Photodynamic therapy for solid tumors: A review of the literature.

Photodynamic therapy (PDT) utilizes a sensitizer agent and light to produce selective cell death. Dermatologists are familiar with PDT for the treatment of actinic keratoses and early nonmelanoma skin cancers, and recent studies have elucidated that PDT has resulted in improved morbidity and secondary outcomes for the treatment of various cancerous and precancerous solid tumors. Light source and dosimetry may be modified to selectively target tissue, and novel techniques such as fractionation, metronomic pulsation, continuous light delivery, and chemophototherapy are under investigation for further optimization of therapy. This article aims to review the expanding indications for PDT and demonstrate the potential of this modality to decrease morbidity and increase quality of life for patients. To illustrate these new indications, we provide a focused review of the latest literature on PDT for dermatologic and other solid tumors including gastrointestinal, peritoneal, lung, genitourinary, brain, breast, and head and neck. Data on efficacy, survival, and side effects vary across tumor types but support PDT for the treatment of numerous solid tumors. With new advances in PDT, indications for this therapeutic modality may expand.

A Prospective, Randomized, Single-Blind Study Comparing Cyanoacrylate Adhesives to Sutures for Wound Closure in Skin Cancer Patients.

BACKGROUND: Cyanoacrylate tissue adhesives are not more likely to result in wound dehiscence or infection than sutured closures. However, suturing is the gold standard for optimal cosmetic appearance of scars. OBJECTIVE: To determine whether cyanoacrylate tissue adhesives produce a cosmetic outcome equivalent to sutures at 3 months. Secondary outcomes include time for wound closure, time spent on wound care, and surgeon and patient satisfaction. MATERIALS AND METHODS: Seventy-one patients scheduled for skin cancer excision at Beverly Hospital were included in this prospective, randomized, single-blind study. Cosmetic appearance was assessed by a masked panel of dermatologists and plastic surgeons who evaluated digital photographs. Secondary outcomes were assessed by nursing recordings and patient and surgeon evaluations. RESULTS: There was no significant difference in wound appearance (Visual Analog Scale: p = .4693, modified Hollander Wound Evaluation Score: p = .6413) between adhesives and sutures. It was faster and easier for a surgeon to use adhesives, and subjects spent less time caring for and were more satisfied by wounds sealed with adhesives than sutures. CONCLUSION: Cyanoacrylate tissue adhesives produce cosmetic outcomes that are not statistically significantly different than sutures; furthermore, they are associated with fast application, easy wound care, and patient satisfaction.

Efficacy and safety of continuous low-irradiance photodynamic therapy in the treatment of chest wall progression of breast cancer.

BACKGROUND: Photodynamic therapy (PDT) is a binary therapy using a drug and high-energy light source. PDT is approved for several premalignant and malignant conditions. Recent in-vitro and animal data suggest that enhanced tumor-specific cytotoxicity can be achieved with far less collateral damage to normal surrounding tissues if PDT is administered continuously at a lower dose rate for extended periods of time. Based on these promising preclinical data, we conducted a Phase I clinical trial of continuous low-irradiance photodynamic therapy (CLIPT) using 630 nm laser energy and intravenously administered porforin sodium as the photosensitizer. We determined the maximum tolerated dose (MTD) of CLIPT on skin and tumor response in subjects with cutaneous and subcutaneous metastatic nodules who had failed radiation and surgery. METHODS: Patients with cutaneous and/or subcutaneous metastatic nodules that had failed radiation and surgery were offered enrollment into the trial. The initial study design planned for sequential cohorts of six subjects to be treated at increasing laser intensity, starting at 100 J/cm(2) administered continuously over 24 h (10(-2) dose rate compared with standard PDT). Dose-limiting toxicity was defined as partial or full-thickness necrosis of the surrounding tumor-free, previously irradiated skin. The MTD was defined as the highest laser energy at which ≤33% of subjects experienced the dose-limiting toxicity. Subjects received intravenous porfirmer sodium 0.8 mg/kg 48 h before commencing CLIPT. Response rates and quality of life measures were assessed. RESULTS: Nine subjects were enrolled with chest wall progression of breast cancer following mastectomy. All had failed prior surgery and electron-beam radiation therapy. The initial two subjects were treated at 100 J/cm(2) and developed partial thickness skin necrosis. Dose reduction was therefore instituted, and the next cohort was treated at 50 J/cm(2). None of the subsequent seven subjects suffered partial or full thickness necrosis, thus establishing the MTD at 50 J/cm(2) over 24 h (0.5 mW irradiance). Six of the nine subjects (67%) had either a complete or partial clinical response. Of note, two subjects had significant regression of tumor nodules distant from the treatment field. Of the eight subjects whose terminal deoxynucleotidyl transferase dUTP nick end labeling assay results were available, 8 (100%) demonstrated histologic response to treatment as evidenced by either tumor apoptosis or regression. Quality of life measures were improved following treatment-particularly bleeding and pain from the tumor nodules. CONCLUSIONS: The MTD of CLIPT was established at 50 J/cm(2) administered continuously over 24 h. These preliminary data suggest CLIPT may be an effective, low-morbidity therapeutic modality in the treatment of cutaneous and subcutaneous metastases of breast cancer following mastectomy. Further evaluation in a larger cohort is warranted to better assess efficacy and optimize the intervention.

Plasmonic photothermal heating of intraperitoneal tumors through the use of an implanted near-infrared source.

Plasmonic nanomaterials including gold nanorods are effective agents for inducing heating in tumors. Because near-infrared (NIR) light has traditionally been delivered using extracorporeal sources, most applications of plasmonic photothermal therapy have focused on isolated subcutaneous tumors. For more complex models of disease such as advanced ovarian cancer, one of the primary barriers to gold nanorod-based strategies is the adequate delivery of NIR light to tumors located at varying depths within the body. To address this limitation, a series of implanted NIR illumination sources are described for the specific heating of gold nanorod-containing tissues. Through computational modeling and ex vivo studies, a candidate device is identified and validated in a model of orthotopic ovarian cancer. As the therapeutic, imaging, and diagnostic applications of plasmonic nanomaterials progress, effective methods for NIR light delivery to challenging anatomical regions will complement ongoing efforts to advance plasmonic photothermal therapy toward clinical use.

Surgical corner: a prospective randomized evaluation of cyanoacrylate glue devices in the closure of surgical wounds.

BACKGROUND: The use of medical adhesives for topical wound closure is gaining in popularity over conventional wound closure materials such as sutures and staples. Adhesives provide advantages in both wound closure and patient management with good cosmetic outcome and surgeon and patient satisfaction reported. OBJECTIVE: To compare the use of two currently marketed medical adhesives; LiquiBand® Flow Control and High Viscosity Dermabond ™ for the topical closure of surgical incisions. METHODS: In a prospective blinded manner, subjects were randomly assigned LiquiBand® or DermabondTM for topical closure of a surgical incision. Variables compared included ease of use, time taken to close wound, subject and surgeon satisfaction with device and wound closure, cosmetic outcome at 90 days, and complication rates. RESULTS: Use of both devices resulted in effective wound closure with similar high levels of cosmesis subject and surgeon satisfaction, with only minor complications reported. There was no statistically significant difference between the devices for all the parameters studied, with the exception that the Liquiband device was found to significantly reduce the amount of time required for closure. CONCLUSION: As the two devices appear substantially equivalent in terms of key surgeon and patient variables, product cost should be the primary determinant in selection of the tissue glue device.

Atypical (dysplastic) nevi: outcomes of surgical excision and association with melanoma.

OBJECTIVE: To evaluate the effect of surgical excision, performed after biopsy diagnosis of dysplastic nevus, on final diagnosis, melanoma prevention, and melanoma detection. DESIGN, SETTING, AND PARTICIPANTS: Outcome study using retrospective review conducted in an academic dermatopathology practice (Boston Medical Center Skin Pathology Laboratory) that receives specimens from community and academic practices across the United States. Consecutive patient pathology samples of dysplastic nevi and cutaneous melanomas evaluated between September 1, 1999 and March 1, 2011, and identified using systematized nomenclature of medicine codes were included. MAIN OUTCOMES AND MEASURES: In dysplastic nevi cases, the rate of clinically significant change in diagnosis and the rate of melanoma detection as a result of excision. In melanoma cases, the rate and characteristics of association with dysplastic nevus. RESULTS: Of dysplastic nevi, 196 of 580 (34%) showed a positive biopsy margin, increasing with grade of atypia (P < .001); 127 of 196 with positive biopsy margin received excision (65%), performed more often as grade of atypia increased (P < .001). Two excisions (2 of 127, 1.6%) resulted in a clinically significant change in diagnosis, from biopsy-diagnosed moderately-to-severely dysplastic nevi before excision to melanoma in situ after excision. In melanomas (n = 216), in situ and superficial spreading subtypes were more often associated with dysplastic nevi (20% and 18%, respectively) (P = .002), most often of moderate-to-severe or severe grade. CONCLUSIONS AND RELEVANCE: Excision of biopsy-diagnosed mildly or moderately dysplastic nevi is unlikely to result in a clinically significant change in diagnosis, and risk of transformation to melanoma appears very low. Moderately-to-severely and severely dysplastic nevi are more often associated with melanoma, and excision may be beneficial for melanoma detection or prevention.

Common complementary and alternative therapies with potential use in dermatologic surgery: risks and benefits.

BACKGROUND: Ambulatory surgery patients often use complementary and alternative medicine (CAM) therapies. CAM therapies may create beneficial and detrimental perioperative conditions. OBJECTIVE: We sought to improve knowledge of CAM effects in dermatologic surgery, allowing dermatologists to potentially capitalize on therapeutic actions and to mitigate complications. METHODS: PubMed literature search of CAM therapies in dermatologic and surgical settings was performed. Common CAM therapies with possible effects on dermatologic surgery were selected. Beneficial and detri-mental effects were reviewed. RESULTS: A myriad of products may be used perioperatively by the patient. Therapies appearing to have some evidence for potential benefit include bromelain, honey, propolis, arnica, vitamin C and bioflavonoids, chamomile, aloe vera gel, grape seed extract, zinc, turmeric, calendula, chlorella, lavender oil, and gotu kola. Potential complications vary according to product and include platelet inhibition, contact dermatitis and, in rare cases, systemic toxicity. LIMITATIONS: This review focuses on CAM having significant published studies evaluating efficacy for wound healing, anti-inflammatory, antipurpuric, or perioperative-related use. Most published studies have been small and often have design flaws. The scope of CAM is large and not all therapies are discussed. CONCLUSION: Selected CAM therapies have been reported to promote wound healing, reduce edema or purpura, and provide anti-inflammatory effects. Because of high rates of CAM use, surgeons should familiarize themselves with common uses, potential benefits, and complications. Further study of effects in the dermatologic surgery setting may improve the patient-doctor relationship and enhance outcomes.

Continuous low-irradiance photodynamic therapy: a new therapeutic paradigm.

A principal factor in determining the biologic consequences of photodynamic therapy (PDT) is the light fluence rate. Preclinical and, more recently, clinical studies have focused on low-irradiance schemes, suggesting that prolonged light exposure, better known as CLIPT (continuous low-irradiance PDT), may improve tumor control while reducing morbidity. After a brief look at the origin of light therapy and photosensitizers, this article turns to the promising animal research supporting the use of low- and ultra-low fluence rate PDT, which serves as the basis of the ongoing CLIPT dosimetry trials for patients with chest wall progression of breast cancer. The future of CLIPT seems to be a home-based therapy using a portable, self-contained energy delivery system.

Incidence of invasive squamous cell carcinomas in biopsy-proven squamous cell carcinomas in situ sent for Mohs micrographic surgery.

BACKGROUND: Squamous cell carcinoma (SCC) in situ (SCCIS) is often treated without any pathologic confirmation of tumor clearance. It is unclear how often an invasive SCC is harbored within a lesion in which the initial biopsy demonstrated SCCIS because of inadequate sampling. This study examines the final histologic diagnosis of cases in which the initial biopsies were diagnosed as SCCIS and evaluates factors that may correlate with a histologic upstaging of the diagnosis. METHODS: We prospectively recruited 29 consecutive patients with biopsy-proven SCCIS sent for Mohs micrographic surgery (MMS). Each tumor underwent MMS, and the central blocks of the Mohs debulking specimens were horizontally sectioned at 30-µm intervals until exhausted. A fellowship-trained Mohs surgeon and a board-certified dermatopathologist processed and examined these sections to determine the final histologic diagnosis of the tumor. RESULTS: Of the 29 subjects with biopsy-proven SCCIS, nine were found to harbor invasive SCC on final histology. Of the remaining lesions, seven had residual SCCIS, whereas the rest exhibited only actinic keratoses or scars. Approximately 31% of lesions showed evidence of invasive SCC. Correlating the clinical characteristics of the lesions with their corresponding final histologic diagnoses, the lesions harboring invasive SCC were more likely to demonstrate clinical signs of residual tumor (scales and papular changes) and be larger than 1.4 cm in diameter. LIMITATIONS: Our experience at a single institution in the northeastern United States may not be reflective of a wider population. There is also a possible referral bias, because only lesions with high clinical suspicion for invasive SCC were referred for MMS. CONCLUSION: Although biopsy-proven SCCIS is often treated with modalities that are best suited for superficial disease and do not involve a final pathologic confirmation of clearance (e.g., cryotherapy, electrodesiccation and curettage), this study demonstrated that up to 31% of biopsy-proven SCCIS lesions may harbor invasive SCC. Clinical signs of residual tumor and a diameter larger than 1.4 cm are statistically significant predictors of underlying invasive SCC. These data suggest that treatment modalities that include histologic control of tumor removal should also be strongly considered for the treatment of select biopsy-proven SCCIS meeting the above criteria.

A randomized, prospective trial evaluating surgeon preference in selection of absorbable suture material.

This study is the first double-blinded, randomized comparison of two absorbable sutures. To better understand product characteristics and surgeon preference, we conducted a study of two similar-appearing FDA-approved sutures, glyconate and poliglecaprone 25. Four dermatologic surgeons were enlisted. A total of 48 patients with 53 surgical sites were examined. One half of each surgical wound was closed with one type of suture and the other half with the other type. Each half was evaluated for product characteristics. There was no statistically significant difference in surgeon preference for glyconate versus poliglecaprone 25 (P=0.64). Of the cohort preferring poliglecaprone 25, there was a correlation with speed of closure (P=0.06). Of the surgeons that preferred glyconate, we found significantly better visibility (P=0.03), reduced suture breakage during knot tying (P=0.05), and correlation with better handling properties (P=0.06) associated with that preference. The data from this study will enable products to be designed towards these needs and allow surgeons to select sutures that more precisely fit their particular requirements.

Superficial acral fibromyxoma: an overview.

Superficial acral fibromyxoma is a rare, slow-growing soft tissue tumor, which is commonly located in the periungual and subungual regions of the fingers and toes in adults. To date, fewer than 50 cases have been reported worldwide. Microscopic examination reveals a moderately circumscribed, nonencapsulated tumor situated in the dermis, which may also extend into the subcutis. The neoplasm consists of a moderately cellular proliferation of stellate and spindle-shaped fibroblast-like cells embedded in a myxocollagenous stroma. Mast cells are easily identified throughout this lesion. Multinucleated stromal cells may also be present, but nuclear atypia and mitotic figures are rare. The tumor shows immunoreactivity for CD34, epithelial membrane antigen, CD99, and less frequently, CD10. Superficial acral fibromyxoma has a benign behavior but may persist or recur if inadequately excised. Therefore, complete excision and close follow-up are advised.

The operative management of melanoma: where does Mohs surgery fit in?

BACKGROUND: Melanoma is a life-threatening malignancy. Surgery is the primary management for melanoma, and management guidelines have evolved gradually over a century from radical surgery with lymph node dissection to conservative margin surgery. There are specific rationales and problems with Mohs micrographic (MMS) surgery for managing melanoma. OBJECTIVE: To review the literature for the surgical management of melanoma and to understand where MMS fits in this spectrum of management options. CONCLUSIONS: MMS should be considered as an option for melanoma surgery, especially when the tumor is found in photodamaged skin. Further randomized prospective clinical trials are needed to select the best therapeutic approach for the treatment of melanoma. Until then, careful margin control is the key for successful tumor removal whether it is standard excision, staged excision, or MMS.

Novel 16-minute technique for evaluating melanoma resection margins during Mohs surgery.

BACKGROUND: Immunohistochemistry (IHC) applied to Mohs micrographic surgery (MMS) is time consuming and labor intensive, and the variability of staining quality has prevented its widespread use in clinical practice. OBJECTIVE: To investigate the readability of immunostains processed by a novel automated 16-minute technique used for evaluation of frozen sections prepared during MMS for melanoma. METHODS: A rapid automated instrument that performs MART-1 (melanoma antigen recognized by T cells) immunostains in 16 minutes was used to stain frozen sections and was compared with MART-1 stains of paraffin (permanent) sections, hematoxylin-eosin (H&E) stains of frozen and permanent sections from the positive or negative control specimens of the Mohs layers for melanoma. A total of 480 interpretations from 48 sections (4 types of stains for each specimen, 12 specimens read by 10 interpreters) were analyzed via blinded examination by 5 dermatopathologists and 5 Mohs surgeons at two institutions. A scoring system was used to assess the readability of each slide. Analysis of variance was used for statistical analysis. RESULTS: In terms of clarity of interpreting melanoma sections, the 16-minute MART-1 IHC of frozen sections is equivalent to the standard MART-1 of permanent sections. The 16-minute MART-1 sections are also significantly easier to interpret than permanent sections stained with H&E for both the dermatopathologists and Mohs surgeons (P < .05). LIMITATIONS: The study represents data collected from only two institutions in the United States. CONCLUSION: The rapid-stained frozen IHC sections are significantly easier to interpret than the "gold standard" permanent sections stained with H&E. This technology facilitates the rapid interpretation of melanoma in frozen sections.

Perineural invasion of cutaneous squamous cell carcinoma and basal cell carcinoma: raising awareness and optimizing management.

BACKGROUND: Perineural invasion (PNI) by cutaneous squamous cell carcinoma (CSCC) and basal cell carcinoma (BCC) is an infrequent but not rare complication of traditionally low-morbidity skin cancers that can lead to catastrophic sequelae; 2.5% to 14% of CSCC and approximately 3% of BCC exhibit PNI. Tumors with PNI tend to be larger, have greater subclinical extension, have a higher rate of recurrence, and have a greater risk of metastases. Tumors with PNI may result in major neurologic deficits. OBJECTIVE: To review current recommendations for the management of PNI and to evaluate a treatment strategy involving excision using Mohs micrographic surgery (MMS) followed by adjunctive radiotherapy. MATERIALS AND METHODS: Cases of PNI treated with MMS and radiotherapy were reviewed for recurrence, disease-free follow-up, and adverse events. RESULTS: Twelve patients with incidental PNI treated with MMS and adjunctive radiotherapy are presented. After 3 to 32 months of follow-up, there had been no recurrences. Adverse events from radiotherapy were minor and self-limited. CONCLUSIONS: The use of adjunctive radiotherapy in these patients remains controversial. When managing superficial skin tumors with PNI, a multidisciplinary team including a cutaneous surgeon and a radiation oncologist familiar with PNI is recommended.

Prospective, randomized, blinded study of a new wound closure film versus cutaneous suture for surgical wound closure.

BACKGROUND: Wound closure devices include sutures, tissue adhesives, adhesive strips, and staples. Recent studies suggest no differences between various tissue adhesives and sutures for dehiscence, infection, and satisfaction when assessed by patients or surgeons. To date, no studies have investigated ClozeX, a novel adhesive strip, for closure of surgical incisions. OBJECTIVE: To compare surgical wounds repaired with ClozeX versus suture. METHODS: A prospective, randomized study was conducted, in which 15 patients with surgical incisions were allocated to closure with ClozeX on half of the wound and monofilament suture on the other half. Physician satisfaction with blinded assessment, patient satisfaction, complication rates, and closure times were recorded. RESULTS: Application with ClozeX was faster than with suture (p=.007). There were no complications in either group. Sixty-nine percent of the patients gave ClozeX a higher satisfaction score (p=.02). More physicians were satisfied with the ClozeX half than with the suture half (p=.007). CONCLUSIONS: This pilot study demonstrates ClozeX to be a safe and effective closure device. The cosmetic outcome seems to be at least as good as simple running suture. Physicians and patients were generally more satisfied with ClozeX. No difference was found in the rate of dehiscence or infection between the groups.

Clinical recognition of actinic keratoses in a high-risk population: how good are we?

BACKGROUND: Actinic keratoses (AKs) are dysplastic epidermal lesions considered to be potential precursors of squamous cell carcinoma. Most AKs are diagnosed clinically and are rarely confirmed histologically. High interobserver variation exists among dermatologists for the diagnosis of AKs. Previous studies of the positive predictive value of the diagnosis of AKs have yielded rates as high as 94%. This study evaluates the rate at which histologic analysis confirms the clinical impression (positive predictive value) of AKs in patients with a history of skin cancer. OBSERVATIONS: Seventeen (74%) of 23 lesions with classic features of AKs, as determined by 3 dermatologists, were confirmed as AKs histologically. These were lesions that would ordinarily not be biopsied. Of the 6 misdiagnoses, 5 (83%) were skin cancer, most often squamous cell carcinoma. CONCLUSIONS: The positive predictive value of 74% for the diagnosis of AKs in this study is substantially lower than that of 2 previous studies, suggesting that physicians may be misdiagnosing many patients with classic features of AKs. Most misdiagnosed cases were forms of skin cancer. These preliminary data suggest that the threshold for biopsy of suspect lesions in patients with a history of skin cancer should be low and warrant further evaluation.

Excision of malignant melanoma overlying a pacemaker.

BACKGROUND: With the increasing number of patients with implantable cardiac devices, dermatologic surgeons must be increasingly familiar with the types of devices and potential interference by surgical procedures. OBSERVATIONS: We report the excision of a 1 cm malignant melanoma in situ occurring on the skin directly overlying the patient's pacemaker. CONCLUSIONS: Successful excision of malignant lesions in the setting of implantable cardiac devices requires an understanding of pacemaker implantation anatomy following well-established guidelines for electrosurgery in the setting of implantable cardiac devices and careful coordination with cardiac and anesthesia specialists.