Skin Cancer Centers Research Articles

Quality of life under treatment with the immune checkpoint inhibitors ipilimumab and nivolumab in melanoma patients. Real-world data from a prospective observational study at the Skin Cancer Center Kiel

PurposeCombined immunotherapy (ipilimumab + nivolumab) has improved survival in stage IV melanoma patients, making Health-related Quality of Life (HrQoL) crucial due to potential immune-related adverse events (irAEs). Previous studies treated HrQoL as secondary/explorative endpoint, and no specific HrQoL questionnaire for melanoma patients on immune checkpoint inhibitor (ICI) therapy exists. This study aimed to gather specific HrQoL data during combined ICI therapy, tracking changes during and after treatment, and examining associations with gender, irAEs, and treatment response.Methods35 melanoma patients (22 males, 13 females) undergoing combined ICI were surveyed using the Short-form 36 questionnaire (SF-36), the Inflammatory Bowel Disease Questionnaire – Deutsch (IBDQ-D), and the distress thermometer (DT). HrQoL was evaluated during treatment, after six months, and at the onset of autoimmune colitis.ResultsirAEs occurred in 51.4% of patients, with colitis being the most common (26.1%). 45.7% had progressive disease. SF-36 showed stable HrQoL during treatment and follow-up. Women had worse HrQoL on the physical component scale than men (p = 0.019). Patients with progression showed worse HrQoL over time in physical (p = 0.015) and mental health scales (p = 0.04). IBDQ-D showed constant HrQoL throughout treatment and follow-up. Distress on DT remained constant, with women reporting higher levels of distress.ConclusionHrQoL remained stable during and after therapy. Female gender and disease progression negatively impacted HrQoL. The development of irAEs was not associated with HrQoL, though this may not apply to severe irAEs like colitis, which were not assessed.

Palliative care in dermatooncology - Current practice in German dermatooncological centers and specialist offices.

Dermato-oncology patients are often treated in certified skin cancer centers or dermato-oncological specialist offices. Especially in higher tumor stages, patients develop symptoms, either disease-related or due to therapy-related side effects, requiring treatment. Despite a markedly improved prognosis since the introduction of targeted therapies and immunotherapies, advance care planning is required in progressive disease. It is unclear how palliative care of skin cancer patients is currently organized in dermato-oncology. In a nationwide survey, all certified skin cancer centers and dermato-oncological specialist offices in Germany were contacted and asked to participate in this anonymized survey. Overall, 45 responses (42%) were received. The majority (98%) of the respondents screen the patients on a regular basis for distressing symptoms, and all centers are connected to palliative medical care providers. Only 5% of the medical staff members have the additional qualification "palliative medicine". In 68% of the participating institutions, the opportunity for care planning is offered to patients. For 89%, palliative care is relevant for everyday work, and 82% desire more research opportunities on this topic. This survey has shown that palliative care plays a major role in dermato-oncological work. Given that only a small proportion of the staff have received specialized training in palliative care, however, an increase of this proportion would be desirable for comprehensive care.

Differential predictive value of tissue-specific PD-L1 expression scores in adjuvant immunotherapy of melanoma.

Adjuvant treatment of stage II-IV melanoma with PD-1-based immune checkpoint inhibitors (ICI) has improved relapse-free survival (RFS) and has therefore become a standard-of-care treatment option. Approximately 25%-30% of patients still recur within 1 year. Predictive biomarkers reflecting real-world data are desired. The predictive relevance of tumour tissue PD-L1 expression in the adjuvant setting remains inconclusive. This retrospective, observational study was conducted to evaluate the value of PD-L1 expression scores in different tumour tissue locations in predicting response towards adjuvant immunotherapeutic treatment. Tumour tissue taken prior to anti-PD-1 adjuvant ICI in 243 stage II-IV melanoma patients was collected at University Skin Cancer Center Hamburg. PD-L1 expression was evaluated on immune cells (ICS), tumour cells (TPS) and combined (CPS). Scores were determined by independent pathological physician quantification and correlated with therapy outcome at different cut-off (CO) levels (relapse-free survival, RFS) for different tumour tissue locations (primary tumour, metastases). A total of 104 patients were eligible for analysis. Positivity of ICS, TPS and CPS showed no predictive RFS outcome association at different CO levels when analysed irrespective of tissue origin. In primary tumours, ICS at CO 1% showed a significantly improved RFS upon positivity (HR 0.22). In contrast, positivity to TPS (CO 1%) correlated significantly and independently with improved RFS when evaluated in metastatic tumour tissue specimens (HR 0.37). PD-L1 tumour tissue expression may serve as a predictive biomarker for adjuvant ICI treatment response stratification in melanoma, but caution should be spent on the origin of tumour tissue analysed. The cell-type relevant for the predictive value of PD-L1 expression is tissue-specific with immune cells being important in primary tumours while tumour cells are key in metastases. The present results should be validated in a multicentre cohort.

Preferences of physicians for treatment-related toxicity vs. recurrence in melanoma (GERMELATOX-A): the doctors’ perspective

IntroductionAdjuvant treatment with immune checkpoint inhibitors, such as PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT), has shown a significant improvement in disease-free survival (DFS) for high-risk melanoma patients. However, due to specific side effects, the choice of treatment is often influenced by the risk of toxicity. Therefore, the role of physicians in treatment decisions of patients is crucial. This study investigated for the first time in a multicenter setting the attitudes and preferences of dermatooncologists in Germany and Switzerland regarding adjuvant treatment with (c)ICI and TT.MethodsIn the GERMELATOX-A study, 108 physicians (median age: 32 yrs, 67.6% female) from 11 skin cancer centers were surveyed to rate typical side effect scenarios of (c)ICI and TT treatments and then compared to patients’ ratings evaluated in a previous analysis from the same centers. The scenarios described mild-to-moderate or severe toxicity and included melanoma relapse leading to death. The physicians were asked about the level of side effects they would tolerate in exchange for a reduction in melanoma relapse and an increase in survival at 5 years.ResultsThe preferences of physicians and patients revealed significant differences regarding adjuvant melanoma treatment with (c)ICI and TT (p < 0.05). Compared to patients, physicians tend to value a melanoma relapse less severe, according to a visual analog scale. They were also less threatened by all scenarios of side effects during adjuvant treatment with (c)ICI or TT, compared to patients. Physicians required lower risk reductions for disease-free survival (DFS) and overall survival (OS) for both ICI and TT and their drug-related side effects to accept these treatments. In case of severe side effects, physicians required similar 5-year DFS rates for ICI and TT (60–65%), while patients needed a 15% improvement of 5-year DFS for ICI compared to TT (80%/65%). For survival, physicians expected an OS improvement of + 10% for all three treatment modalities, whereas patients required a higher increase: + 18–22% for ICI and + 15% for TT.ConclusionOur study highlights the importance of understanding the patient’s perspective and a potential difference to the doctor’s view when making decisions about adjuvant melanoma treatment with (c)ICI and TT, especially as these treatments are increasingly being implemented in earlier stages.

Outpatient psychosocial screening in askin cancer center: acceptance, psychosocial distress and utilization of support : Aposthoc analysis in aquality management program

Psychosocial care of cancer patients is an important aspect throughout the entire course of oncological treatment. Since 2015, psychosocial screening has been implemented in the outpatient clinics of the Skin Cancer Center in Freiburg. We present here apost hoc analysis in the context of aquality management program. Acceptance, psychosocial distress and desire for counseling were evaluated. Exploratively, we investigated which patient and disease characteristics are related to increased subjective distress. In afull survey from 06/2015 to 12/2015, we evaluated acceptance, psychosocial distress by distress thermometer (DT), and desire for counseling. Of 753 patients, 345 (45.8%) participated in psychosocial screening and data from 310 (174men, 136women; 89.7% melanoma patients, mean time since initial diagnosis 4.7 ± 3.9years) could be analyzed. The mean burden on the DT was 2.97 ± 2.83 (median2, range 0-10). High distress (DT ≥ 5) was reported by 84patients (28.8%). Thirty-four patients (11%) indicated adesire for counseling, and 23patients took up the counseling offer. The patient group with high distress was younger, more often under ongoing or recently completed systemic therapy, and had more often adesire for counseling. In addition to assessing psychosocial distress with validated screening instruments, the survey of the subjective desire for care represents an important parameter for the identification of patients in need of care. Young patients and patients with ongoing systemic therapy should be the focus of attention.

Hydrochlorothiazide and increased risk of atypical fibroxanthoma and pleomorphic dermal sarcoma.

Previous work has demonstrated that hydrochlorothiazide (HCTZ) is a risk factor for squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) due to pro-photocarcinogenic effects. Atypical fibroxanthoma (AFX) and pleomorphic sarcoma (PDS), both ultraviolet-induced cancers, display a rare but rising cutaneous tumor entity. This study aimed to evaluate if the use of HCTZ is higher in patients with AFX/PDS than in patients with SCC/BCC and subsequently may be a risk factor for AFX/PDS-development. In a retrospective study of four German skin cancer centers, AFX/PDS cases and SCC/BCC controls were sex and age matched (1:3) over a time-period of 7years (2013-2019) to evaluate the use of HCTZ, immunosuppressive medication, second malignancies, and presence of diabetes mellitus. Overall, 146 AFX/PDS and 438 controls (SCC/BCC) were included in the study. The use of HCTZ was significantly higher in patients with AFX/PDS (44.5%) compared to patients with SCC/BCC (25.3%). Additionally, the presence of diabetes mellitus was significantly higher in AFX/PDS patients. This study demonstrates a significantly higher use of HCTZ in patients with AFX/PDS compared to SCC/BCC. This result suggests that HCTZ may be a risk factor for AFX/PDS. Additionally, diabetes mellitus or its comorbidities may be associated with an increased risk for AFX/PDS.

Digital decision support for structural improvement of melanoma tumor boards: using standard cases to optimize workflow

PurposeChoosing optimal cancer treatment is challenging, and certified cancer centers must present all patients in multidisciplinary tumor boards (MDT). Our aim was to develop a decision support system (DSS) to provide treatment recommendations for apparently simple cases already at conference registration and to classify these as “standard cases”. According to certification requirements, discussion of standard cases is optional and would thus allow more time for complex cases.MethodsWe created a smartphone query that simulated a tumor conference registration and requested all information needed to provide a recommendation. In total, 111 out of 705 malignant melanoma cases discussed at a skin cancer center from 2017 to 2020 were identified as potential standard cases, for which a digital twin recommendation was then generated by DSS.ResultsThe system provided reliable advice in all 111 cases and showed 97% concordance of MDT and DSS for therapeutic recommendations, regardless of tumor stage. Discrepancies included two cases (2%) where DSS advised discussions at MDT and one case (1%) with deviating recommendation due to advanced patient age.ConclusionsOur work aimed not to replace clinical expertise but to alleviate MDT workload and enhance focus on complex cases. Overall, our DSS proved to be a suitable tool for identifying standard cases as such, providing correct treatment recommendations, and thus reducing the time burden of tumor conferences in favor for the comprehensive discussion of complex cases. The aim is to implement the DSS in routine tumor board software for further qualitative assessment of its impact on oncological care.

Baseline metastatic growth rate is an independent prognostic marker in patients with advanced BRAF V600 mutated melanoma receiving targeted therapy

BackgroundTargeted therapy (TT) of BRAF V600 mutated unresectable melanoma with inhibitors of the MAPK pathway achieves response rates of up to 76%, but most patients develop secondary resistance. Albeit TT is strikingly efficacious during the first days of treatment, even in advanced cases, long-term survival is highly unlikely, especially in patients with unfavorable baseline characteristics like elevated lactate dehydrogenase (LDH). In patients treated with anti-PD-1 immune checkpoint inhibitors, elevated baseline metastatic growth rate (MGR) was the most important prognostic factor. Here, we aimed at investigating the prognostic impact of MGR in patients with unresectable melanoma receiving TT. MethodsClinical records of 242 patients with at least one measurable target lesion (TL) receiving TT at seven skin cancer centers were reviewed. Baseline MGR was determined measuring the largest TL at baseline and at one earlier timepoint. ResultsOverall survival (OS) and progression-free survival (PFS) were significantly impaired in patients with an MGR > 3.9 mm/month (median OS: 11.4 vs. 35.5 months, P < 0.0001; median PFS: 4.8 vs. 9.2 months, P < 0.0001). Multivariable analysis of OS and PFS revealed that the prognostic impact of elevated MGR was independent of LDH, presence of brain and liver metastases, tumor burden, and line of treatment. The prognostic significance of elevated MGR was highest in patients with normal LDH. ConclusionsBaseline MGR is an important independent prognostic marker for OS and PFS in melanoma patients treated with TT. Its implementation in clinical routine is easy and could facilitate the prognostic stratification.

Identifying biomarkers and novel therapeutic targets in uveal melanoma.

Uveal melanoma (UM) is an orphan cancer despite being the most common eye tumor in adults. Patients often present to skin cancer centers for treatment of metastatic disease although there are significant genetic, biological, and clinical differences from cutaneous melanoma. The treatments most commonly used for metastatic UM are tebentafusp and combined immune checkpoint blockade, both of which yield low response rates and may be accompanied by high treatment costs and significant immune-related toxicities. Thus, it is of paramount importance to identify biomarkers and clinical profiles predictive of treatment response and to find novel therapeutic targets. The use of immune checkpoint blockade showed more favorable outcomes in patients with extrahepatic disease and normal levels of serum lactate dehydrogenase in a panel of retrospective studies, making its use more reasonable in this subgroup. To identify novel drug targets, we will analyze the expression and relevance of neural crest transcription factors in patient bio-specimens using next-generation nanopore sequencing. Computer algorithms and network-based analysis will facilitate the identification of druggable targets which will subsequently be validated in patient-derived short-term cell cultures. This approach will help to find novel and personalized treatments for UM.

Evaluation of a 3‐year teledermoscopy project in primary healthcare centres in Belgium

AbstractBackgroundWith the increasing incidence of skin cancer and limited access to specialised care, teledermoscopy (TDS) may represent a useful triage tool for skin cancer detection.ObjectivesAn evaluation of a 3‐year TDS project in primary healthcare centres (PHCs) in Belgium (TELESPOT project).MethodsA total of nine PHCs were trained to use an in‐house developed smartphone‐based application for macroscopic and dermoscopic acquisition of skin lesions, subsequently analysed independently by two investigators in a tertiary university skin cancer centre. The primary outcome was the proportion of high‐priority management (HPM) recommendations. Secondary outcomes included the TDS diagnoses, the quality of image acquisition, the mean time between HPM recommendations and subsequent surgery, the correlation between HPM reports and histopathology after surgery as well as patient and general practitioner satisfaction scores. All the endpoints were compared between the initial year of the TDS project and the subsequent 2‐year extension period of the study.ResultsOver 3 years, a total of 478 lesions were analysed in 335 patients: initial phase (105 lesions from 76 patients in six PHCs) and extension phase (373 lesions from 259 patients in nine PHCs). An HPM was recommended in 9.2% (initial and extension phases: 7.6% and 15.7%, respectively). The dermoscopic‐histological correlation achieved 84.1%. The median delay between HPM and surgery was 9 days.ConclusionsThis TDS project avoided unnecessary tertiary care visits in about 9 out of 10 cases, increased the HPM by a ninefold in comparison with the conventional care pathway and provided excellent satisfaction levels for PHCs and patients. Long‐term participation improved the triage quality for suspect skin lesions by 2.24‐fold.

Causes of Death in Cutaneous T-Cell Lymphoma Patients

Background: The advancing evolution toward a Th2 immune environment confers a progressive immunosuppression in patients with longstanding cutaneous T-cell lymphoma (CTCL). The conjunction of the disease-related immunosuppression as well as the immunosuppressive character of some CTCL treatments increase the risk of infectious and neoplastic diseases, sometimes with fatal outcomes. Objectives: The aim of the study was to prospectively study the causes of death in a cohort of CTCL patients, in a tertiary university skin cancer center. Methods: All CTCL patients who died between 2008 and 2020 were included. The cause of the death was classified as directly or indirectly related or unrelated to CTCL. Results: Over the study period, 31 (13F/18m) patients with CTCL died (mean age: 75.2 years), mean delay between diagnosis and death: 3.2 years (min: 1, max: 12 years), 58.1% of death causes were classified as indirect (infection), 12.9% directly related (blastic transformation), 22.5% unrelated, and 6.5% of unknown cause. 51.6% of mycosis fungoides (MF) patients who died had early-stage disease (1A–2A) or were on remission. 45.2% of dead patients had advanced-stage MF (2B–4B). Mean CRP level is increased in patients who died from infection whereas LDH level increased in patients with blastosis. A tertiary center is expected to manage of a higher proportion of CTCL patients with advanced-stage disease. Conclusions: As infection represented more than 50% of the causes of death in CTCL patients, particular attention should be given to preventive measures such as anti-infective vaccination. Regular surveillance of CRP and LDH levels could be helpful for follow-up of MF patients, respectively, with regards to infection and blastosis.

Prognostic factors in the primary care of patients with Merkel cell carcinoma: A monocentric cohort study of 108 patients from a tertiary referral centre

AbstractBackgroundMerkel cell carcinoma (MCC) is one of the deadliest skin cancers. Despite existing national guidelines, treatment of MCC patients is not as well standardized as for more common skin cancers.ObjectivesThe study objective was to investigate factors predisposing to favourable/unfavourable patient outcomes and to which extent guideline‐based care affects patient survival.MethodsThis noninterventional study investigated a monocentre real‐world patient cohort with a histologically confirmed diagnosis of MCC who presented at the skin cancer centre, University Hospital Essen. Patient and tumour characteristics (age, sex, primary localization, Merkel cell polyomavirus [MCPyV], tumour stage at initial diagnosis and primary treatment measures [surgery, radiation]) were correlated with the patient outcome in terms of recurrence‐free survival (RFS) and overall survival (OS).ResultsA total of 108 patients were identified. The median age of the patients was 69.9 years (range 39–88), with patients aged &lt;70 years showing a trend towards a longer RFS (p = 0.192). Regarding sex, 69 (63.9%) of the patients were male, with females showing a trend towards a longer RFS (0.189). MCPyV+ primary tumours are less frequently located in the head/neck region (p = 0.003). Patients with primary tumours in the head/neck region had a significantly worse OS than patients with primary tumours at the trunk/extremities (p = 0.007). Patients with positive sentinel lymph nodes (SLNs) showed a tendency towards shorter RFS (p = 0.126) and OS (p = 0.089). Patients with American Joint Committee on Cancer stages I, IIA and IIB had a slightly better RFS (p = 0.803) and OS (p = 0.820) compared to patients with stages IIIA and IIIB. Moreover, the administration of adjuvant radiotherapy resulted in a slightly better RFS (p = 0.299) and OS (p = 0.276) in patients with tumour stages I, IIA and IIB.ConclusionsIn the present study, the outcome of MCC patients depended on primary tumour localization, SLN status, sex and age. The tumour stage and the adjuvant radiation had only limited effects on patient outcomes.

The Efficacy of Sonidegib in Treating Locally Advanced Basal Cell Carcinoma Involving the Periocular Area.

Basal cell carcinoma (BCC) is the most common skin malignancy in Caucasians. Globally, about 20% of BCCs involve the periocular region. The treatment of periocular BCC may be very challenging because of its proximity to the intracranial structures. Thus, early diagnosis and early treatment is mandatory. Recently, the introduction of Hedgehog pathway inhibitor therapy revolutionized the management of unresectable BCCs. The aim of our study was to evaluate the outcome of sonidegib treatment in patients affected by periocular locally advanced (la) BCC at our skin cancer center. A 3-year retrospective study was carried out enrolling patients with periocular laBCC treated with sonidegib. Therapeutic response was defined as complete remission (CR) in case of complete regression of the tumor, partial remission (PR) in case of tumor regression not achieving complete remission, and stable disease (SD). A total 16 patients (11 men and 5 women; medium age 71.6 ± 11.5years) with periocular laBCCs undergoing treatment with 200mg/day of sonidegib were included in our study. Patients included in the study were treated for at least 6months for a median duration of 9months. Overall, CR was reported in 9/16 (56.2%) patients, PR was reported in 4/16 patients (25%), and tumor remained stable in 3 patients (18.8%). No cases of disease progression were collected. Fourteen out of 16 patients experienced multiple adverse events (AEs): dysgeusia was reported in 12 (75%) patients, muscle spasms in 13 (81%) patients, and 7 (43.7%) patients presented with alopecia. However, all of the AEs were mild and none required treatment discontinuation. To the best of our knowledge, this is the first study investigating the effectiveness and safety of sonidegib in the management of BCC localized at the periocular region. Even if limited, our study suggests this drug as a valuable and safe option in periocular BCC management.

Dermoscopy of very small basal cell carcinoma (≤3 mm)

BackgroundBasal cell carcinoma (BCC) dermoscopy is key to lower the biopsy threshold of suspicious lesions. There is a scarcity of published data on the dermoscopy of very small BCC (≤3mm) and its differences from larger BCCs. ObjectiveTo describe and compare dermoscopic features of BCCs measuring ≤3mm, with those from 3 to 10mm. MethodsAn analytical cross-sectional study, included biopsy-proven BCCs that had dermoscopic photographic images, between January 2017 and December 2022 in a Skin Cancer Center in Medellín, Colombia. Demographic, clinic-pathological and dermoscopic features were compared between very small BCCs (vsBCCs) and a reference group. ResultsA total of 326 BCCs in 196 patients were included, of whom 60% were male. The most common Fitzpatrick phototype was III. vsBCCs accounted for 25% of the lesions (81/326). Face and neck were the most frequent locations (53%), especially in very small tumors. The nodular type was more common in very small tumors than in larger lesions, the superficial type was less frequent, and aggressive types were equally prevalent in both groups. On dermoscopy, very small tumors were statistically more likely to present pigmented structures than reference lesions, especially blue-gray dots (67% vs. 54%), vessels were less frequent, particularly short-fine telangiectasias (SFT) (52% vs. 66%), as were other structures such as shiny white structures (SWS), ulceration, micro-erosions, and scales. Study limitationsLatin-American sample, lacks information on dark phototypes ConclusionsPigmented structures, especially blue-gray dots, were most common in vsBCCs when compared to larger lesions; SFT, SWS and other findings were less prevalent.

Preferences of German and Swiss melanoma patients for toxicities versus melanoma recurrence during adjuvant treatment (GERMELATOX-A-trial).

Adjuvant treatment with immune checkpoint inhibitors like PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT) in high-risk melanoma patients demonstrate a significant improvement in disease-free survival (DFS). Due to specific side effects, the choice of treatment is very often driven by the risk for toxicity. This study addressed for the first time in a multicenter setting the attitudes and preferences of melanoma patients for adjuvant treatment with (c)ICI and TT. In this study ("GERMELATOX-A"), 136 low-risk melanoma patients from 11 skin cancer centers were asked to rate side effect scenarios typical for each (c)ICI and TT with mild-to-moderate or severe toxicity and melanoma recurrence leading to cancer death. We asked patients about the reduction in melanoma relapse and the survival increase at 5years they would require to tolerate defined side-effects. By VAS, patients on average valued melanoma relapse worse than all scenarios of side-effects during treatment with (c)ICI or TT. In case of severe side effects, patients required a 15% higher rate of DFS at 5years for (c)ICI (80%) compared to TT (65%). For survival, patients required an increase of 5-10% for melanoma survival during (c)ICI (85%/80%) compared to TT (75%). Our study demonstrated a pronounced variation of patient preferences for toxicity and outcomes and a clear preference for TT. As adjuvant melanoma treatment with (c)ICI and TT will be increasingly implemented in earlier stages, precise knowledge of the patient perspective can be helpful for decision making.

Liver-directed treatment is associated with improved survival and increased response to immune checkpoint blockade in metastatic uveal melanoma: results from a retrospective multicenter trial

Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.

Illuminating the Shadows: Exploring the Causes, Overcoming Challenges, and Advancing Solutions for Skin Cancers in Pakistan

Skin cancer poses a significant and growing public health concern in Pakistan, with rising incidence rates and a burden that weighs heavily on individuals, families, and healthcare systems. Understanding the causes, addressing the challenges, and implementing effective solutions are critical steps in combating this escalating issue.1 In this editorial, we shed light on the complexities of skin cancers in Pakistan, exploring the underlying causes, the challenges faced, and the pathways to advancing solutions for prevention, early detection, and treatment. The primary cause of skin cancers, including melanoma and non-melanoma types, is excessive and prolonged exposure to ultraviolet (UV) radiation from the sun1. Pakistan's geographical location, with abundant sunshine and a predominantly sunny climate, places its population at a heightened risk of developing skin cancers. Cultural practices, such as limited sun protection measures and a preference for fair skin, further contribute to increased UV exposure and vulnerability to skin cancers.1 Public awareness campaigns and education on the importance of sun protection practices, such as wearing protective clothing, using sunscreen, and seeking shade during peak sun hours, are crucial for reducing UV-related risks. Another significant challenge in combating skin cancers in Pakistan is the lack of comprehensive and consistent data on the incidence, prevalence, and mortality rates. Limited national registries and fragmented data collection systems impede accurate assessment and hinder evidence-based decision-making.2 Strengthening surveillance mechanisms, establishing cancer registries, and promoting data sharing and collaboration among healthcare institutions and researchers are pivotal in obtaining a comprehensive understanding of the burden and trends of skin cancers. Access to healthcare services, particularly in rural areas, poses a significant obstacle to early detection and timely treatment of skin cancers. Limited healthcare infrastructure, inadequate training of healthcare professionals and financial constraints restrict access to dermatological expertise, specialized diagnostics, and appropriate treatment modalities. Investment in dermatology services, the training of healthcare professionals, and the establishment of skin cancer centers can enhance early detection, diagnosis, and treatment accessibility for all individuals across Pakistan.3 Community engagement and health education programs play a pivotal role in raising awareness about skin cancers, dispelling misconceptions, and encouraging early detection behaviors4. Collaboration with community leaders, schools, and local organizations can facilitate the dissemination of information on risk factors, warning signs, and the importance of regular self-examinations4. By empowering individuals to recognize suspicious lesions and seek timely medical attention, we can promote early diagnosis and improve treatment outcomes.4 Furthermore, innovative technological solutions, such as telemedicine and mobile health applications, have the potential to bridge the geographical gaps and improve access to dermatological expertise in remote areas. Telemedicine platforms enable dermatologists to remotely assess and diagnose skin lesions, providing guidance on further evaluation and treatment options. Integrating these digital solutions into the healthcare system can greatly enhance dermatology services and improve outcomes for individuals with skin cancers.5 Collaborative research efforts and partnerships between academia, healthcare institutions, and governmental bodies are vital in advancing the understanding of skin cancers in Pakistan.6 Research studies focused on epidemiology, genetic factors, environmental influences, and treatment outcomes can provide valuable insights into the unique characteristics of skin cancers in the Pakistani population. These insights can inform the development of tailored prevention strategies, treatment guidelines, and targeted interventions. In conclusion, addressing the rising burden of skin cancers in Pakistan requires a multifaceted approach that encompasses awareness, prevention, early detection, treatment accessibility, and research collaboration. By illuminating the shadows cast by skin cancers, we can create a comprehensive framework that combines public education, healthcare infrastructure development, technological innovations, and research advancements. Together, we can combat this growing epidemic and improve the lives of individuals affected by skin cancers in Pakistan.7-10 How to Cite This: Rani B. Illuminating the Shadows: Exploring the Causes, Overcoming Challenges, and Advancing Solutions for Skin Cancers in Pakistan. Isra Med J. 2023; 15(1):35-36. DOI: https://doi.org/10.55282/imj.ltr35

Breaking primary checkpoint inhibitor resistance: Interim analysis of a multicenter phase II study by intermittent application of an alkylating agent among patients with metastatic melanoma.

9544 Background: Patients with BRAF wildtype (wt) metastatic melanoma with primary resistance to immune checkpoint inhibitors (ICI) have a dismal prognosis. Chemotherapy has been shown to induce mutations, alter the tumor microenvironment as well as the microbiome, and modulate the immune system. This prospective phase II trial investigates whether two applications of an alkylating agent (dacarbazine/DTIC) can render ICI non-responsive patients with metastatic melanoma responsive to the same checkpoint inhibitor regime. Methods: The PROMIT trial (NCT04225390) targets patients with histologically confirmed BRAFwt metastatic melanoma showing primary resistance to ICI therapy. Applying an optimal two-step design, the uninteresting responder rate was set to 5% with an expected rate of 20%. Response is defined as complete or partial response by week 14 according to RECIST 1.1. Design foresaw 29 assessable patients at first step and 38 patients overall (alpha one-sided 5%, 90% power).After showing primary resistance to ICI, patients received 2 doses of DTIC (850 mg/m2 i.v.) on days 1 and 21, and were subsequently re-exposed to the same ICI therapy they had previously shown resistance to. Results: In total, 38 patients were screened at 4 skin cancer centers. Interim analysis was performed after 29 patients who had received at least one ICI re-exposure were assessable for efficacy. Overall response rate was 24% (90%CI 12-41%) with 7 out of 29 patients showing a partial response; disease control rate was 38%. Application was well tolerated with 16% grade 3 or more adverse events and no new safety signals. Conclusions: Interim analyses results indicate that this approach of a short-term chemotherapy can break resistance in a subgroup of patients and allows us to continue the phase II trial to assess relevance of this treatment approach for metastatic melanoma. Enrolment is ongoing. Clinical trial information: NCT04225390 .

Advanced melanoma-A curable disease? Implications of systemic treatment on patients' daily life.

Advanced melanoma-A curable disease? Implications of systemic treatment on patients' daily life.

Adjuvant treatment in advanced melanoma: How far have we come?

Adjuvant treatment in advanced melanoma: How far have we come?