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Basal cell carcinoma (BCC) is a common epithelial skin cancer. Other than cutaneous squamous cell carcinoma, apart from its aggressive loco-regional destructive growth, it has a very good prognosis. However, metastasis is reported in the literature. Nevertheless, its existence is still discussed controversially and the diagnosis is difficult. We describe the case of a 60-year-old man who had been diagnosed with lymph node and lung metastases of a basaloid carcinoma. Re-microscopy of earlier excised skin tumors revealed a locally recurrent BCC with a histomorphological similar appearance. Additionally performed molecular genetic analysis revealed identical telomerase reverse transcriptase-promoter mutation in the cutaneous BCC and in the lymph node metastasis with a typical UV-signature.

Selected patients with early-stage melanoma have a “hidden high risk” of poor oncologic outcomes. They might benefit from clinical trials, and ultimately, if warranted by trial results, judicious everyday use of adjuvant therapy. A promising tool to identify these individuals is the immunoprint® assay. This immunohistochemical 7-biomarker prognostic test was clinically validated in three independent cohorts (N = 762) to classify early-stage patients as high-risk or low-risk regarding melanoma recurrence and mortality. Using College of American Pathologists (CAP) recommendations, we analytically validated this assay in primary melanoma specimens (N = 20 patients). We assessed assay precision by determining consistency of risk classification under repeated identical conditions (repeatability) or across varying conditions (reproducibility), involving separate assay runs, operators (laboratory scientists), and/or observers (e.g., dermatopathologists). Reference classification was followed by five analytical validation phases: intra-run/intra-operator, intra-observer, inter-run, inter-operator, and inter-observer. Concordance of classifications in each phase was assessed via Fleiss’ kappa (primary endpoint) and percent agreement (secondary endpoint). Seven-marker signature classification demonstrated high consistency across validation categories (Fleiss’ kappa 0.864–1.000; overall percent agreement 95–100%), in 9/10 cases, exceeding, and in 1/10 cases, closely approaching, CAP’s recommended 0.9 level. The 7-marker assay has now been verified to provide excellent repeatability, reproducibility, and precision, besides having been clinically validated.

Sezary Syndrome (SS) is a rare leukemic variant of primary cutaneous T-cell lymphoma. Relapsed or refractory disease is generally considered incurable by conventional therapeutic approaches, although durable responses can be achieved with novel monoclonal antibodies. Allogeneic hematopoietic stem cell transplantation (alloHSCT) may have potential value by inducing graft vs-lymphoma (GvL) effects, but there is currently no consensus regarding the timing of alloHSCT or type of conditioning regimen. Here we present the case of a male patient who achieved a complete remission (CR) of primary refractory SS after non-myeloablative alloHSCT. Patient: Two years prior to HSCT, the patient had been refractory to CHOEP-based chemotherapy, interferon, extracorporeal photopheresis (ECP), and bexarotene. Directly prior to alloHSCT brentuximab-vedotin (BV) was applied resulting in a partial remission of the skin compartment and overall in a stable disease. Prior to HSCT, flow cytometry of the bone marrow and peripheral blood showed an infiltration with T-cells positive for CD5, CD4, low CD3, low CD2 and negative for CD7, CD38, HLA-DR and CD8. The trephine biopsy showed a 7% infiltration of SS cells. The CD4:CD8 ratio in peripheral blood (pb) was massively increased at 76.67, with 63.5% of white blood cells expressing a SS immune phenotype. The conditioning regimen included 30 mg/m2 fludarabine on days -5, -4 and -3 and total body irradiation with 2 Gy on day -1. Immunosuppression consisted of cyclosporine A from day-1 and mycophenolate mofetil from day 0. The patient received 6.55x106 CD34+ cells and 1.11x108 CD3+ cells/kg body weight. Bone marrow evaluation on day 28 still showed persistent SS cells by flow cytometry. After tapering immunosuppression until day 169, the CD4:CD8 ratio in pb normalized. CR was documented on day 169 after alloHSCT and is now ongoing for almost 3 years after alloHSCT. Conclusions: We confirm that an alloHSCT can be a curative option for refractory patients with SS. The achievement of a CR after tapering the immunosuppressive therapy indicates a significant role of the GvL effect. In present treatment algorithms for patients with SS, the timing of an alloHSCT and the intensity of conditioning should be further explored.

Background: Patients with steroid-refractory intestinal acute graft-versus-host disease (aGvHD) and bronchiolitis obliterans syndrome (BOS) represent a population with a high need for alternative and effective treatment options. Methods: We report real-life data from 18 patients treated with extracorporeal photopheresis (ECP). This cohort consisted of nine patients with steroid-refractory intestinal aGvHD and nine patients with BOS. Results: We document partial or complete clinical response and reduction of symptoms in half of the patients with intestinal acute GvHD and patients with BOS treated ECP. Responding patients tended to stay on treatment longer. In patients with BOS, stabilization of lung function and forced expiratory volume was observed, whereas, less abdominal pain, less diarrhea, and a reduction of systemic corticosteroids were seen in patients with intestinal acute GvHD. Conclusions: ECP might not only abrogate symptoms but also reduce mortality caused by complications from high-dose steroid treatment. Taken together, ECP offers a serious treatment avenue for patients with steroid-refractory intestinal acute GvHD and BOS.

Background Checkpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies.Methods MGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB–IV melanoma patients (discovery cohort: n=53, confirmation cohort: n=126, independent multicenter validation cohort: n=158). MGR was computed during the pretreatment period before initiation of therapy with anti-PD-1 antibodies nivolumab or pembrolizumab by measuring the increase of the longest diameter of the largest target lesion. Tumor doubling time served as quality control. Kaplan-Meier analysis and univariable as well as multivariable Cox regression were used to examine the prognostic impact of MGR.Results Pretreatment MGR >3.9 mm/month was associated with impaired OS in the discovery cohort (HR 6.19, 95% CI 2.92 to 13.10, p

Background: Most patients with high-risk melanomas develop metastasis within the first few years after diagnosis. However, late recurrence of melanoma is seen in patients that metastasize more than 10 years after the primary diagnosis; a metastasis after 15 years is considered an ultra-late recurrence. It is critical to better understand the clinical and biological characteristics of this subset of melanoma patients in order to offer an individual treatment plan and prevent metastasis. Methods: We retrospectively analyzed melanoma patients with recurrence ≥10 years after a primary diagnosis documented between 1993 and 2012 at the skin cancer center of the University Medical Center Leipzig, Germany. We conducted a comprehensive review of the literature and compared the results with our data. Available archived primary melanoma tissue was investigated with a seven-marker immunohistochemical signature (immunoprint®) previously validated to reliably identify high-risk patients within stages IB-III. Results: Out of 36 analyzed patients, a third metastasized ultra-late (≥15 years). The mean age at initial diagnosis was 51 years, with women being diagnosed comparatively younger than men. The largest proportion of patients with late recurrence had primary melanomas located on the trunk. The immunoprint® signature of the available primary melanomas allowed the accurate prediction of a high risk. However, it is difficult to draw a definitive conclusion from the small number of cases that could be analyzed with immunoprint® (n = 2) in this study. Apart from the primary tumor characteristics, the laboratory values at time of metastasis, comorbidities and outcome are also shown. Conclusion: Late and ultra-late recurrent melanomas seem not to differ from melanomas in general, apart from a distinctly higher proportion of lower leg localizations in ultra-late recurrent melanomas. The immunoprint® signature may help to identify high-risk primary tumors at the time of initial diagnosis. However, apart from the risk profile of the primary tumor, it seems that individual immune surveillance can control residual tumor cells for more than a decade. Advanced age and increasing comorbidities may contribute to a disturbed immunological balance.

To identify potential early biomarkers of treatment response and immune-related adverse events (irAE), a pilot immune monitoring study was performed in stage IV melanoma patients by flow cytometric analysis of peripheral blood mononuclear cells (PBMC). Overall, 17 patients were treated with either nivolumab or pembrolizumab alone, or with a combination of nivolumab and ipilimumab every three weeks. Of 15 patients for which complete response assessment was available, treatment responders (n = 10) as compared to non-responders (n = 5) were characterized by enhanced PD-1 expression on CD8+ T cells immediately before treatment (median ± median absolute deviation/MAD 26.7 ± 10.4% vs. 17.2 ± 5.3%). Responders showed a higher T cell responsiveness after T cell receptor ex vivo stimulation as determined by measurement of programmed cell death 1 (PD-1) expression on CD3+ T cells before the second cycle of treatment. The percentage of CD8+ effector memory (CD8+CD45RA−CD45RO+CCR7−) T cells was higher in responders compared to non-responders before and immediately after the first cycle of treatment (median ± MAD 39.2 ± 7.3% vs. 30.5 ± 4.1% and 37.7 ± 4.6 vs. 24.0 ± 6.4). Immune-related adverse events (irAE) were accompanied by a higher percentage of activated CD4+ (CD4+CD38+HLADR+) T cells before the second treatment cycle (median ± MAD 14.9 ± 3.9% vs. 5.3 ± 0.4%). In summary, PBMC immune monitoring of immune-checkpoint inhibition (ICI) treatment in melanoma appears to be a promising approach to identify early markers of treatment response and irAEs.

Background: We aim to validate a seven-marker immunohistochemical signature, consisting of Bax, Bcl-X, PTEN, COX-2, (loss of) ß-Catenin, (loss of) MTAP and (presence of) CD20, in an independent patient cohort and test clinical feasibility. Methods: We performed staining of the mentioned antibodies in tissue of 88 primary melanomas and calculated a risk score for each patient. Data were correlated with clinical parameters and outcome (recurrence-free, distant metastasis-free and melanoma-specific survival). Results: The seven-marker signature was able to identify high-risk patients within stages IB-III melanoma patients that have a significantly higher risk of disease recurrence, metastasis, and death. In particular, the high sensitivity of relapse prediction (>94%) in sentinel negative patients (stages IB–IIC) was striking (negative predictive value of 100% for melanoma-specific survival and distant metastasis-free survival, and 97.5% for relapse-free survival). For stage III patients (positive nodal status), the negative predictive value was 100% with the seven-marker signature. Conclusions: The seven-marker signature can help to further select high-risk patients in stages IIB-C but also in earlier stages IB–IIA and be a useful tool for therapy decisions in the adjuvant and future neo-adjuvant settings. Stage III patients with measurable lymph node disease classified as high-risk with the seven-marker signature are potential candidates for neoadjuvant immunotherapy.

Clinically, pyoderma gangrenosum (PG) is characterized by a rapidly progressive, painful cutaneous ulcer with an irregular, violaceous and undermined border. PG occurs most frequently on the lower extremities and the trunk of middle-aged individuals. The face is only very rarely affected. We present an 89- and a 90-year-old patient, who developed a facial ulcer consistent with PG.

Cutaneous T-cell lymphomas (CTCLs) are characterized by the recruitment of malignant T-cell clones, predominantly of the CD4+ T-helper subpopulation, into the skin. Mycosis fungoides (MF) is the most common type of CTCL and accounts for almost 50% of all primary cutaneous lymphomas. The ProteinChip technology surface-enhanced laser desorption/ionization time of flight/mass spectrometry (SELDI-TOF-MS) was used to detect biomarkers in sera from MF patients (n = 25) and healthy controls (n = 26). Therefore, diluted sera were applied to IMAC30 ProteinChip arrays, and the resulting protein profiles were bioinformatically analyzed. A protein set that distinguishes MF patients from healthy controls with a sensitivity of 82.6% and a specificity of 100% was identified. Four significant peaks were identified by two-dimensional gel electrophoresis, immunodepletion, and SELDI-TOF-MS as transthyretin (TTR) and three TTR modifications. A subsequent enzyme-linked immunosorbent assay confirmed these findings. The ability to detect and identify proteins and protein modifications using SELDI-TOF-MS might reveal a better insight on this kind of disease and may lead to a better understanding and earlier detection of MF patients.

Lysophosphatidic acid (LPA) is an activator and chemoattractant of NK cells, which are critical members of the immunological tumor surveillance machinery. Here, we analyzed the influence of LPA on the interaction of human NK cells with tumor cells such as the Burkitt lymphoma cell line Raji and the human melanoma cell line A2058. Thereby we found that LPA inhibits the release of perforin and cytotoxic activity of NK cells. Analysis of signal transduction showed that LPA induces common signaling pathways of chemotaxins such as Gi protein-dependent actin re-organization, activation of the mitogen-activated protein kinase p38 as well as phosphatidylinositol-3-kinase-dependent signal molecules [protein kinase B/Akt and glycogen synthase kinase-3β (GSK-3β)]. In contrast to most chemotaxins, LPA is also able to activate Gs-dependent signaling molecules. This signaling cascade involves the LPA receptor type-2, increase cAMP levels and protein kinase A (PKA) activation, which in turn are responsible for the modulatory effect of LPA on NK cell-mediated cytotoxicity. Moreover, blocking the regulatory subunits of PKA I abrogates the inhibitory effect of LPA, whereas the catalytic subunits are not involved. Based on our data, one can assume that LPA contributes to the tumor escape from the immunological surveillance machinery. [ABSTRACT FROM AUTHOR]