Recent advances in digital pathology have enabled accurate and standardised enumeration of tumour-infiltrating lymphocytes (TILs). Here, we aim to evaluate TILs as a percentage electronic TIL score (eTILs) and investigate its prognostic and predictive relevance in cutaneous melanoma. We included stage I to IV cutaneous melanoma patients and used hematoxylin-eosin-stained slides for TIL analysis. We assessed eTILs as a continuous and categorical variable using the published cut-off of 16.6% and applied Cox regression models to evaluate associations of eTILs with relapse-free, distant metastasis-free, and overall survival. We compared eTILs of the primaries with matched metastasis. Moreover, we assessed the predictive relevance of eTILs in therapy-naïve metastases according to the first-line therapy. We analysed 321 primary cutaneous melanomas and 191 metastatic samples. In simple Cox regression, tumour thickness (p < 0.0001), presence of ulceration (p = 0.0001) and eTILs ≤16.6% (p = 0.0012) were found to be significant unfavourable prognostic factors for RFS. In multiple Cox regression, eTILs ≤16.6% (p = 0.0161) remained significant and downgraded the current staging. Lower eTILs in the primary tissue was associated with unfavourable relapse-free (p = 0.0014) and distant metastasis-free survival (p = 0.0056). In multiple Cox regression adjusted for tumour thickness and ulceration, eTILs as continuous remained significant (p = 0.019). When comparing TILs in primary tissue and corresponding metastasis of the same patient, eTILs in metastases was lower than in primary melanomas (p < 0.0001). In therapy-naïve metastases, an eTILs >12.2% was associated with longer progression-free survival (p = 0.037) and melanoma-specific survival (p = 0.0038) in patients treated with anti-PD-1-based immunotherapy. In multiple Cox regression, lactate dehydrogenase (p < 0.0001) and eTILs ≤12.2% (p = 0.0130) were significantly associated with unfavourable melanoma-specific survival. Assessment of TILs is prognostic in primary melanoma samples, and the eTILs complements staging. In therapy-naïve metastases, eTILs ≤12.2% is predictive of unfavourable survival outcomes in patients receiving anti-PD-1-based therapy. See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.

Patients with cutaneous melanoma stage I/IIA disease are currently not eligible for adjuvant therapy, despite their risk for relapses and death. This study validates the ability of a model combining clinicopathologic factors with gene expression profiling (CP-GEP) to identify patients at high risk for disease recurrence in stage I/II and subgroup stage I/IIA. 543 patients with stage I/II primary cutaneous melanoma from the University of Tuebingen diagnosed between 2000 and 2017 were analysed. All patients received sentinel lymph node biopsy (SLNB). Analysis was conducted for a separate group of 80 patients who did not undergo SLNB. CP-GEP stratified 424 stage I/IIA patients (78% of the cohort) according to their risk for recurrence, with five-year relapse-free survival (RFS) rates of 77.8% and 93% for CP-GEP high risk (195 patients) and low risk (229 patients), respectively, and hazard ratio of 3.53 (p-value <0.001). In patients who did not receive SLNB biopsy, CP-GEP captured 6 out of 7 relapses. CP-GEP can be used to identify primary cutaneous melanoma patients with a high risk for disease recurrence - especially for stage I/IIA, who are considered low risk by AJCC 8th. These patients may benefit from adjuvant therapy. Also, in the future, when SLNB may become irrelevant, CP-GEP may serve as a risk stratification tool.

Objective: Lichen sclerosus (LS) is a disease affecting mostly genital and perianal areas. Photodynamic therapy (PDT) has gained interest during the past years. The present study accumulates current evidence on the efficacy of PDT in the management of vulvar LS. Methods: We used Medline (1966–2017), Scopus (2004–2017), ClinicalTrials.gov (2008–2017) and Cochrane Central Register of Controlled Trials CENTRAL (1999–2017) databases in our primary search along with the reference lists of electronically retrieved full-text papers. Results: Eleven studies were finally included in our systematic review, which recruited 337 women. The existing evidence supports that PDT results in significant relief of symptoms related to LS, hence remains confusing in evaluating the progress in the clinical appearance of the lesion. No major adverse effects were reported during therapy and during the posttreatment period. Pathologic findings seem to be conflicting, as current data do not unanimously support a beneficial histological effect. Conclusions: According to the findings of our study, PDT seems to be promising in the treatment of patients with vulvar LS. Nonetheless, current knowledge is extremely limited, and further observational studies with large patient series are needed in the field to elucidate the efficacy of PDT.

Background: Despite durable responses achieved with Immune Checkpoint Inhibitors (ICIs), data about optimal duration of treatment, especially in the context of adverse events, remain scarce.Objective: To systematically review the evidence concerning the impact of treatment discontinuation with ICIs for reasons other than progressive disease (PD) on relapse rates and survival of melanoma patients.Methods: A systematic literature search was conducted in three electronic databases until July 2024. Studies referring to melanoma patients who ceased ICIs electively (i.e. due to complete response (CR), protocol completion or patient/physician’s wish) or due to treatment-limiting toxicities (TLTs) were selected. Relapse rates (RRs) post cessation, time to PD, rechallenge and disease control rate (DCR) after 2^nd course were the main outcomes. Random-effects models were preferred, and subgroup and sensitivity analyses were conducted to investigate possible sources of heterogeneity.Results: 38 and 35 studies were included in qualitative and quantitative synthesis, respectively. From 2542 patients discontinued treatment with ICIs electively or due to TLTs, 495 experienced progression [number of studies (n)=34, RR 20.9%, 95%CI 17.1 – 24.7%, I² 85%) and higher rates were detected in patients with TLTs compared to elective discontinuation. Mean time to PD was 14.26 months (n=18, mean time 14.26, 95%CI 11.54 – 16.98, I² 93%) and was numerically higher in patients who ceased for CR compared to patients with TLTs. Treatment duration before cessation was not associated with risk and time to relapse, while mucosal melanomas and non-CR as BOR during treatment led to increased risk for relapse and shorter time to PD compared to other histologic subtypes or CR. Rechallenge with ICI resulted in 57.3% DCR and 28.6% pooled CR rates (n=22, CR rate 28.6%, 95%CI 17.1 – 40.2, I² 68%). Heterogeneity among studies was high, but subgroup analysis based on type of ICI used (anti-CTL4 and anti-PD1 inhibitor or anti-PD1 monotherapy) and type of study (RCTs or observational studies), along with sensitivity analyses did not reveal significant alterations in results.Conclusion: Discontinuation of ICIs in patients without progression is possible. Outcomes to rechallenge with ICIs may differ depending on the reason for discontinuation, but remains a considerable option.Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024547792.

Paraoxonase-1 (PON-1) is a calcium-dependent enzyme that is synthesized in the liver and then secreted in blood where it is bound to high density lipoprotein (HDL). PON-1 is a hydrolase with a wide range of substrates, including lipid peroxides. It is considered responsible for many of the antiatherogenic properties of HDL. PON-1 prevents low density lipoprotein (LDL) oxidation, a process that is considered to contribute to the initiation and development of atherosclerosis. PON-1 activity and levels are influenced by gene polymorphisms; of the 2 common variants, one is in position 192 (Q192R) and one in position 55 (M55L). Also, many drugs affect PON-1 activity. The role of PON-1 in carotid atherosclerosis is inconsistent. Some studies show an association of PON-1 polymorphisms with carotid plaque formation, whereas others do not. The aim of this review is to summarize the characteristics of PON-1, its interactions with drugs and its role in atherosclerosis and especially its relationship with carotid artery disease.

Background Immune checkpoint inhibition (ICI) has changed the melanoma treatment spectrum. Few studies have examined the characteristics and long-term outcomes of patients achieving complete response (CR) under ICI. Materials and methods We evaluated patients with unresectable stage IV melanoma treated with first-line ICI. The characteristics of those achieving CR were compared with those not achieving CR. Progression-free survival (PFS) and overall survival (OS) were assessed. Late-onset toxicities, response to second-line treatment, the prognostic value of clinicopathologic features, and blood markers were examined. Results A total of 265 patients were included; 41 (15.5%) achieved CR, while 224 (84.5%) had progressive disease, stable disease, or partial response. At the therapy start, those who had CR were more likely to be older than 65 years of age (p = 0.013), have a platelet-to-lymphocyte ratio below 213 (p = 0.036), and have lower lactate dehydrogenase levels (p = 0.008) than those not achieving a CR. For those who discontinued therapy after CR, the median follow-up time after CR was 56 months (interquartile range [IQR] 52–58) and the median time from CR to therapy end was 10 months (IQR 1–17). Five-year PFS after CR was 79% and 5-year OS was 83%. Most complete responders had a normalization of S100 at the time of CR (p < 0.001). In simple Cox regression analysis, age below 77 years at CR (p = 0.04) was associated with better prognosis after CR. Eight patients received second-line ICI; disease control was seen in 63%. Late immune-related toxicities occurred in 25% of patients, most being cutaneous immune-related toxicities. Conclusions Response, according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, is, until now, the most important prognostic factor, and CR is a valid surrogate marker for long-term survival in patients treated with ICI. Our results highlight the importance of investigating the optimal therapy duration in complete responders. Graphical Abstract