Isolated melanoma cells in sentinel lymph node in stage IIIA melanoma correlate with a favorable prognosis similar to stage IB.

BACKGROUND: The American Joint Committee on Cancer 8th edition (AJCC v8) defines sentinel lymph nodes (SLN) containing any tumor cells as positive SLN. Consequently, even thin melanomas with isolated tumor cells (ic) in SLN are classified as stage IIIA, making them candidates for adjuvant therapy. OBJECTIVES AND ENDPOINTS: We aimed to evaluate survival outcomes of melanoma stage IIIA (ic) and compare them with stage IIIA with lymph node (LN) metastases > 0.1 mm. Primary endpoints were relapse-free survival (RFS) and distant metastases-free survival (DMFS). Secondary endpoint was melanoma specific survival (MSS). RESULTS: The discovery cohort from the Department of Dermatology, University Hospital Tuebingen, included 237 patients; confirmation cohort included 143 patients from the DeCOG trial. The Tuebingen cohort included 95 patients with stage IIIA (ic) and 142 patients with stage IIIA. The DeCOG trial included 39 patients with stage IIIA (ic) and 104 patients with stage IIIA. In the Tuebingen cohort, 10-year RFS rates for stage IIIA (ic) and IIIA were 84% (95% CI 75-94) and 49% (95% CI 39-59), respectively (p < 0.001). 10-year DMFS rates for stage IIIA (ic) and IIIA were 89% (95% CI 81-97) and 56% (95% CI 45-67), respectively; (p < 0.001). In the DeCOG cohort, 10-year RFS for stage IIIA (ic) and stage IIIA were 88% (95% CI 78-99) and 35% (95% CI 7-62), respectively; (p = 0.009). 10-year DMFS for stage IIIA (ic) and IIIA was 88% (95% CI 77-99) and 60% (95% CI 39-80), respectively (p = 0.061). CONCLUSION: Stage IIIA (ic) melanoma exhibits a prognosis similar to stage IB. Recommendation of adjuvant therapy in Stage IIIA (ic) warrants thorough discussion.

Features and Long-Term Outcomes of Stage IV Melanoma Patients Achieving Complete Response Under Anti-PD-1-Based Immunotherapy.

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.

Real-world Treatment Patterns and Outcomes with Systemic Therapies in Unresectable Locally Advanced and Metastatic Cutaneous Squamous Cell Carcinoma in Germany.

Advanced cutaneous squamous cell carcinoma is a challenge to treat. Conventional systemic treatment options include chemotherapy and epidermal growth factor receptor-inhibitors. The aim of this study was to assess clinical outcomes with systemic treatments in advanced cutaneous squamous cell carcinoma. Patients receiving systemic treatment at the Tübingen Dermato-Oncology centre between 2007 and 2017 were identified (n = 59). Median age was 76 years (interquartile range (IQR) 71-80 years), 83.1% of patients were male, 72.9% had metastatic cutaneous squamous cell carcinoma, and 27.1% had unresectable locally advanced cutaneous squamous cell carcinoma. During median follow-up of 52 weeks (IQR 27-97 weeks), overall response rate was 14.3%, and disease control rate was 53.6%. Median progression-free survival was 15 weeks (IQR 8-42 weeks), and median overall survival was 52 weeks (IQR 27-97 weeks). Patients receiving chemoradiation vs chemotherapy alone showed better overall survival (hazard ratio 0.41, p = 0.014,) and progression-free survival (hazard ratio 0.42, p = 0.009); no differences were observed for metastatic cutaneous squamous cell carcinoma vs locally advanced cutaneous squamous cell carcinoma patients. Although chemotherapy and/or cetuximab showed limited outcomes in advanced cutaneous squamous cell carcinoma, such therapy may still be an option when anti-PD-1 treatment is contraindicated.

An open-label, single-arm, phase II trial of buparlisib in patients with melanoma brain metastases not eligible for surgery or radiosurgery-the BUMPER study.

BACKGROUND: Patients with melanoma brain metastasis (MBM) still carry a dismal prognosis. Preclinical data originated in xenograft models showed that buparlisib therapy was highly effective in therapy-naïve MBM. PATIENTS AND METHODS: In this open-label, phase II trial, we investigate the safety and efficacy of monotherapy with buparlisib, a PI3K inhibitor, in patients with asymptomatic MBM who were not candidates for local therapy. These patients had also progressed under immunotherapy if BRAF wild-type or under targeted therapy with BRAF/MEK inhibitors if carrying a BRAFV600E/K mutation. The primary endpoint was the intracranial disease control rate assessed by the investigators. The secondary endpoints were overall response rate, duration of response (DOR) of intracranial disease, overall response, progression-free survival (PFS), overall survival (OS), safety, and tolerability of buparlisib. RESULTS: A total of 20 patients were screened and 17 patients were treated with buparlisib. Twelve patients had progressed under more than 2 systemic therapy lines and 17 had received at least 1 previous local therapy. There were no intracranial responses. Three patients achieved intracranial stable disease; the median DOR was 117 days. The median PFS was 42 days (95% confidence interval [CI]: 23-61 days) and the median OS was 5.0 months (95% CI: 2.24-7.76 months). No new safety signs were observed. CONCLUSIONS: Buparlisib was well tolerated but no intracranial responses were observed. These results might be explained in part by the inclusion of only heavily pretreated patients. However, preclinical data strongly support the rationale to explore PI3K inhibitor-based combinations in patients with MBM displaying hyperactivation of the PI3K-AKT pathway.

Diagnostic Accuracy of Electrical Impedance Spectroscopy in Non-melanoma Skin Cancer.

Electrical impedance spectroscopy is a non-invasive technique that can help clinicians in diagnosing malignant skin tumours. Depending on the cellular irregularity of the lesion, electrical impedance spectroscopy can reveal changes in the structure and form of the cells, using a harmless electrical current applied to the skin. A score between 0 and 10 is generated by the electrical impedance spectrometer, where 0 is considered benign and 10 is malignant. This prospective study was conducted in 101 patients with a total of 200 skin lesions; 62 benign and 138 malignant. There was a significant difference between the electrical impedance of malignant and benign lesions (p < 0.001). The sensitivity, specificity, positive predictive value and negative predictive value of electrical impedance spectroscopy for non-melanoma skin cancer were 94.2%, 41.9%, 78.3% and 76.5%, respectively, when the cut-off for the electrical impedance spectroscopy score was set at between 5 and 6. The area under the curve in receiver operating characteristics analyses was 0.758.

Immune checkpoint inhibition therapy for advanced skin cancer in patients with concomitant hematological malignancy: a retrospective multicenter DeCOG study of 84 patients.

BACKGROUND: Skin cancers are known for their strong immunogenicity, which may contribute to a high treatment efficacy of immune checkpoint inhibition (ICI). However, a considerable proportion of patients with skin cancer is immuno-compromised by concomitant diseases. Due to their previous exclusion from clinical trials, the ICI treatment efficacy is poorly investigated in these patients. The present study analyzed the ICI treatment outcome in advanced patients with skin cancer with a concomitant hematological malignancy. METHODS: This retrospective multicenter study included patients who were treated with ICI for locally advanced or metastatic melanoma (MM), cutaneous squamous cell carcinoma (cSCC), or Merkel cell carcinoma (MCC), and had a previous diagnosis of a hematological malignancy irrespective of disease activity or need of therapy at ICI treatment start. Comparator patient cohorts without concomitant hematological malignancy were extracted from the prospective multicenter skin cancer registry ADOREG. Treatment outcome was measured as best overall response, progression-free (PFS), and overall survival (OS). RESULTS: 84 patients (MM, n=52; cSCC, n=15; MCC, n=17) with concomitant hematological malignancy were identified at 20 skin cancer centers. The most frequent concomitant hematological malignancies were non-Hodgkin's lymphoma (n=70), with chronic lymphocytic leukemia (n=32) being the largest entity. While 9 patients received ICI in an adjuvant setting, 75 patients were treated for advanced non-resectable disease (55 anti-PD-1; 8 anti-PD-L1; 5 anti-CTLA-4; 7 combinations). In the latter 75 patients, best objective response (complete response+partial response) was 28.0%, disease stabilization was 25.3%, and 38.6% showed progressive disease (PD). Subdivided by skin cancer entity, best objective response was 31.1% (MM), 26.7% (cSCC), and 18.8% (MCC). Median PFS was 8.4 months (MM), 4.0 months (cSCC), and 5.7 months (MCC). 1-year OS rates were 78.4% (MM), 65.8% (cSCC), and 47.4% (MCC). Comparison with respective ADOREG patient cohorts without hematological malignancy (n=392) revealed no relevant differences in ICI therapy outcome for MM and MCC, but a significantly reduced PFS for cSCC (p=0.002). CONCLUSIONS: ICI therapy showed efficacy in advanced patients with skin cancer with a concomitant hematological malignancy. Compared with patients without hematological malignancy, the observed ICI therapy outcome was impaired in cSCC, but not in MM or MCC patients.

Treatment Motivations and Expectations in Patients with Actinic Keratosis: A German-Wide Multicenter, Cross-Sectional Trial.

Patient-centered motives and expectations of the treatment of actinic keratoses (AK) have received little attention until now. Hence, we aimed to profile and cluster treatment motivations and expectations among patients with AK in a nationwide multicenter, cross-sectional study including patients from 14 German skin cancer centers. Patients were asked to complete a self-administered questionnaire. Treatment motives and expectations towards AK management were measured on a visual analogue scale from 1-10. Specific patient profiles were investigated with subgroup and correlation analysis. Overall, 403 patients were included. The highest motivation values were obtained for the items "avoid transition to invasive squamous cell carcinoma" (mean ± standard deviation; 8.98 ± 1.46), "AK are considered precancerous lesions" (8.72 ± 1.34) and "treating physician recommends treatment" (8.10 ± 2.37; p < 0.0001). The highest expectation values were observed for the items "effective lesion clearance" (8.36 ± 1.99), "safety" (8.20 ± 2.03) and "treatment-related costs are covered by health insurance" (8.00 ± 2.41; p < 0.0001). Patients aged ≥77 years and those with ≥7 lesions were identified at high risk of not undergoing any treatment due to intrinsic and extrinsic motivation deficits. Heat mapping of correlation analysis revealed four clusters with distinct motivation and expectation profiles. This study provides a patient-based heuristic tool for a personalized treatment decision in patients with AK.

Primary Resistance to PD-1-Based Immunotherapy-A Study in 319 Patients with Stage IV Melanoma.

BACKGROUND: Primary resistance to immunotherapy can be observed in approximately 40-65% of the stage IV melanoma patients treated with immune checkpoint inhibitors. A minority of the patients receive a second-line therapy, and the clinical benefit is small. PATIENTS AND METHODS: Stage IV melanoma patients treated with first-line PD-1-based immunotherapy between January 2015 and December 2018 were investigated. Primary resistance was defined as progressive disease (PD) at the time of the first tumor assessment after starting immunotherapy. Patients with complete response, partial response, and stable disease were classified as having disease control (DC). Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier estimator. Univariate and multivariate logistic regression analyses were performed to determine prognostic factors associated with OS. RESULTS: Three hundred and nineteen patients were included, and 40% had primary resistance to immunotherapy. The median follow-up time was 22 months. Patients with primary resistance had 1-, 2-, and 3-year OS rates of 41%, 15%, and 10%, respectively, compared to 91%, 81%, and 65% for the patients who achieved DC. The following independently significant prognostic factors for OS were identified: protein S100B level and primary tumor localization. There was a statistically significant difference for OS (p < 0.0001) but not for PFS (p = 0.230) when analyzing risk groups formed with a combination of these two variables (low-, intermediate-, and high-risk subgroups). CONCLUSIONS: Melanoma patients with primary resistance to immunotherapy have a dismal prognosis. Response at the first tumor assessment after starting immunotherapy is a stronger prognostic factor for the further course of the disease than pretreatment risk factors.

The lane to the brain: how African trypanosomes invade the CNS.

African trypanosomes induce sleeping sickness. Although it is clear that this parasite moves from the blood to the central nervous system (CNS) to induce the second stage of the disease, little is known about the molecular details of this process. Considering new findings of the trypanosome localization, this opinion paper will summarize the current knowledge about CNS infection, propose a different perception of the invasion process, and discuss possible consequences for drug development.

Cyclical appearance of African trypanosomes in the cerebrospinal fluid: new insights in how trypanosomes enter the CNS.

It is textbook knowledge that human infective forms of Trypanosoma brucei, the causative agent of sleeping sickness, enter the brain across the blood-brain barrier after an initial phase of weeks (rhodesiense) or months (gambiense) in blood. Based on our results using an animal model, both statements seem questionable. As we and others have shown, the first infection relevant crossing of the blood brain border occurs via the choroid plexus, i.e. via the blood-CSF barrier. In addition, counting trypanosomes in blood-free CSF obtained by an atlanto-occipital access revealed a cyclical infection in CSF that was directly correlated to the trypanosome density in blood infection. We also obtained conclusive evidence of organ infiltration, since parasites were detected in tissues outside the blood vessels in heart, spleen, liver, eye, testis, epididymis, and especially between the cell layers of the pia mater including the Virchow-Robin space. Interestingly, in all organs except pia mater, heart and testis, trypanosomes showed either a more or less degraded appearance of cell integrity by loss of the surface coat (VSG), loss of the microtubular cytoskeleton and loss of the intracellular content, or where taken up by phagocytes and degraded intracellularly within lysosomes. This is also true for trypanosomes placed intrathecally into the brain parenchyma using a stereotactic device. We propose a different model of brain infection that is in accordance with our observations and with well-established facts about the development of sleeping sickness.