells.

Implementing chemoradiation treatment for patients with cervical cancer in a comprehensive cancer center community oncology practice.

In 1999, the National Cancer Institute broadcast a clinical alert promoting the coadministration of radiation therapy and chemotherapy for women with advanced-stage cervical cancer. Since then, patterns of care studies suggest that implementation of these guidelines has been slow. We tested the hypothesis that women with advanced-stage cervical cancer were just as likely to receive coadministration of radiation therapy and chemotherapy at community oncology practices as at hospital-based cancer centers. Between January 2000 and December 2009, 198 women underwent radiation therapy for advanced-stage cervical cancer at treatment centers within a comprehensive cancer center community oncology practice. The majority, 140 (71%), received concurrent radiation therapy and cisplatin chemotherapy. Relative chemotherapy dose, relative time of chemotherapy administration, and relative dose intensity of chemotherapy were similar among the hospital-based comprehensive cancer center and the affiliated community oncology practices. This finding attests to the successful implementation of chemoradiotherapy for cervical cancer in a large networked oncology practice.