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Purpose: Conventional photosensitizers for photodynamic therapy (PDT) typically have wide tissue distribution and poor water solubility. A hyaluronic acid (HA) polymeric nanoparticle with specific lymphatic uptake and highly water solubility was developed to deliver pyropheophorbide-a (PPa) for locally advanced head and neck squamous cell carcinoma (HNSCC) treatment., Methods and Results: PPa was chemically conjugated to the HA polymeric nanoparticle via an adipic acid dihydrazide (ADH) linker. The conjugates were injected subcutaneously in a region near the tumor. Near-infrared (NIR) imaging was used to monitor distribution, and diode laser was used to activate PPa. The singlet oxygen generation efficiency of PPa was not affected by conjugation to HA nanoparticles at a PPa loading degree of 1.89 w.t.%. HA-ADH-PPa inhibited human HNSCC MDA-1986 cell growth only when photo-irradiation was applied. After HA-ADH-PPa treatment and radiation, NU/NU mice bearing human HNSCC MDA-1986 tumors showed reduced tumor growth and significantly enhanced survival time compared with an untreated group (p < 0.05)., Conclusions: These results demonstrate that HA-ADH-PPa could be useful for in vivo locoregional photodynamic therapy of HNSCC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The toll-like receptor 7 and 8 (TLR7/8) agonist Resiquimod (R848) has been recognized as a promising immunostimulator for the treatment of cutaneous cancers in multiple clinical trials. However, systemic administration of R848 often results in strong immune-related toxicities while having limited therapeutic effects to the tumor. In the present study, a prodrug-based nanocarrier delivery system was developed that exhibited high therapeutic efficiency. R848 was conjugated to α-tocopherol to constitute an R848-Toco prodrug, followed by formulating with a tocopherol-modified hyaluronic acid (HA-Toco) as a polymeric nano-suspension. In vitro evaluation showed that the delivery system prolonged the release kinetics while maintaining TLR agonist activities. When administered subcutaneously, the nano-suspension formed a depot at the injection site, inducing localized immune responses without systemic expansion. This formulation also suppressed tumor growth and recruited immune cells to the tumor in a murine model of head and neck cancer. In a preclinical canine study of spontaneous mast cell tumors, the treatment led to a 67% response rate (three partial remissions and one complete remission)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cellulitis, a bacterial infection of the skin and subcutaneous tissue, is often misdiagnosed. Cellulitis accounts for a large number of all infectious disease-related hospitalizations in the U.S. Cellulitis can be challenging to diagnose since it lacks pathognomonic findings. We reviewed all articles on cellulitis within the last 20 years that included a statistical analysis, with odds ratios (OR), of specific clinical features of cellulitis. We then constructed a mnemonic encompassing the features with the highest odds ratios. Our mnemonic is CELLULITIS for cellulitis history, edema, local warmth, lymphangitis, unilateral, leukocytosis, injury, tender, instant onset, and systemic signs. The first characteristic has the highest OR and may be the easiest to recall: past episode(s) of cellulitis.

Distinct populations of effector memory T cells use different homing receptors to traffic to the skin and gut. Whether tissue-selective T cells are needed for early rejection of a neoplasm growing in these tissues remains an open question. We chose to study an allogeneic tumor model because growth of such a fully mismatched tumor would signify a profound immune deficit. We implanted allogeneic tumor cells in the skin or gut of mice deficient in either α(1,3) fucosyltransferases IV and VII, enzymes critical for generating E-selectin ligands on skin-homing T cells, or β7 integrin, a component of the α4β7 integrin ligand for the mucosal adressin MAdCAM. During the first 9 days after tumor implantation, FucTVII -/- mice showed a profoundly impaired capacity to reject tumors growing in the skin, but readily rejected tumors implanted in the gut. Rejection of tumors in the skin was even more impaired in mice deficient in both FucTIV and FucTVII. This impairment was corrected by infusion of T cells from normal mice. By contrast, β7 integrin -/- mice showed profoundly impaired rejection of tumors in the gut, but no defect in the skin tumor rejection. These differences were unrelated to antigen recognition or effector function of T cells, since all strains of mice were capable of generating tumor-specific CTLs in vitro against the tumor cell line used in vivo. These results demonstrate that T-cell homing defects in vivo impair immune surveillance of peripheral epithelial tissues in a specific and selective fashion.

Promotion in academic dermatology requires evidence of scholastic production. The h-index is a bibliometric measure that combines both volume and impact of scientific contributions. Its calculation better predicts future scientific success than do publication or citation counts. In this epidemiologic survey of associate and full professors of dermatology in residency training programs in the United States, we measured mean and median h-indices among associate and full professors as well as regional differences in h-index. These findings could be used to track individual achievement and as a parameter in considering an individual for professional advancement in dermatology.

Weight loss clinics are common in the United States.  Unfortunately, some offer dubious weight loss methods such as self-administered human chorionic gonadotropic (HCG) injections. HCG products are unregulated, yet, widely available. Infection is among the risks potentially associated with this treatment.  We report a case of skin infection caused by Mycobacterium fortuitum after HCG injection.

OBJECTIVE To conduct a phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate (HA-Pt) in dogs with naturally occurring malignant tumors. ANIMALS 18 healthy rats, 9 healthy mice, and 16 dogs with cancer. PROCEDURES HA-Pt was prepared and tested by inductively coupled plasma mass spectrometry; DNA-platinum adduct formation and antiproliferation effects of cisplatin and HA-Pt were compared in vitro. Effects of cisplatin (IV) and HA-Pt (SC) in rodents were tested by clinicopathologic assays. In the clinical trial, dogs with cancer received 1 to 4 injections of HA-Pt (10 to 30 mg/m(2), intratumoral or peritumoral, q 3 wk). Blood samples were collected for pharmacokinetic analysis; CBC, serum BUN and creatinine concentration measurement, and urinalysis were conducted before and 1 week after each treatment. Some dogs underwent hepatic enzyme testing. Tumors were measured before the first treatment and 3 weeks after each treatment to assess response. RESULTS No adverse drug effects were detected in pretrial assessments in rodents. Seven of 16 dogs completed the study; 3 had complete tumor responses, 3 had stable disease, and 1 had progressive disease. Three of 7 dogs with oral and nasal squamous cell carcinoma (SCC) that completed the study had complete responses. Myelosuppression and cardiotoxicosis were identified in 6 and 2 dogs, respectively; none had nephrotoxicosis. Four of 5 dogs with hepatic enzymes assessed had increased ALT activities, attributed to diaquated cisplatin products in the HA-Pt. Pharmacokinetic data fit a 3-compartment model. CONCLUSIONS AND CLINICAL RELEVANCE HA-Pt treatment resulted in positive tumor responses in some dogs, primarily those with SCC. The adverse effect rate was high. IMPACT FOR HUMAN MEDICINE Oral SCC in dogs has characteristics similar to human head and neck SCC; these results could be useful in developing human treatments.

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.

Background: Psoriasis is a common but complex chronic inflammatory skin Disease. Array-based studies can help identify therapeutic targets., Objective: To reproducibly assess single-gene transcriptional changes in psoriatic skin., Methods: We evaluated 210 top candidate genes from a first psoriasis study group (population 1), and then confirmed differential expression in a second independent psoriasis study group (population 2)., Results: One hundred and thirty-eight differentially expressed genes were replicated in the 2 studies, of which 57 have not previously been reported as associated with psoriasis. This is significantly greater than the 10 expected false positives. Lesional skin vs uninvolved areas showed inflammatory and cell regulation changes., Conclusion: Previously undescribed psoriasis-associated genes revealed in this study may provide potential future targets for development and assessment of novel therapeutic agents for psoriasis.

Cutaneous T-cell lymphoma is a cancer of skin-homing T cells, of which mycosis fungoides (MF) is the most common variant. MF treatments range from topical steroids to systemic chemotherapy. Resistant cutaneous MF nodules can present a special challenge in that typical topical therapies may not penetrate thick lesions, and increasing systemic therapy brings added risk of side effects. We report successful use of intralesional steroids (ILS) for treatment-resistant MF, including tumor-stage plaques and nodules in 4 consecutive patients with focally resistant MF. ILS have been widely used to treat a broad range of cutaneous conditions such as alopecia areata and keloids. Side effects of ILS include hypopigmentation, atrophy, telangiectasias, lilac discoloration, acne, and striae. Rarely, and in circumstances involving unusually large doses, ILS may cause Cushing's syndrome, hypothalamus-pituitary-adrenal axis suppression, and reduced bone mineral density. The MF patients tolerated treatment well without any of the above side effects other than local hypopigmention in a single patient. These results point toward further exploration into ILS as a treatment for focally resistant MF.

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.

Background: Intravenous immunoglobulin (IVIG) can be used to treat potentially deadly toxic epidermal necrolysis (TEN), milder Stevens Johnson Syndrome (SJS) and intermediate TEN/SJS overlap. Some formularies now deny IVIG for TEN based on the EuroSCAR TEN/SJS study that reported a nonsignificant trend toward increased mortality in 75 IVIG-treated TEN/SJS patients; of note the IVIG patients had more TEN and less SJS than patients in other treatment arms. EuroSCAR data on mortality among the 25 IVIG-treated TEN patients, use of nonsucrose IVIG, and admission to specialized settings such as burn units was not disclosed. The impact of treatment setting (specialized unit vs general ward) on IVIG efficacy has not previously been studied., Objective: To evaluate efficacy of treating TEN with early nonsucrose IVIG in a burn unit., Methods: Data were retrospectively collected from 13 IVIG-treated TEN patients admitted to a burn unit over a 6-year period., Results: We report 0% mortality among 13 IVIG-treated TEN patients. Mortality was significantly lower than predicted by SCORTEN. Mortality was also significantly lower than the EuroSCAR groups receiving IVIG (P<.005), supportive care (P<.018), and corticosteroids only (P<.046)., Conclusion: TEN patients may benefit from early nonsucrose IVIG administered in burn units or other specialized settings.

Slowing aging is a widely shared goal. Plant-derived polyphenols, which are found in commonly consumed food plants such as tea, cocoa, blueberry and grape, have been proposed to have many health benefits, including slowing aging. In-vivo studies have demonstrated the lifespan-extending ability of six polyphenol-containing plants. These include five widely consumed foods (tea, blueberry, cocoa, apple, pomegranate) and a flower commonly used as a folk medicine (betony). These and multiple other plant polyphenols have been shown to have beneficial effects on aging-associated changes across a variety of organisms from worm and fly to rodent and human.

Targeted lymphatic delivery of nanoparticles for drug delivery and imaging is primarily dependent on size and charge. Prior studies have observed increased lymphatic uptake and retentions of over 48 h for negatively charged particles compared to neutral and positively charged particles. We have developed new polymeric materials that extend retention over a more pharmaceutically relevant 7-day period. We used whole body fluorescence imaging to observe in mice the lymphatic trafficking of a series of anionic star poly-(6-O-methacryloyl-D-galactose) polymer-NIR dye (IR820) conjugates. The anionic charge of polymers was increased by modifying galactose moieties in the star polymers with succinic anhydride. Increasing anionic nature was associated with enhanced lymphatic uptake up to a zeta potential of ca.-40 mV; further negative charge did not affect lymphatic uptake. Compared to the 20% acid-conjugate, the 40-90% acid-star-polymer conjugates exhibited a 2.5- to 3.5-fold increase in lymphatic uptake in both the popliteal and iliac nodes. The polymer conjugates exhibited node half-lives of 2-20 h in the popliteal nodes and 19-114 h in the deeper iliac nodes. These polymer conjugates can deliver drugs or imaging agents with rapid lymphatic uptake and prolonged deep-nodal retention; thus they may provide a useful vehicle for sustained intralymphatic drug delivery with low toxicity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

New lymphatic imaging technologies are needed to better assess immune function and cancer progression and treatment. Lymphatic uptake depends mainly on particle size (10-100 nm) and charge. The size of carriers for imaging and drug delivery can be optimized to maximize lymphatic uptake, localize chemotherapy to lymphatic metastases, and enable visualization of treatment deposition. Toward this end, female BALB/c mice were injected subcutaneously in the hind footpad or forearm with a series of six different molecular weight hyaluronan (HA) near-infrared dye (HA-IR820) conjugates (ca. 5-200 nm). Mice were imaged using whole body fluorescent imaging over two weeks. HA-IR820 fluorescence was clearly visualized in the draining lymphatic capillaries, and in the popliteal and iliac or axillary lymph nodes. The 74-kDa HA-IR820 had the largest lymph node area-under-the-curve. In contrast to prior reports, mice bearing limb tumors exhibited three-fold longer retention of 74-kDa HA-IR820 in the popliteal node compared to mice without tumors. HA conjugate kinetics and disposition can be specifically tailored by altering their molecular weight. The specific lymphatic uptake and increased nodal retention of HA conjugates indicate significant potential for development as a natural biopolymer for intralymphatic drug delivery and imaging.

Dietary restriction (DR) extends lifespan across multiple species including mouse. Antioxidant plant extracts rich in polyphenols have also been shown to increase lifespan. We hypothesized that polyphenols might potentiate DR-induced lifespan extension. Twenty week old C57BL/6 mice were placed on one of three diets: continuous feeding (control), alternate day chow (Intermittent fed, IF), or IF supplemented with polyphenol antioxidants (PAO) from blueberry, pomegranate, and green tea extracts (IF+PAO). Both IF and IF+PAO groups outlived the control group and the IF+PAO group outlived the IF group (all p<0.001). In the brain, IF induced the expression of inflammatory genes and p38 MAPK phosphorylation, while the addition of PAO reduced brain inflammatory gene expression and p38 MAPK phosphorylation. Our data indicate that while IF overall promotes longevity, some aspects of IF-induced stress may paradoxically lessen this effect. Polyphenol compounds, in turn, may potentiate IF-induced longevity by minimizing specific components of IF-induced cell stress., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: The current standard of care for hidradenitis suppurativa (HS) includes antibiotics (oral/topical), retinoids (oral/topical) and intralesional steroids and is unsatisfactory. Photodynamic therapy (PDT) with 20% 5-aminolevulinic acid (ALA) has been used ?off label? to treat acne vulgaris and may hold promise as a therapy for HS. This open-label, non-blinded study investigated the efficacy and safety of ALA PDT for the treatment of HS using two blue light sources and intense pulsed light (IPL) for photoactivation., Methods: Twelve subjects with active HS enrolled to undergo ALA PDT once weekly for four weeks with follow-up visits 4, 8, and 12 or more weeks later. Nine subjects completed the study through the week 8 follow-up visit. Lesions were counted at each treatment visit at week 4, week 8 and at the final week., Results: Mean lesion counts were 11.25 at baseline, 6.5 at 4 weeks (50.8% reduction), and 7.5 at 8 weeks (29.9% reduction). Mean Global Severity Scores were 2.2 at baseline, 1.5 at 4 weeks, and 1.8 at 8 weeks. Mean DLQI scores were 17.3 at baseline, 13.1 at 4 weeks (27.2% improvement), 14.00 at 8 weeks (19.3% improvement) and 14.0 (19.3% improvement) at the final week (16-62 weeks). Three subjects (25%) had complete clearance and no active lesions 4 weeks after the final treatment. Treatments were more tolerable for subjects treated with blue light than with IPL., Conclusion: ALA PDT may be a safe and effective treatment of hidradenitis suppurativa.

Background: Photodynamic therapy (PDT) is increasing in dermatology. Antibiotic resistance and the challenges of isotretinoin therapy have led to investigation of PDT in the treatment of acne vulgaris., Objective: To review the results of clinical trials and case series with respect to light source, topical photosensitizing agent, adverse events, efficacy and skin type., Methods: A non-critical review is presented of a PubMed search for studies examining PDT in the treatment of acne vulgaris., Results: The authors found 21 clinical trials and case series of various designs. Eight studies employed a split-face design comparing photosensitizer to placebo, no treatment or another photosensitizer. Two trials used three test spots and one control spot per patient. Three studies utilized control subjects receiving no photosensitizer with or without light therapy. All 21 studies reported a reduction in inflammatory lesions and/or a significant improvement in acne. The light sources utilized included blue light, pulsed-dye laser (PDL), intense pulsed light (IPL) and red light. Studies comparing the use of PDT to light therapy alone demonstrated greater improvement in treatment groups pretreated with a photosensitizer., Conclusion: All studies reported reduction in inflammatory lesions or significant improvement in acne. Several studies confirm a light source combined with photosensitizer is superior to light alone. Adverse reactions including photosensitivity, pustular eruptions, and crusting varied among photosensitizers and light sources. PDT appears to be a useful therapeutic option for acne patients who are recalcitrant to standard treatments and poor candidates for systemic retinoids. Further studies are still needed before a consensus protocol can be established. Additional investigations are needed to establish optimal incubation time, activating light source and frequency of treatment.

Dermatosis papulosa nigra (DPN) is a chronic skin condition characterized by verrucous hyperpigmented papules on the face, neck and upper trunk in African American patients. The lesions are more common in females and in older patients. Although the lesions are benign, treatment is often sought for cosmetic reasons. We report two cases of patients with facial DPN who achieved an excellent cosmetic result following a single treatment with a long-pulsed 1064 nm Nd:YAG laser. We suggest this modality for consideration in treating patients with DPN.

Background: Surgical repair of cleft lip, while correcting deformity and dysfunction, may leave residual cosmetic imperfections. The resultant asymmetry and low volume of the upper lip can be addressed surgically and via less invasive methods., Objective: We present the first reported use of injectable hyaluronic acid to correct the characteristic lip asymmetry and poor volume after surgical repair of a cleft lip., Methods and Materials: Using injectable hyaluronic acid, we treated the patient's upper lip to restore symmetry and achieve an augmented volume., Results: We obtained a symmetric correction and aesthetically pleasing volume augmentation in the affected lip. These results lasted approximately 4 months., Conclusion: Using a temporary, alloplastic, injectable soft tissue filler such as hyaluronic acid satisfactorily achieves correction of asymmetry and low volume in a surgically repaired cleft lip. For patients who have endured multiple corrective surgeries, this is a novel and less invasive way to improve their cosmetic concerns.

Cutaneous T-cell lymphoma (CTCL) is defined by infiltration of activated and malignant T cells in the skin. The clinical manifestations and prognosis in CTCL are highly variable. In this study, we hypothesized that gene expression analysis in lesional skin biopsies can improve understanding of the disease and its management. Based on 63 skin samples, we performed consensus clustering, revealing 3 patient clusters. Of these, 2 clusters tended to differentiate limited CTCL (stages IA and IB) from more extensive CTCL (stages IB and III). Stage IB patients appeared in both clusters, but those in the limited CTCL cluster were more responsive to treatment than those in the more extensive CTCL cluster. The third cluster was enriched in lymphocyte activation genes and was associated with a high proportion of tumor (stage IIB) lesions. Survival analysis revealed significant differences in event-free survival between clusters, with poorest survival seen in the activated lymphocyte cluster. Using supervised analysis, we further characterized genes significantly associated with lower-stage/treatment-responsive CTCL versus higher-stage/treatment-resistant CTCL. We conclude that transcriptional profiling of CTCL skin lesions reveals clinically relevant signatures, correlating with differences in survival and response to treatment. Additional prospective long-term studies to validate and refine these findings appear warranted.

Acne vulgaris is an extremely common disorder affecting many adolescents and adults throughout their lifetimes. The pathogenesis of acne is multifactorial and is thought to involve excess sebum, follicular hyperkeratinization, bacterial colonization, and inflammation. Many therapeutic options exist for treating acne, including topical benzoyl peroxide, topical and oral antibiotics, topical and oral retinoids, and oral contraceptives. Oral antibiotics have been a mainstay in the treatment of acne for decades and function by exerting an antibacterial effect by reducing the follicular colonization of Propionibacterium acnes. Systemic antibiotics also have anti-inflammatory and immunomodulatory properties. This article reviews the English language literature on the efficacy of various systemic antibiotics for treating acne vulgaris, including second-line and less historically used medications. We discuss the tetracyclines, including subantimicrobial dose doxycycline, macrolides (notably azithromycin), trimethoprim-sulfamethoxazole, cephalosporins, and fluoroquinolones as treatment options for acne vulgaris.