Caroline V. Caperton

Exacerbation of facial acne vulgaris after consuming pure chocolate

REFERENCES 1. Mueller TJ, Wu H, Greenberg RE, Hudes G, Topham N, Lessin SR, et al. Cutaneous metastases from genitourinary malignancies. Urology 2004;63:1021-6. 2. Miyamoto T, Ikehara A, Araki M, Akaeda T, Mihara M. Cutaneous metastatic carcinoma of the penis: suspected metastasis implantation from a bladder tumor. J Urol 2000;163:1519. 3. Wang NP, Zee S, Zarbo RJ, Bacchi CE, Gown AM. Coordinate expression of cytokeratins 7 and 20 defines unique subsets of carcinomas. Appl Immunohistochem 1995;3:99-107. 4. Amin MB. Histologic variants of urothelial carcinoma: diagnostic, therapeutic and prognostic implications.Mod Pathol 2009;22:S96. 5. Swick B, Gordon J. Superficially invasive transitional cell carcinoma of the bladder associated with distant cutaneous metastases. J Cutan Pathol (Epub ahead of print). 6. HoW, Lee L, Chen C, Tsengand J, Tsai T. An interesting and unique pattern of two distinct coexisting cutaneous metastases of a transitional cell carcinoma. Clin Exp Dermatol 2009;34:e336-8.

Effect of behavioral interventions on insulin sensitivity and atherosclerosis in the watanabe heritable hyperlipidemic rabbit

Objective: A previous study suggested that insulin metabolic variables play a role in the progression of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. The present study sought to determine: 1) if young, individually caged WHHLs are insulin-resistant relative to New Zealand white (NZW) rabbits and 2) whether dietary or exercise interventions can improve insulin sensitivity and slow the development of atherosclerosis in these animals. Methods: Forty-two WHHLs were assigned to a dietary, exercise, or control condition, and 12 NZWs were used as a comparison control group. The intervention ran from 3 to 7 months of age, and all animals received an intravenous glucose tolerance test at the beginning and end of the intervention. Results: WHHLs were insulin-resistant relative to NZWs at 3 months of age. Whereas the dietary intervention was effective in controlling insulin resistance, WHHLs in the exercise group without dietary restriction and the control group exhibited significant increases in insulin resistance. No intervention significantly influenced the progression of atherosclerosis. Conclusions: Young WHHLs are insulin-resistant during an early period when atherosclerosis is developing rapidly. Dietary restriction, but not exercise without weight control, is effective in controlling insulin metabolic variables in the WHHL model. Although dietary intervention can reduce cardiovascular risk factors such as insulin resistance, it is not effective in slowing the development of atherosclerosis in these genetically dyslipidemic animals. Similarly, exercise training, without dietary control, does not influence the progression of disease in WHHLs. WHHL = Watanabe heritable hyperlipidemic rabbit; VLDL = very-low-density lipoprotein; LDL = low-density lipoprotein; HDL = high-density lipoprotein; NZW = New Zealand white rabbit; IVGTT = intravenous glucose tolerance test; HOMA = Homeostasis Model Assessment; CV = coefficient of variation; SBP = systolic blood pressure; MAP = mean arterial pressure; DBP = diastolic blood pressure; HR = heart rate; BMI = body mass index; CNS = central nervous system.

Clostridium subterminale sepsis in adult acute lymphoblastic leukemia

Infections are a major cause of morbidity and mortality in patients with hematologic malignancies who are undergoing chemotherapy, and anaerobic infections may occur in this patient population when there is disruption of a mucous membrane. We report a case of sepsis caused by Clostridium subterminale in a 51-year-old man with acute lymphoblastic leukemia (ALL) who failed to obtain complete remission after multiple treatment trials. Clostridium species are ubiquitous in the environment and are one of the most commonly isolated anaerobes; however, this is the first case, to our knowledge, of a patient with ALL-associated C. subterminale infection. A 51-year-old man with Philadelphia chromosome-positive T-cell ALL was treated initially with imatinib 400 mg twice daily, five cycles of HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), and intrathecal methotrexate, but failed to obtain complete remission. Five months later, a peripherally inserted central catheter was placed due to difficulties in obtaining venous access. Imatinib was discontinued, as numerous circulating blasts were still seen on peripheral smear. One month later, dasatinib 70 mg twice daily was added, then changed to nilotinib 400 mg twice daily after 3 months. The patient presented to the emergency department shortly thereafter with hemorrhoidal pain, and was found to have an ulceration near the anal verge, along with erythema and induration of the right perianal region. The patient was tachycardic, febrile, and neutropenic; therefore, blood cultures were drawn, one from the patient’s central venous catheter and one from a peripheral vein. Broad-spectrum antibiotics were started empirically (cefepime 2 g every 12 h, vancomycin 1 g every 8 h, and metronidazole 500 mg every 6 h). Gram stain was positive and revealed rods with sporulation, indicative of a Clostridium species. Unusual colony morphology was observed for anaerobic culture in the form of subterminal spores, which are also seen in several Clostridium species. Because of the rarity of this morphology, it was decided to pursue amplification and sequence analysis of the bacterial 16S ribosomal RNA gene that showed 100% identification of C. subterminale (matched to approximate 1450 nucleotide sequence provided by the European Molecular Biology Laboratory [EMBL] Data Library), with all other aerobic cultures remaining sterile (no bacteria growth was appreciated). This rod-shaped obligate anaerobe bacterium is usually susceptible to vancomycin, penicillins, cephalosporins, clindamycin, quinolones, and carbapenems, although Clostridium species have shown variable resistance to cephalosporins, tetracyclines, aminoglycosides, and quinolones [1,2]. Unfortunately, susceptibility testing on anaerobic organisms is not routinely performed by our hospital’s microbiology department. Due to persistent fevers, cefepime was switched to imipenem on the fifth day of admission, with minimal clinical improvement. The patient’s leukocyte count continued to rise, reaching 123 000/ mm, with 28% blasts. Based on his poor prognosis,

Safety, efficacy, and patient acceptability of imiquimod for topical treatment of actinic keratoses

Imiquimod, an immune-modulating imidazoquinoline compound, has been approved in topical formulation for the treatment of actinic keratoses, superficial basal cell carcinomas, and external genital warts. Its use in the treatment of field cancerization, in particular, has been rapidly evolving. With the recent approval of a new drug application for a new concentration, as well as generic formulations, this drug has emerged at the forefront of treatment for actinic keratoses, with improved dosage scheduling and more patients having access to generic options. In the nearly 15 years since its original approval by the Food and Drug Administration for the treatment of actinic keratoses in 1997, topical imiquimod has been reviewed and studied extensively, not only for its safety and efficacy, but also for its tolerability in patients. This paper provides an indepth review of the literature, and provides clinical evidence for its inclusion in the arsenal of treatment options for patients with actinic keratoses.

Pyruvic acid facilitates the removal of actinic keratoses and seborrheic keratoses

Alpha-hydroxy acids (AHAs) are naturally or synthetically derived chemical compounds. The chemical structure is a carboxylic acid with a hydroxy functional group on the alpha or adjacent carbon. These AHAs lyse desmosomes and produce the accelerated exfoliation of keratinocytes and proliferation of new cells. Van Scott and Yu popularized the use of these AHAs for the control of hyperkeratinization in the 1980s. The family of AHAs have been used widely for their ability to resurface the skin and treat photoaging. Glycolic acid is the smallest of these acids, and pyruvic acid is an enol isomer of the next largest acid: lactic acid (Figure 1). Pyruvic acid is technically an alpha-keto acid, and it is the most potent of these resurfacing acids. Griffin and Van Scott reported the use of pyruvic acid in the treatment of actinic keratoses (AK), but its use was combined with treatment with 5-fluorouracil. This study documents the use of pyruvic acid alone in combination with a curette.

Laser Treatment of Tattoos

Tattoos are a long-standing part of human culture. • Techniques used in tattooing have evolved over • the centuries. Although 24% of Americans between the ages of • 18–50 years have at least one tattoo, 28% of people who get tattoos regret the decision within the first month. The three lasers most commonly used are the • Q-switched Nd:YAG, Q-switched Ruby, and Q-switched Alexandrite. Potential side effects of using lasers in the removal • of tattoos include discoloration, redness, scarring, and rarely, stimulating allergic reactions.

Pharmacotherapy of Basal Cell Carcinoma, Anogenital Warts, and Actinic Keratoses: Focus on Topical Imiquimod

Imiquimod, an imidazoquinoline compound, has been widely-recognized for its ability to induce both innate and adaptive immune responses. Topical imiquimod has been approved for the treatment of actinic keratoses (AK), external genital warts (EGW), and superficial basal cell carcinoma (BCC). There are reports of many successful off-label uses as well. The pharmacology and mechanisms of action, safety, efficacy, and adverse effects with regards to differing concentrations and dosing regimens are discussed in depth in this chapter. Field-directed therapies for AK along with non-surgical treatments for BCC are rapidly-evolving, with increasing numbers of studies providing evidence-based rationale for their use in management.

Abstract 1565: API 31510 as a potential agent in management of CNS leukemia

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Infiltration of cancer cells into the cerebrospinal milieu remains a challenge to oncologists. Thus, prophylactic therapy to avoid CNS tumors is now standard of care to avoid the development of tumors in the central nervous system (CNS). Despite the advances in oncological care, this issue remains poorly understood. In this regard, we have created a model of CNS chloroleukemia using Fischer 344 rats, in which chloroleukemic cells were injected when they are newborns and lipopolysaccharide (LPS) is given as a first-line of treatment. The cure rate with this regimen is 50%, and approximately 10% of survivors develop CNS leukemia as judged by their motor skills and the presence of quadriplegia and paraplegia. For this study, we injected 2400 Fischer 344 neonates with MIAC51 and treated them with LPS. All animals with overt signs of leukemia were sacrificed by day 26. By day 35, survivors started exhibiting CNS abnormalities. Of that cohort, we selected 150 animals with hind leg paraplegia on day 40. These animals were then re-randomized into 5 groups: group 1 received no treatment, group 2 received excipient control IV, group 3 received 5mg/kg API 31510 IV, group 4 received 25mg/kg IV, and group 5 received 100 mg/kg IV for 4 weeks, 3 times daily. Rats in groups 1, 2, 3 and 4 did not exhibit any signs of improvement and were sacrificed due to metastatic malignancy. These findings were recorded by MRI positive for tumor cells. In sharp contrast, animals injected with 100mg/kg IV exhibited a significant recovery of their motor skills and regained their ability to walk. MRI distinctly shows the lack of tumor cells in this group. Taken together, these results strongly indicate that API 31510 may provide a cure for CNS leukemia and may also be an effective prophylactic agent to prevent the extravasation of leukemic cells into the CNS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1565. doi:10.1158/1538-7445.AM2011-1565

Abstract 686: Treatment of pancreatic carcinoma by Cytotech Labs API 31510

Pancreatic Carcinoma (PC) is one of the deadliest cancers most clinically difficult to manage since diagnoses usually occur in late-stage disease. In early PC, resection is possible; however in most patients advanced disease mitigates the feasibility of resection. All chemotherapeutic regimens are ineffective for patients, with best outcome usually only palliative. In this regard, we have developed a novel intravenous formulation, API 31510, which induces apoptosis of a pancreatic carcinoma cell line, MIA-PaCa-2 in vitro. We therefore proceeded to test this formula in immunocompromised animals injected with 10×10 6 MIA-Paca2 cells. For these experiments, immunocompromised animals were injected with MIA-PaCa2 suspended in matrigel. 2 weeks after transplantation with MIA Paca2, API 31510 and vehicle controls were administered 3 times/week for 4 weeks with surviving animals sacrificed at day 60. Animals were randomized into 8 groups of 30 rats each; group 1 (no treatment), group 2 (saline), group 3 (vehicle), group 4 (0.5 mg/kg API 31510), group 5 (5 mg/kg API 31510), group 6 (10 mg/kg API 31510), group 7 (25 mg/kg API 31510), and group 8 (50 mg/kg API 31510). In groups 1, 2 and 3 deaths were recorded 21 days after the injection of MIA-PaCa-2. In contrast, all other groups showed significant dose-dependent increase in survival times. Group 8 had 60% of animals alive with only 4 animals exhibiting visible tumors at day 60. In separate experiments, we explored whether API 31510 protects from doxorubicin toxicity. To this effect, we treated rats with doxorubicin (35 mg/kg) and then injected API 31510 in one group. Those who were not treated, died on days 6-11, whereas those treated with API 31510 were protected against doxorubicin toxicity. To assess the mechanism of action of Cytotech API 31510 in Mia-Paca2, a combination of transcriptomic, proteomic and metabolic analysis was employed. Mia-Paca2 cells exhibit the Warburg effect characterized by high glycolytic flux and extracellular acidification rates (ECAR) that is reversed in the presence of API 31510. Exposure to API 31510 induces a change in the gene expression profiling of intrinsic apoptotic factors and proteomic analysis using DAVID show increase in components regulating protein expression, processing and cytoskeletal remodeling with concomitant decrease in components regulating nuclear metabolic processes and chromatin function. The ability of Cytotech API 31510 to induce global changes in cellular transcriptomic and proteomic functions along induction of programmed cell death in association with shift in mitochondrial energy utilization pathways represents a unique mechanism targeting pathways within the spectrum of Warburg Phenomenon for therapy of pancreatic cancer. Taken together, these findings suggest that API 31510 may offer a new approach to treatment and management of pancreatic cancer, while mitigating dose-limiting toxicities in other chemotherapeutic interventions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 686. doi:10.1158/1538-7445.AM2011-686

Abstract 5409: Protection of chemotherapy-induced myelosuppresion by cytotech labs API 31543

High pulses of Calcitriol have been demonstrated to treat myelodysplastic syndrome without hypercalcemia. We have previously demonstrated that calcitriol protects chemotherapy-induced alopecia without calcemic effects. We thus hypothesized that a regimen of non-hypercalcemic high pulses of API 31543, a formulation containing calcitriol, may protect the bone marrow and circulating progenitors without protecting the cancer cells. 5-day old Long Evans rats were injected with MIAC51, a chloroleukemic cell line. On day 21, rats were randomized into 3 groups for each chemotherapy regimen. Group I received vehicle, group II received 10 µg API 31543. A pulse dose of vehicle or API 31543 was given 4 days prior to chemotherapy administration. Groups I and II were separated on day 21 into 2 groups and received the following chemotherapies: cyclophosphamide (CTX; 150mg/kg), cyclophosphamide and doxorubicin (CTX/DOXO; 100 mg/kg, 25 mg/kg, respectively) and cyclophosphamide, doxorubicin and paclitaxel, (CTX/DOXO/PAC 100 mg/kg, 25 mg/kg, 10 mg/kg, respectively). Starting on day 20 through day 32, complete granulocyte counts were then assessed. Baseline absolute neutrophil counts (ANC) prior to chemotherapy administration ranged from 3621 ±154 mm 3 to 3000 ±254 mm 3. Once chemotherapy was administered, ANC values dropped significantly between days 24 and 27. For CTX and vehicle the nadir ANC was 10% of the normal values. In contrast, the nadir of CTX and API 31543 was close to the normal count. In the group receiving CTX/DOXO, ANC was also reduced by 90%. For CTX/DOXO and vehicle nadir ANC was less than 10% of normal counts, while groups receiving CTX/DOXO and API 31543 were normal. Similarly, in groups receiving CTX/DOXO/PAC and vehicle, nadir ANC was less than 10%, while in groups receiving CTX/DOXO and API 31543 ANC values were normal. On day 32, a complete leukocyte count was performed in all animals and those positive for MIAC51 were sacrificed. Bone marrow cultures were performed on days 22, 25 and 32. Bone marrow cultures supported the ANC data. We therefore performed the same experiments on adult rats to mimic the multiple courses of chemotherapy. For the second cycle of chemotherapy, survivors were re-randomized and treated with the same chemotherapy regimens. Neutrophil counts were measured as previously described. The second pulse of API 31543 was administered on day 48, and chemotherapy was started. On day 52, rats were re-randomized for each chemotherapy regimen. Group I received vehicle only, group II received 20 µg API 31543. Results with the both regimens and all chemotherapies were similar. These results indicate that API 31543 significantly decreases the nadir ANC and confers bone marrow protection against chemotherapy, while not protecting the cancer cell. The data herein supports further development of this work and suggest that API 31543 may be a potential clinical agent for prevention of chemo-induced myelosuppression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5409. doi:10.1158/1538-7445.AM2011-5409