Intratumoral therapies in head and neck squamous cell carcinoma: A systematic review and future perspectives.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) presents an ideal scenario for intratumoral therapies (IT), due to its local recurrence pattern and frequent superficial extension. IT therapies aim to effect tumor regression by directly injecting antineoplastic agents into lesions. However, there is a lack of updated evidence regarding IT therapies in HNSCC. PATIENTS AND METHODS: A systematic literature search (CRD42023462291) was conducted using WebOfScience, ClinicalTrials.gov, and conference abstracts from ESMO and ASCO, identifying for IT clinical trials in patients with HNSCC, from database creation to September 12th, 2023. Efficacy as well as safety (grade ≥ 3 treatment-related adverse events[trAEs]) were reported. RESULTS: After evaluation of 1180 articles identified by the systematic search, 31 studies treating 948 patients were included. IT injectables were categorized as chemotherapies with or without electroporation (k = 4, N = 268), oncolytic viruses, plasmids, and bacteria-based (k = 16, N = 446), immunotherapies and EGFR-based therapies (k = 5, N = 160), radioenhancer particles (k = 2, N = 68), and calcium electroporation (k = 1, n = 6). EGFR-antisense plasmids, NBTXR3 radioenhancer and immune innate agonists show best overall response rates, at 83 %, 81 % and 44 % respectively. Eleven (35 %) studies added systemic therapy or radiotherapy to the IT injections. No study used predictive biomarkers to guide patient selection. 97 % studies were phase I-II. Safety-wise, electroporation and epinephrine-based injectable trials had significant local symptoms such as necrosis, fistula formation and post-injection dysphagia. Treatment-related tumor haemorrhages of various grades were described in several trials. Grade ≥ 3 trAEs attributable to the other therapies mainly comprised general symptoms such as fatigue. There were 3 injectable-related deaths across the systematic review. CONCLUSION: This is the first review to summarize all available evidence of IT in HNSCC. As of today, IT therapies lack sufficient evidence to recommend their use in clinical practice. Continuing research on potential molecules, patient selection, safe administration of injections and controlled randomized trials are needed to assess their added benefit.

Enhanced Insights into Frontal Fibrosing Alopecia: Advancements in Pathogenesis Understanding and Management Strategies.

Frontal fibrosing alopecia (FFA) represents a distinctive form of primary lymphocytic scarring alopecia characterized by fronto-temporal hair recession and eyebrow hair loss. While predominantly affecting postmenopausal women, FFA also occurs in women of reproductive age and men, with variations observed across different ethnic groups. Genetic predisposition, environmental factors and inflammatory pathways contribute to its pathogenesis, with evolving diagnostic criteria enhancing accuracy. FFA treatment lacks standardization, encompassing topical, systemic and physical therapies, while hair transplantation remains a temporary solution. This article reviews the current understanding of FFA, aiming to provide clinicians with updated insights for its management.

Surgical pearl: Modified hypodermic needle and its cap for guarded prick incision.

There are many instruments to prick the comedone before its extraction and scalp during hair transplantation. These instruments are not well guarded, and it can cause deep injury and fear in the patients. Here we described how to guard these needle for safety during procedure.

Systematic Review of Intralesional Therapies for Cutaneous Warts.

Intralesional therapies are used for recalcitrant warts, but no Food and Drug Administration-approved treatment exists nor is there consensus regarding the most efficacious therapy. Therefore, this systematic review aims to summarize efficacy and adverse events reported in 62 randomized controlled trials (RCTs) of intralesional therapies for cutaneous warts. The most studied intralesional therapies included measles, mumps, rubella (MMR) vaccine (n = 24 studies), purified protein derivative (PPD) (n = 19 studies), vitamin D3 (n = 15 studies), and Candida antigen (n = 14 studies). Most studies included adult and pediatric patients or adults alone, with only 4 studies on pediatric patients alone. MMR vaccine was the most studied treatment (n = 853 patients). MMR had a complete response rate of 27-90%. The next most common treatment, PPD, had a complete response rate of 45-87%. Other treatments included Candida antigen and vitamin D3, with complete response rates of 25-84% and 40-96%, respectively. The most frequent side effects were injection-site reactions and flu-like symptoms. This systematic review represents a useful summary of intralesional therapy RCTs for clinician reference. This study also highlights the lack of large multi-institutional RCTs, despite many patients being treated for this widespread problem.

Safety and Effectiveness of Percutaneous Ultrasound-Guided Galvanic Current in Tunnels of Patients with Hidradenitis Suppurativa: A Pilot Study.

INTRODUCTION: The recurrent nature of hidradenitis suppurativa (HS), even under maintained systemic treatment, makes it necessary to have effective local treatments; however, the response to these therapies is variable (44-81%). The application of galvanic current (GC) has demonstrated its utility in humans in treating lesions structurally similar to those of HS. With this background, the main objective of this study was to evaluate the efficacy and safety of ultrasound-guided percutaneous GC in inflamed and/or draining tunnels of HS. METHODS: This was an open study (one-way repeated measures design over time). Patients were evaluated at 4 and 12 weeks after receiving GC. A combined clinical response at week 12 (absence of suppuration/inflammation on examination and clinical interview) was considered the principal variable of efficacy. Adverse effects potentially associated with GC were reported by telephone and at each visit. RESULTS: Twenty-six patients were included, with a male/female ratio of 5:8. The mean age was 35.84 (13.14) years. At 12 weeks after the administration of GC, a complete response was achieved in 77% (20/26) of the treated lesions. No serious adverse effects were observed, and the mean procedural pain assessed by the numeric rating scale was 0.03 (0.2). CONCLUSION: GC has proven to be effective and well tolerated in inflamed and draining tunnels of patients with HS.

Sealing of Follicular Openings in Keloid with Cyanoacrylate Glue for Effective Intralesional Therapy.

Intralesional therapy is a common treatment for keloid. However, because of some follicular openings and comedones on the surface of the keloid on the hairy chest and acne keloidalis, there is a risk of drug leakage, and sometimes ejection of drugs like a jet spray leads to therapy being ineffective. The authors describe a novel and effective method for preventing drug loss from follicular openings during intralesional therapy. To prevent drug loss during intralesional injection, cyanoacrylate glue is applied to the follicular and comedone openings on the keloid's surface.

Intralesional cidofovir for the management of refractory cutaneous verrucae: a review of applications and opportunities.

Viral warts - manifestations of cutaneous infection by human papilloma virus - can be a significant physical and emotional burden for patients when common treatments fail, particularly for individuals who are immunocompromised or with multiple lesions. Cidofovir, an antiviral agent typically used for the treatment of cytomegalovirus infection, has emerged as an alternative treatment option for viral warts when administered topically or intralesionally. In this review, we highlight the scientific rationale, published evidence, and practical clinical uses of intralesional cidofovir for the management of cutaneous warts as well as ongoing questions requiring further research and exploration of this emerging therapy for refractory verrucae.

Advances in Intralesional Therapy for Locoregionally Advanced and Metastatic Melanoma: Five Years of Progress.

Locoregionally advanced and metastatic melanoma are complex diagnoses with a variety of available treatment options. Intralesional therapy for melanoma has been under investigation for decades; however, it has advanced precipitously in recent years. In 2015, the Food and Drug Administration (FDA) approved talimogene laherparepvec (T-VEC), the only FDA-approved intralesional therapy for advanced melanoma. There has been significant progress since that time with other oncolytic viruses, toll-like receptor agonists, cytokines, xanthene dyes, and immune checkpoint inhibitors all under investigation as intralesional agents. Further to this, there has been exploration of numerous combinations of intralesional therapies and systemic therapies as various lines of therapy. Several of these combinations have been abandoned due to their lack of efficacy or safety concerns. This manuscript presents the various types of intralesional therapies that have reached phase 2 or later clinical trials in the past 5 years, including their mechanism of action, therapeutic combinations under investigation, and published results. The intention is to provide an overview of the progress that has been made, discuss ongoing trials worth following, and share our opinions on opportunities for further advancement.

A comparative evaluation of therapeutic response in warts to intralesional vitamin D3 versus intralesional measles, mumps, and rubella vaccine.

The infection of keratinocytes by human papilloma virus (HPV) causes warts. These are of different types based on morphological and anatomical grounds. This has led to the development of strategies involved in the treatment of warts by induction of delayed hypersensitivity reactions. The current study aims to compare the therapeutic response and side effect profile of intralesional vitamin D3 and measles, mumps, and rubella (MMR). The aim of this study is to study the therapeutic response of two intralesional immunotherapies in warts and compare their efficacies and side effects. A single-blind randomized control trial was conducted over 12 months on 100 patients using the purposive sampling technique. Randomly, half of the participants received one of the two immunotherapies. The clinical response was evaluated on the basis of decrease in wart size, wart number, wart distribution, and photographic comparison. The mean size of the largest wart in the vitamin D3 group was found to be 0.70 cm, and in the MMR group, it was 0.79 cm in breadth. The mean onset of first response was 3.55 weeks in the vitamin D3 group and 3.85 weeks in the MMR group. Complete response was seen in 54% and 62% of study participants in the vitamin D3 and MMR groups respectively. The study recommends that both intralesional vitamin D3 and MMR are efficacious in treating cutaneous warts, with MMR agents being moderately better compared to vitamin D3 in terms of warts clearance and side effects profile.

Future Treatments in Melanoma.

Melanoma is a highly malignant tumor that is relatively common in the United States. Surgical extirpation is the mainstay in treatment, but a multimodal therapeutic approach is increasingly important in the era of highly effective immune and targeted therapies. Although resection of melanoma will continue to be the mainstay of management for the conceivable future, improvements in multimodality therapy have and will continue to rewrite the therapeutic playbook for this lethal and increasingly complex malignancy for head and neck surgeons treating patients with melanoma.

Oncolytic viruses in melanoma.

Malignant melanoma recurrence remains heterogeneous in presentation, ranging from locoregional disease (i.e., local recurrence, satellites, in transit disease) to distant dermal and visceral metastases. This diverse spectrum of disease requires a personalized approach to management and has resulted in the development of both local (e.g., surgery, radiation, intralesional injection) and systemic (intravenous or oral) treatment strategies. Intralesional agents such as oncolytic viruses may also evoke local immune stimulation to induce and enhance the antitumor immune response. Further, it is hypothesized that these oncolytic viruses may convert immunologically "cold" tumors to more reactive "hot" tumor microenvironments and thereby overcome anti-PD-1 therapy resistance. Currently, talimogene laherparepvec (T-VEC), a modified herpes virus, is FDA-approved in this population, with many other oncolytic viruses under investigation in both preclinical and trial settings. Herein, we detail the scientific rationale, current landscape, and future directions of oncolytic viruses in melanoma.

Intralesional therapies for vascular malformations of the head and neck.

Vascular malformations of the head and neck represent a spectrum of complex vascular anomalies, requiring a multidisciplinary approach toward diagnosis and treatment. Several intralesional therapeutic agents have been devised and pioneered over the years, some of which are now primary and standard of care for the management of these lesions. In this article, the authors discuss the currently available intralesional therapeutic agents for the management of vascular malformations in the head and neck region.

Debulking followed by intralesional 5-fluorouracil for the treatment of cutaneous squamous cell carcinoma and keratoacanthoma: A retrospective analysis.

Debulking followed by intralesional 5-fluorouracil (deb-IL5FU) is a nonsurgical modality which has been used to treat skin cancer anecdotally for many years. There are few in depth studies examining this technique and success rate of intralesional 5-fluorouracil (IL5FU) for the treatment of cutaneous squamous cell carcinoma (cSCC). To evaluate the response rate of deb-IL5FU for the treatment of cSCC and to determine which patient factors were associated with tumor clearance or treatment failure. A retrospective chart analysis of patients with the diagnosis of cSCC or keratoacanthoma (KA) and subsequent deb-IL5FU treatment. Sixty-one patients with a total of 315 tumors (cSCC and KA), were treated using deb-IL5FU. The overall tumor clearance rate was 89%. This was highest for well-differentiated SCC, SCC, KA-type SCC, and KA. Tumors on the trunk and extremities showed high clearance rates while tumors on the scalp/face/neck/ears showed lower clearance rates. Immunocompetent patients cleared more tumors compared to immunocompromised patients. Limitations included the retrospective nature of this analysis as well as a small sample size. Treatment of cSCC and KA with deb-IL5FU demonstrated high tumor clearance rates. Lower rates of clearance were seen in males, immunosuppressed patients, tumors located on the scalp and face/neck/ears.

Real-World Experience of Talimogene Laherparepvec (T-VEC) in Old and Oldest-Old Patients with Melanoma: A Retrospective Single Center Study.

PURPOSE: Rising melanoma incidences lead to an increasing need for individual therapy strategies in old patients. Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, approved for the local treatment of unresectable metastatic melanoma. Since data on the efficacy and safety of geriatric patients are sparse, this study was conducted to gain further real-world experience in the treatment of old and oldest-old patients with T-VEC and to obtain data on therapy costs in this population in Germany. PATIENTS AND METHODS: We performed a retrospective analysis, including all patients with a minimum age of 75 years who were treated with T-VEC from August 2016 to September 2020 in the Skin Cancer Center of the University Hospital Frankfurt, Germany. Patient clinicopathological data, treatment responses, toxicities, treatment-specific data and therapy costs were assessed. RESULTS: Twelve patients with a median age of 83 years (75-89 years) at the start of treatment were identified. By the end of the study, three (25%) patients experienced complete remission (CR), four (33%) experienced partial response (PR), two patients (17%) remained at stable disease (SD) and three (25%) patients suffered from progressive disease (PD). Overall response rate was 58.3%, and durable response rate was 41.7%. There were no treatment-related adverse events grade 3 or higher. The median duration of treatment was seventeen weeks (3-57 weeks). Median medication costs in the patients who had completed treatment (n=10) were calculated to be 27,325 Euros in Germany. CONCLUSION: This study provides further evidence for an effective use of T-VEC in old and oldest-old patients. The low rate of adverse events seems to be favorable compared to other systemic melanoma therapies. Furthermore, duration of treatment was short and therapy costs were lower than would have been expected from clinical trial data. Altogether, these data encourage the use of T-VEC in this special patient cohort.

Clinical characteristics and therapy response in unresectable melanoma patients stage IIIB-IIID with in-transit and satellite metastases.

INTRODUCTION: Cutaneous melanoma is notorious for the development of in-transit metastases (ITM). For unknown biological reasons, ITM remain the leading tumour manifestation without progression to distant sites in some patients. METHODS: In total, 191 patients with initially unresectable stage III ITM and satellite metastases from 16 skin cancer centres were retrospectively evaluated for their tumour characteristics, survival and therapy response. Three groups according to disease kinetics (no distant progress, slow (>6 months) and fast (<6 months) distant progression) were analysed separately. RESULTS: Median follow-up time was 30.5 (range 0.8-154.0) months from unresectable ITM. Progression to stage IV was observed in 56.5% of cases. Patients without distant metastasis were more often female, older (>70 years) and presented as stage III with lymph node or ITM at initial diagnosis in 45.7% of cases. Melanoma located on the leg had a significantly better overall survival (OS) from time of initial diagnosis compared to non-leg localised primaries (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.40-0.91; p = 0.017), but not from diagnosis of unresectable stage III (HR = 0.67, 95% CI 0.45-1.02; p = 0.06). Forty percent of patients received local therapy for satellite and ITM. Overall response rate (ORR) to all local first-line treatments was 38%; disease control rate (DCR) was 49%. In total, 72.3% of patients received systemic therapy for unresectable stage IIIB-D. ORR for targeted therapy (n = 19) was highest with 63.2% and DCR was 84.2% compared to an ORR of 31.4% and a DCR of 54.3% in PD-1 treated patients (n = 70). Patients receiving PD-1 and intralesional talimogene laherparepvec (n = 12) had an ORR of 41.7% and a DCR of 75%. CONCLUSION: Patients with unresectable ITM and without distant progression are more often female, older, and have a primary on the leg. Response to PD-1 inhibitors in this cohort was lower than expected, but further investigation is required to elucidate the biology of ITM development and the interplay with the immune system.

Contemporary Neoadjuvant Therapies for High-Risk Melanoma: A Systematic Review.

Despite advances in adjuvant immuno- and targeted therapies, the risk of relapse for stage III melanoma remains high. With 43 active entries on clinicaltrials.gov (8 July 2020), there is a surge of interest in the role of contemporary therapies in the neoadjuvant setting. We conducted a systematic review of trials performed in the last decade evaluating neoadjuvant targeted, immuno- or intralesional therapy for resectable stage III or IV melanoma. Database searches of Medline, Embase, and the Cochrane Central Register of Controlled Trials were conducted from inception to 13 February 2020. Two reviewers assessed titles, abstracts, and full texts. Trials investigating contemporary neoadjuvant therapies in high-risk melanoma were included. Eight phase II trials (4 randomized and 4 single-arm) involving 450 patients reported on neoadjuvant anti-BRAF/MEK targeted therapy (3), anti-PD-1/CTLA-4 immunotherapy (3), and intralesional therapy (2). The safest and most efficacious regimens were dabrafenib/trametinib and combination ipilimumab (1 mg/kg) + nivolumab (3 mg/kg). Pathologic complete response (pCR) and adverse events were comparable. Ipilimumab + nivolumab exhibited longer RFS. Contemporary neoadjuvant therapies are not only safe, but also demonstrate remarkable pCR and RFS-outcomes which are regarded as meaningful surrogates for long-term survival. Studies defining predictors of pCR, its correlation with oncologic outcomes, and phase III trials comparing neoadjuvant therapy to standard of care will be crucial.

Conservative Therapy for Peyronie's Disease: a Contemporary Review of the Literature.

PURPOSE OF REVIEW: To analyze the literature on current conservative treatment options for Peyronie's disease (PD). RECENT FINDINGS: Conservative therapy with intralesional collagenase clostridium histolyticum (CCH) is safe and efficacious in either the acute or chronic phases of PD. Combination treatment with penile traction therapy (PTT) can produce even better results. While most PTT devices require extended periods of therapy up to 8 h per day, the RestoreX® device can be effective at 30-90 min per day. A variety of conservative therapies are available for treatment of PD. The available literature does not reveal any treatment benefit of oral therapies. Intralesional therapy is the mainstay conservative treatment of PD. Intralesional CCH therapy is the first Food and Drug Administration-approved intralesional therapy and represents the authors' preference for medical therapy. The most effective conservative management of PD likely requires a combination of therapies.

A retrospective cohort study of the effectiveness and adverse events of intralesional pentavalent antimonials in the treatment of cutaneous leishmaniasis.

INTRODUCTION: The standard therapy for American cutaneous leishmaniasis (ACL) is intravenous meglumine antimoniate (IV-MA). However, treatment interruptions due to adverse events (AEs) and non-adherence are frequent. Consequently, intralesional MA (IL-MA) was proposed. OBJECTIVE: This study examined the effectiveness of and AEs associated with IL-MA. METHODS: We performed a retrospective cohort study of 240 patients with ACL. We excluded patients with mucous lesions and disseminated leishmaniasis and those who received treatment in the previous 6 months. We considered protocol treatments as the main risk factors. IL-MA was performed using a subcutaneous injection of MA in a volume sufficient to elevate the lesion base (approximately 1 mL/cm2 of lesion area) once weekly for 1-8 weeks. IV-MA was performed via intravenous injections of MA at a dosage of 10-20 mg Sb5+/kg/day for 20 days. The primary outcome was defined as a lesion cure 3 months after treatment, and AEs were secondary outcomes. RESULTS: Seventy-three patients were included. The IL-MA group consisted of 21 patients, and the IV-MA group consisted of 52 patients. The IL-MA group was older, had more comorbidities and more previous unsuccessful treatment of ACL. The antimonial dose was significantly lower in this group. The cure rate for IL-MA was 66.7%, which was lower than that in the IV-MA group (relative risk (RR) = 0.68, 95% CI: 0.50-0.92, p < 0.001), while the rate of AEs was similar. Female sex (RR = 1.16, 95% CI: 1.02-1.33), lesion diameter ≤1 cm (RR = 1.25, 95% CI: 1.00-1.56) and treatment with IV-MA (RR = 1.43, 95% CI: 1.06-1.93) were independently associated with achieving a cure. Comorbidities (RR = 1.7, 95% CI: 1.06-2.98) were independently associated with AEs. CONCLUSIONS: Patients of IL-MA group were older, had more comorbidities and more previous unsuccessful treatment of ACL. Nevertheless, IL-MA had a cure rate of 66.7%, and it was useful in this context. A prospective randomized trial is recommended.

Infantile Hemangioma: A Review of Current Pharmacotherapy Treatment and Practice Pearls.

Infantile hemangioma (IH) is the most common vascular tumor of infancy, affecting as many as 5% to 10% of all infants. The exact cause is unclear, but specific risk factors, such as low birth weight, prematurity, female sex, white race, and family history are associated with IH development. Most IHs are benign and self-resolving, but a small subset of patients with IHs are at risk of severe or life-threatening outcomes. Systemic and topical ß-blockers are effective and safe for use in pediatric patients and considered first-line treatment for both complicated and uncomplicated IHs. Recently published guidelines provide a thorough review of IH and management. This article focuses on IH pharmacotherapy and provides practice pearls to support health care providers in IH medication management.