Economic Costs Avoided by Diagnosing Melanoma Six Months Earlier Justify >100 Benign Biopsies.

New melanoma drugs bring enormous benefits but do so at significant costs. Because melanoma grows deeper and deadlier over time, deeper lesions are costlier due to increased sentinel lymph node biopsy, chemotherapy, and disease-associated income loss. Prior studies have justified pigmented lesion biopsies on a "value per life" basis; by contrast we sought to assess how many biopsies are justified per melanoma found on a purely economic basis. We modeled how melanomas in the United States would behave if diagnosis were delayed by 6 months, eg, not biopsied, only observed until the next surveillance visit. Economic loss from delayed biopsy is the obverse of economic benefit of performing biopsy earlier. Growth rates were based on Liu et al. The results of this study can be applied to all patients presenting to dermatologists with pigmented skin lesions suspicious for melanoma. In-situ melanomas were excluded because no studies to date have modeled growth rates analogous to those for invasive melanoma. We assume conservatively that all melanomas not biopsied initially will be biopsied and treated 6 months later. Major modeled costs are (1) increased sentinel lymph node biopsy, (2) increased chemotherapy for metastatic lesions using increased 5-yr death as metastasis marker, and (3) income loss per melanoma death at $413,370 as previously published. Costs avoided by diagnosing melanoma earlier justify 170 biopsies per melanoma found. Efforts to penalize "unnecessary" biopsies may be economically counterproductive.

J Drugs Dermatol. 2016;15(5):527-532.

Biopsy rates vary with patient profile across different physicians in an academic dermatology practice.

Current healthcare trends promote data-driven "benchmarking" to decrease cost and increase quality. Dermatologists perform 79% of skin biopsies and biopsy rate is an easily measured benchmark. To reduce the risk of a misguided "one size fits all" benchmark for biopsies, it will help to document the factors driving divergent biopsy rates.This letter compares biopsy rates and high-risk patient ratios for 1000 sequential patients from two academic dermatologists. Elevated biopsy rates (0.55 vs 0.42, p < 0.001) were associated with elevated ratios of high-risk patients (.52 versus .30, p< 0.001). Although limited by small sample size, this research takes a first step toward future efforts to improve accuracy of biopsy benchmarking.

In vivo efficacy of nano hyaluronan-conjugated cisplatin for treatment of murine melanoma.

BACKGROUND: Melanoma is a deadly skin cancer with rapidly rising incidence. While localized melanoma can be treated with excision, there are at present no similarly effective treatments for regional and distant disease, so survival rates are low. One problem is that melanoma is chemo-resistant, and most chemotherapy doses are limited by systemic toxicity. A method for delivering high-dose chemotherapy directly to tumors and draining lymph nodes could have the advantage of allowing much higher effective doses with reduced systemic exposure. METHODS: Human melanoma cell line A-2058 tumor cells were injected into athymic mice. After tumors grew to 50~100 mm³ mice were divided into five groups: (1) nontreated (2) intravenous (i.v.) cisplatin, (3) i.v. nano hyaluronan-conjugated cisplatin (HA-Pt), (4) subcutaneous (s.c.) peri-tumoral cisplatin, and (5) s.c. peri-tumoral HA-Pt. All treatment groups received 3 weekly doses of 10 mg/kg. RESULTS: Tumors grew progressively in all control, i.v. cisplatin, and s.c. cisplatin groups. Tumors showed a trend toward slower growth in the i.v. HA-Pt group, but all animals died or were euthanized per protocol within 3 weeks of treatment. Tumors showed shrinkage only in the subcutaneous peri-tumoral HA-cisplatin group; one of these mice appeared to be cured. CONCLUSIONS: Peri-tumoral HA-cisplatin may be shown potential as a therapeutic option in treatment of certain types of melanoma.

Analysis of the N-terminal positively charged residues of the simian immunodeficiency virus Vif reveals a critical amino acid required for the antagonism of rhesus APOBEC3D, G, and H.

Previous studies have shown that apolipoprotein B mRNA editing, enzyme catalytic, polypeptide G (APOBEC3G; hA3G) and F (APOBEC3F; hA3F) proteins interact with a nonlinear binding site located at the N-terminal region of the HIV-1 Vif protein. We have analyzed the role of 12 positively charged amino acids of the N-terminal region of the SIV Vif. Simian-human immunodeficiency viruses (SHIV) were constructed that expressed each of these amino acid substitutions. These viruses were examined for replication in the presence of rhesus macaque APOBEC3 proteins (rhA3A-rhA3H), incorporation of the different A3 proteins into virions, and replication in rhesus macaque PBMC. Similar to other studies, we found that K27 was essential for rhA3G activity and rhA3F but was not important for restriction of SHIVΔvif by rhA3A, rhA3D or rhA3H. Our results identified the arginine at position 14 of the SIV Vif as a critical residue for virus restriction by rhA3D, rhA3G and rhA3H.

HIV neuropathogenesis: a tight rope walk of innate immunity.

During the course of HIV-1 disease, virus neuroinvasion occurs as an early event, within weeks following infection. Intriguingly, subsequent central nervous system (CNS) complications manifest only decades after the initial virus exposure. Although CNS is commonly regarded as an immune-privileged site, emerging evidence indicates that innate immunity elicited by the CNS glial cells is a critical determinant for the establishment of protective immunity. Sustained expression of these protective immune responses, however, can be a double-edged sword. As protective immune mediators, cytokines have the ability to function in networks and co-operate with other host/viral mediators to tip the balance from a protective to toxic state in the CNS. Herein, we present an overview of some of the essential elements of the cerebral innate immunity in HIV neuropathogenesis including the key immune cell types of the CNS with their respective soluble immune mediators: (1) cooperative interaction of IFN-γ with the host/virus factor (platelet-derived host factor (PDGF)/viral Tat) in the induction of neurotoxic chemokine CXCL10 by macrophages, (2) response of astrocytes to viral infection, and (3) protective role of PDGF and MCP-1 in neuronal survival against HIV Tat toxicity. These components of the cerebral innate immunity do not act separately from each other but form a functional immunity network. The ultimate outcome of HIV infection in the CNS will thus be dependent on the regulation of the net balance of cell-specific protective versus detrimental responses.

Investigations on four host response factors whose expression is enhanced in X4 SHIV encephalitis.

HIV encephalopathy, one of the major complications of HIV infection, involves productive virus replication in macrophages in the brain in association with heightened expression of several host response factors. One or more of these factors are thought to be the cause of the degenerative changes in neurons in the brain. Macaques infected with SIV and SHIV viruses have provided excellent working models for studying mechanisms of the human disease. Although HIV encephalopathy is primarily associated with CCR5-utilizing viruses, our findings have shown that CXCR4-utilizing SHIVs were also capable of causing the syndrome in rhesus macaques. In SHIV-infected macaques, approximately 30% of the animals developed encephalitis. In order to understand the factors leading to end-stage encephalitis, we performed microarray analyses on brains of encephalitic and non-encephalitic-infected macaques, and found pronounced enhancement of expression of interleukin-4, platelet-derived growth factor-B chain, monocyte chemoattractant protein-1 and CXCL10 in the brains of the encephalitic animals. This review discusses the role of each of these factors in mediating SHIV encephalitis.