Whole-Body Imaging for the Primary Staging of Melanomas-A Single-Center Retrospective Study.

BACKGROUND: Melanoma staging at diagnosis predominantly depends on the tumor thickness. Sentinel lymph node biopsy (SLNB) is a common tool for primary staging. However, for tumors of >4 mm with ulceration, 3D whole-body imaging and, in particular, Fluor-18-Deoxyglucose positron emission tomography combined with computed tomography (18F-FDG-PET/CT), is recommended beforehand. This study aimed to investigate the real-world data of whole-body imaging for initial melanoma staging and its impact on the subsequent diagnostic and therapeutic procedures. METHODS: In this retrospective single-center study, 94 patients receiving 18F-FDG-PET/CT and six patients with whole-body computed tomography (CT) scans were included. The clinical characteristics, imaging results, and histologic parameters of the primary tumors and metastases were analyzed. RESULTS: Besides the patients with primary tumors characterized as pT4b (63%), the patients with pT4a tumors and pT3 tumors close to 4 mm in tumor thickness also received initial whole-body imaging. In 42.6% of the patients undergoing 18F-FDG-PET/CT, the imaging results led to a change in the diagnostic or therapeutic procedure following on from this. In 29% of cases, sentinel lymph node biopsy was no longer necessary. The sensitivity and specificity of 18F-FDG-PET/CT were 66.0% and 93.0%, respectively. CONCLUSION: Whole-body imaging as a primary diagnostic tool is highly valuable and influences the subsequent diagnostic and therapeutic procedures in a considerable number of patients with a relatively high tumor thickness. It can help avoid the costs and invasiveness of redundant SLNB and simultaneously hasten the staging of patients at the time of diagnosis.

A distinct four-value blood signature of pyrexia under combination therapy of malignant melanoma with dabrafenib and trametinib evidenced by an algorithm-defined pyrexia score.

Pyrexia is a frequent adverse event of BRAF/MEK-inhibitor combination therapy in patients with metastasized malignant melanoma (MM). The study's objective was to identify laboratory changes which might correlate with the appearance of pyrexia. Initially, data of 38 MM patients treated with dabrafenib plus trametinib, of which 14 patients developed pyrexia, were analysed retrospectively. Graphical visualization of time series of laboratory values suggested that a rise in C-reactive-protein, in parallel with a fall of leukocytes and thrombocytes, were indicative of pyrexia. Additionally, statistical analysis showed a significant correlation between lactate dehydrogenase (LDH) and pyrexia. An algorithm based on these observations was designed using a deductive and heuristic approach in order to calculate a pyrexia score (PS) for each laboratory assessment in treated patients. A second independent data set of 28 MM patients, 8 with pyrexia, was used for the validation of the algorithm. PS based on the four parameters CRP, LDH, leukocyte and thrombocyte numbers, were statistically significantly higher in pyrexia patients, differentiated between groups (F = 20.8; p = <0.0001) and showed a significant predictive value for the diagnosis of pyrexia (F = 6.24; p = 0.013). We provide first evidence that pyrexia in patients treated with BRAF/MEK-blockade can be identified by an algorithm that calculates a score.

Post-transplant Malignancies Show Reduced T-cell Abundance and Tertiary Lymphoid Structures as Correlates of Impaired Cancer Immunosurveillance.

PURPOSE: An increased risk to develop cancer is one of the most challenging negative side effects of long-term immunosuppression in organ transplant recipients and impaired cancer immunosurveillance is assumed as underlying mechanism. This study aims to elucidate transplant-related changes in the tumor immune microenvironment (TME) of cancer. EXPERIMENTAL DESIGN: Data from 123 organ transplant recipients (kidney, heart, lung, and liver) were compared with historic data from non-immunosuppressed patients. Digital image analysis of whole-section slides was used to assess abundance and spatial distribution of T cells and tertiary lymphoid structures (TLS) in the TME of 117 tumor samples. Expression of programmed cell death 1 ligand 1 (PD-L1) and human-leucocyte-antigen class I (HLA-I) was assessed on tissue microarrays. RESULTS: We found a remarkably reduced immune infiltrate in the center tumor (CT) regions as well as the invasive margins (IM) of post-transplant cancers. These differences were more pronounced in the IM than in the CT and larger for CD8+ T cells than for CD3+ T cells. The Immune-score integrating results from CT and IM was also lower in transplant recipients. Density of TLS was lower in cancer samples of transplant recipients. The fraction of samples with PD-L1 expression was higher in controls whereas decreased expression of HLA-I was more common in transplant recipients. CONCLUSIONS: Our study demonstrates the impact of immunosuppression on the TME and supports impaired cancer immunosurveillance as important cause of post-transplant cancer. Modern immunosuppressive protocols and cancer therapies should consider the distinct immune microenvironment of post-transplant malignancies.

[What is new in the diagnosis and therapy of malignant melanoma?] / Was ist neu bei der Diagnostik und Therapie des malignen Melanoms?

Melanoma incidence and mortality rates are increasing. The sentinel lymph node biopsy plays an important prognostic role and is pivotal for the decision to undergo an adjuvant therapy making it an important diagnostic tool. The lack of survival benefit in patients with sentinel lymph node-positive (SLN+) melanoma upon immediate complete lymphadenectomy (CLND) suggest a parallel and not stepwise development of lymph node metastasis and distant metastasis thus questioning the role of immediate CLND. These findings also suggest adjuvant therapy may play a more important role for SLN+ melanoma patients than CLND. Recently, the PD-1 inhibitor Nivolumab and Pembrolizumab as well as the BRAF/MEK inhibitor Dabrafenib and Trametinib were approved for the adjuvant therapy of stage III malignant melanoma. Another novelty in the therapy of malignant melanoma is the approval of the first oncolytic virus, Talimogene laherparepvec, for the treatment of unresectable stage III and IV (M1a) melanoma. Significant progress has also been made in the treatment of patients with cerebral melanoma metastasis since studies indicate that both BRAF/MEK inhibitors and the immunotherapy with CTLA4 and PD-1 inhibitors are efficient in this group of patients. With this wide range of possible systemic therapies for advanced melanoma further studies regarding therapy sequence, combinations between targeted therapies and immunotherapy as well as biomarkers for treatment response are needed to help guide physicians find the optimal therapy for patients with advanced malignant melanoma.

The use of circulating cell-free tumor DNA in routine diagnostics of metastatic melanoma patients.

Modern advances in technology such as next-generation sequencing and digital PCR make detection of minor circulating cell-free tumor DNA amounts in blood from cancer patients possible. Samples can be obtained minimal-invasively, tested for treatment-determining genetic alterations and are considered to reflect the genetic constitution of the whole tumor mass. Furthermore, tumor development can be determined by a time course of the quantified circulating cell-free tumor DNA. However, systematic studies which prove the clinical relevance of monitoring patients using liquid biopsies are still lacking. In this study, we collected 115 samples from 47 late stage melanoma patients over 1.5 years alongside therapy-associated clinical routine monitoring. Mutation status was confirmed by molecular analysis of primary tumor material. We can show that detectable levels of circulating cell-free tumor DNA correlate with clinical development over time. Increasing levels of circulating cell-free tumor DNA during melanoma treatment with either targeted therapy (BRAF/MEK inhibitors) or immunotherapy, during recovery time or the intervals between last treatment cycle and second-line treatment point towards clinical progression before the progression becomes obvious in imaging. Therefore, this is a further possibility to closely screen our patients for tumor progression during therapy, in therapy-free phases and in earlier stages before therapy initiation.

Predicting risk for seroma development after axillary or inguinal sentinel lymph node biopsy in melanoma patients.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is currently a routine procedure in the staging of patients with cutaneous melanoma; however, little information is available about the risk factors for postoperative complications, especially for the risk of seroma formation. METHODS: Medical records of patients undergoing SLNB at the University Hospital of Cologne, Germany, between 2011 and 2016, were reviewed. Binary logistic regression was used to analyze the influence of a wide range of variables on seroma development. RESULTS: A total of 615 patients were included in the study. Overall, 20.4% of patients developed complications with seroma being the most common postoperative complication. Development of seroma was significantly more common among smokers than nonsmokers (OR = 1.956, P = 0.007). Inguinal localization (OR = 3.644, P < 0.0001) was also associated with seroma formation. Male patients developed a seroma significantly more often than female patients following SLNB (OR = 2.104, P = 0.001). The presence or absence of metastasis in the lymph node did not influence seroma development. CONCLUSIONS: Male sex, inguinal localization, and smoking are risk factors for the development of seroma.

First report on two cases of pleomorphic dermal sarcoma successfully treated with immune checkpoint inhibitors.

Pleomorphic dermal sarcoma (PDS) is one of the most common sarcoma of the skin. Currently, limited treatment options exist for advanced stages of the disease. While immune checkpoint inhibitors (CPIs) have revolutionized cancer treatment options-their efficacy in PDS has not been explored yet. Here, we present two advanced PDS cases that showed response to anti-PD-1 therapy. Patient A had a locally metastasized PDS and reached a complete remission of the disease after eight cycles of Pembrolizumab. Patient B developed an inoperable relapse of PDS with a complete remission of the disease 4 months after treatment with Pembrolizumab in combination with radiotherapy. To our knowledge, this is the first report of two individuals with advanced PDS that successfully underwent anti-PD1 treatment. By comparing the immune micromilieu to a previously published cohort, we show that the two cases are representative for PDS tumors - potentially making these results more generalizable.

The expression of the immune checkpoint regulator VISTA correlates with improved overall survival in pT1/2 tumor stages in esophageal adenocarcinoma.

Immune checkpoint modulation in cancer has been demonstrated as a high-value therapeutic strategy in many tumor entities. VISTA is an immune checkpoint receptor regulating T-cell function. To the best of our knowledge, nothing is known about the expression and prognostic impact of VISTA on tumor infiltrating lymphocytes (TILs) in the tumor microenvironment of esophageal adenocarcinoma (EAC). We analyzed in total 393 EACs within a test-cohort (n = 165) and a validation-cohort (n = 228) using a monoclonal antibody (clone D1L2G). These data were statistically correlated with clinical as well as molecular data. 22.2% of the tumor cohort presented with a VISTA expression on TILs. These patients demonstrated an improved median overall survival compared to patients without VISTA expression (202.2 months vs. 21.6 months; p < 0.0001). The favorable outcome of VISTA positive tumors is significant in the entire cohort but mainly driven by the general better prognosis of T1/T2 tumors. However, in the pT1/2 group, VISTA positive tumors show a tremendous survival benefit compared to VISTA negative tumors revealing real long-term survivors in this particular subgroup. The survival difference is independent of the T-stage. This unique characteristic could influence neoadjuvant therapy concepts for EAC, since a profit of therapy could be reduced in the already favorable subgroup of VISTA positive tumors. VISTA emerges as a prognostic biomarker for long-term survival especially in the group of early TNM-stages. Future studies have to show the relevance of VISTA positive TILs within a tumor concerning response to specific immune checkpoint inhibition.

Complete lymph node dissection or observation in melanoma patients with multiple positive sentinel lymph nodes: A single-center retrospective analysis.

Although the role of sentinel lymph node biopsy (SLNB) as a prognostic factor is well established, its consequences for therapy are controversial. The aim of this study was to analyze if complete lymph node dissection (CLND) in patients with more than one positive sentinel lymph node (SLN) significantly improves melanoma-specific survival (MSS) and progression-free survival (PFS). Medical records of patients who underwent SLNB between 2001 and 2016 at the University Hospital of Cologne were reviewed, and patients with positive SLN were identified. Patient and tumor characteristics, patterns of recurrence, progression-free and melanoma-specific survival were analyzed. Seventy-eight patients with multiple positive and 197 patients with one positive SLN were included in this study. Patients with multiple positive SLN had significantly more positive non-SLN compared with patients with only one positive SLN (26.9% vs 8.6%, P = 0.01). However, in the subgroup of patients with multiple positive SLN, CLND did not significantly improve MSS (mean MSS 95 vs 75 months, P = 0.5) and PFS (mean PFS 59 vs 68 months P = 0.167). CLND did not result in a significant improvement in PFS and MSS in patients with multiple positive SLN.

Shared and independent functions of aPKCλ and Par3 in skin tumorigenesis.

The polarity proteins Par3 and aPKC are key regulators of processes altered in cancer. Par3/aPKC are thought to dynamically interact with Par6 but increasing evidence suggests that aPKC and Par3 also exert complex-independent functions. Whereas aPKCλ serves as tumor promotor, Par3 can either promote or suppress tumorigenesis. Here we asked whether and how Par3 and aPKCλ genetically interact to control two-stage skin carcinogenesis. Epidermal loss of Par3, aPKCλ, or both, strongly reduced tumor multiplicity and increased latency but inhibited invasion to similar extents, indicating that Par3 and aPKCλ function as a complex to promote tumorigenesis. Molecularly, Par3/aPKCλ cooperate to promote Akt, ERK and NF-κB signaling during tumor initiation to sustain growth, whereas aPKCλ dominates in promoting survival. In the inflammatory tumorigenesis phase Par3/aPKCλ cooperate to drive Stat3 activation and hyperproliferation. Unexpectedly, the reduced inflammatory signaling did not alter carcinogen-induced immune cell numbers but reduced IL-4 Receptor-positive stromal macrophage numbers in all mutant mice, suggesting that epidermal aPKCλ and Par3 promote a tumor-permissive environment. Importantly, aPKCλ also serves a distinct, carcinogen-independent role in controlling skin immune cell homeostasis. Collectively, our data demonstrates that Par3 and aPKCλ cooperate to promote skin tumor initiation and progression, likely through sustaining growth, survival, and inflammatory signaling.