Anti-EGFR-Based Therapy in Recurrent or Metastatic HNSCC - What Difference Does it Make?

Patients with R/M HNSCC treated with palliative first-line therapy at Hannover Medical School between October 2005 and December 2016 have been included to show changes in survival following broad utilization of cetuximab. Treatment periods were defined from 10/2005 to 12/2008 (Period A) and 01/2009 to 12/2016. Overall survival did not improve over time. However, in subgroup analysis cetuximab utilized at any time vs. never showed a significant improve of overall survival (11.3 vs. 6.3 months, HR: 0.55, 95%-CI: 0.4-0.8, p = 0.04). Therefore, this study supports the application of cetuximab in this real-world population.

Improving survival in metastatic renal cell carcinoma (mRCC) patients: do elderly patients benefit from expanded targeted therapeutic options?

INTRODUCTION: Treatment advances in metastatic renal cell carcinoma (mRCC) have improved overall survival (OS) in mRCC patients over the last two decades. This single center retrospective analysis assesses if the purported survival benefits are also applicable in elderly mRCC patients. METHODS: 401 patients with mRCC treated at Hannover Medical School from 01/2003-05/2016 were identified and evaluated by chart review. Treatment periods were defined as 01.01.2003-31.12.2009 (P1) and 01.01.2010-31.05.2016 (P2). Age groups were defined according to WHO classes (≤ 60 years: younger, > 60-75 years: elderly and > 75 years: old). Descriptive statistics, Kaplan-Meier analysis and logistic regression were performed. RESULTS: Median OS improved from 35.1 months in P1 to 59.1 months in P2. Sub-division into the respective age groups revealed median survival of 38.1 (95%-CI: 28.6-47.6) months in younger patients, 42.9 (95%-CI: 29.5-56.3) months among elderly patients and 27.3 (95%-CI: 12.8-41.8) months among old patients. Risk reduction for death between periods was most evident among old patients (young: HR 0.71 (95%-CI: 0.45-1.13, p = 0.2); elderly: HR 0.62 (95%-CI: 0.40-0.97, p = 0.04); old: HR 0.43 (95%-CI: 0.18-1.05, p = 0.06)). Age ≥ 75 years was an independent risk factor for death in P1 but not in P2. CONCLUSION: Improved OS in the targeted treatment period was confirmed. Surprisingly elderly and old patients seem to profit the most form expansion of therapeutic armamentarium, within the TKI-dominated observation period.

The Prognostic Impact of PD-L2 in Papillary Renal-Cell Carcinoma.

INTRODUCTION: Programmed death-1 ligand (PD-L1) has been often studied in different types of renal-cell carcinoma (RCC). For example, in clear-cell renal carcinoma it is well established that programmed death-1 receptor and PD-L1 are important prognostic markers. In contrast, the role of programmed death-2 ligand (PD-L2) as prognostic marker remains unclear. The aim of this study was to evaluate if PD-L2 expression could play a role as a prognostic marker for papillary RCC (pRCC). METHODS: The patients' sample collection was a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of PD-L2 was determined by immunohistochemistry. In total, PD-L2 staining was evaluable in 185 of 240 type 1 and 99 of 128 type 2 pRCC cases. RESULTS: PD-L2 staining was positive in 67 (36.2%) of type 1 and in 31 (31.3%) of type 2 pRCC specimens. The prevalence of PD-L2+ cells was significantly higher in high-grade type 1 tumors (p = 0.019) and in type 2 patients with metastasis (p = 0.002). Kaplan-Meier analysis disclosed significant differences in 5-year overall survival (OS) for patients with PD-L2- compared to PD-L2+ in pRCC type 1 of 88.4% compared to 73.6% (p = 0.039) and type 2 of 78.8% compared to 39.1% % (p < 0.001). However, multivariate analysis did not identify the presence of PD-L2+ cells neither in type 1 nor type 2 pRCC as an independent predictor of poor OS. DISCUSSION/CONCLUSION: PD-L2 expression did not qualify as an independent prognostic marker in pRCC. Future studies will have to determine whether anti-PD-L2-targeted treatment may play a role in pRCC and expression can potentially serve as a predictive marker for these therapeutic approaches.

Impact of sarcopenia in advanced and metastatic soft tissue sarcoma.

INTRODUCTION: Advanced or metastatic soft tissue sarcoma (a/mSTS) is associated with a dismal prognosis. Patient counseling on treatment aggressiveness is pivotal to avoid over- or undertreatment. Recently, evaluation of body composition markers like the skeletal muscle index (SMI) became focus of interest in a variety of cancers. This study focuses on the prognostic impact of SMI in a/mSTS, retrospectively. METHODS: 181 a/mSTS patients were identified, 89 were eligible due to prespecified criteria for SMI assessment. Baseline CT-Scans were analyzed using an institutional software solution. Sarcopenia defining cut-off values for the SMI were established by optimal fitting method. Primary end point was overall survival (OS) and secondary endpoints were progression free survival (PFS), disease control rate (DCR), overall response rate (ORR). Descriptive statistics as well as Kaplan Meier- and Cox regression analyses were administered. RESULTS: 28/89 a/mSTS patients showed sarcopenia. Sarcopenic patients were significantly older, generally tended to receive less multimodal therapies (62 vs. 57 years, P = 0.025; respectively median 2.5 vs. 4, P = 0.132) and showed a significantly lower median OS (4 months [95%CI 1.9-6.0] vs. 16 months [95%CI 8.8-23.2], Log-rank P = 0.002). Sarcopenia was identified as independent prognostic parameter of impaired OS (HR 2.40 [95%-CI 1.4-4.0], P < 0.001). Moreover, DCR of first palliative medical treatment was superior in non-sarcopenic patients (49.2% vs. 25%, P = 0.032). CONCLUSION: This study identifies sarcopenia as a prognostic parameter in a/mSTS. Further on, the data suggest that sarcopenia shows a trend of being associated with first line therapy response. SMI is a promising prognostic parameter, which needs further validation.

[Diagnosis and therapy of tumors with NTRK gene fusion]. / Diagnostik und Therapie von Tumoren mit NTRK-Genfusionen.

NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities. Whereas they are quite rare in most solid tumors they are present at much higher frequencies in certain rare tumors such as infantile fibrosarcoma, congenital mesoblastic nephroma, secretory breast, or salivary gland carcinoma. NTRK gene fusions or TRK fusion proteins are considered strong oncogenic drivers. If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity. So far only larotrectinib is approved in the European Union. Both drugs have been shown to be effective and well tolerated in phase I and phase II studies. The low prevalence of TRK fusion-positive cancers poses challenges for diagnostic and clinical work-flows. On one hand, patients with NTRK gene fusions should be identified; on the other hand, epidemiological, histological, and resource-related aspects have to be taken into account. Based on these premises, we suggest a diagnostic algorithm for TRK fusion cancers and present current data on TRK inhibitors.

Consensus paper: current state of first- and second-line therapy in advanced clear-cell renal cell carcinoma.

The therapy of advanced (clear-cell) renal cell carcinoma (RCC) has recently experienced tremendous changes. Several new treatments have been developed, with PD-1 immune-checkpoint inhibition being the backbone of therapy. Diverse immunotherapy combinations change current first-line standards. These changes also require new approaches in subsequent lines of therapy. In an expert panel, we discussed the new treatment options and how they change clinical practice. While first-line immunotherapies introduce a new level of response rates, data on second-line therapies remains poor. This scenario poses a challenge for clinicians as guideline recommendations are based on historical patient cohorts and agents may lack the appropriate label for their in guidelines recommended use. Here, we summarize relevant clinical data and consider appropriate treatment strategies.

Bevacizumab-associated glomerular microangiopathy.

Bevacizumab is a humanized monoclonal IgG1 antibody, which neutralizes vascular endothelial growth factor and is used for treating multiple cancer types. As a known and frequent adverse event, this therapy can lead to renal damage including proteinuria and nephrotic syndrome. In a retrospective approach, we analyzed 17 renal biopsies from patients receiving bevacizumab treatment. We observed a distinctive histopathological pseudothrombotic pattern different from the previously reported thrombotic microangiopathy. Since this pattern includes some features similar to acute and chronic thrombotic microangiopathy, focal segmental glomerulosclerosis and cryoglobulinemic membranoproliferative glomerulonephritis, biopsies with these diagnoses were included for comparison. Clinical, laboratory, light microscopic, immunohistochemical (including a proximity ligation assay), proteomic and electron microscopic features were assessed. Nephrotic syndrome was present in 15 of the 17 bevacizumab-treated patients. All 17 displayed a patchy pattern of variably PAS-positive hyaline pseudothrombi occluding markedly dilated glomerular capillaries in their biopsies. Mass spectrometry-based proteome analysis revealed a special protein pattern demonstrating some features of thrombotic microangiopathy and some of cryoglobulinemic glomerulonephritis, including a strong accumulation of IgG in the pseudothrombi. Proximity ligation assay did not show interaction of IgG with C1q, arguing for accumulation without classic pathway complement activation. In contrast to thrombi in thrombotic microangiopathy cases, the hyaline pseudothrombi did not contain clusters of CD61-positive platelets. Electron microscopy of bevacizumab cases did not show fibrin polymers or extensive loss of podocyte foot processes. Even though cases of bevacizumab-associated microangiopathy share some features with thrombotic microangiopathy, its overall histopathological pattern is quite different from acute or chronic thrombotic microangiopathy cases. We conclude that bevacizumab therapy can lead to a unique hyaline occlusive glomerular microangiopathy, likely arising from endothelial leakage followed by subendothelial accumulation of serum proteins. It can be diagnosed by light microscopy and is an important differential diagnosis in cancer patients with nephrotic syndrome.

Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Nutrition- and life style-associated risk factors are increasingly prevalent. Metformin, the mainstay of type 2 diabetes mellitus (T2DM)-treatment, reduces the risk of hepatocarcinogenesis. However, its influence on the prognosis of patients with HCC has not been investigated on a large scale, yet. METHODS: Five thousand and ninety-three patients treated for HCC between 2000 and 2016 at three referral centres were included in this retrospective multicentre study. The aim of this study was to assess whether treatment with metformin for T2DM is associated with a prolonged overall survival (OS) in patients diagnosed with HCC. RESULTS: Among 5093 patients with HCC, 1917 patients (37.6%) were diagnosed with T2DM, of which 338 (17.6%) received treatment with metformin. Compared to diabetic patients not treated with metformin, patients on metformin had a significantly better hepatic function (Child-Pugh-Score A: 69.2% vs 47.4%, P < 0.001) and underwent significantly more often tumour resection (22.1% vs 16.5%, P = 0.024). Patients on metformin had a significantly longer median OS (mOS) compared to diabetic patients not treated with metformin (22 vs 15 months, P = 0.019). The prolongation of survival was most significant in patients treated with surgery. Using a propensity score match (PSM), patients were adjusted for hepatic function and initial therapy. In the matched cohorts, mOS remained significantly longer in metformin-treated patients (22 vs 16 months, P = 0.021). Co-treatment of metformin and sorafenib was associated with a survival disadvantage. CONCLUSION: Treatment with metformin was associated with an improved survival in patients with T2DM and HCC. This effect was most pronounced in patients at potentially curative tumour stages.

Renal cell carcinoma in kidney transplant recipients: descriptive analysis and overview of a major German transplant center.

Aim: Elevated risk of malignancy-related death after renal transplantation is reported and renal malignancy was ranked as the third most frequent site of malignancy-related death. However, there is a lack of data characterizing renal cell carcinoma associated with end-stage renal disease and kidney transplantation. Patients & methods: We retrospectively identified 5250 patients who underwent kidney transplantation at the Hannover Medical School since 1970. Results: 124 patients with renal cell carcinoma (incidence 2.36%) were identified. Among all patients, metastatic recurrence was noted in 4.8%. In multivariate analysis, tumor stage and hemoglobin were identified as independent prognostic markers of OS, while tumor grading was predictive for disease recurrence. Conclusion: Apart from showing the prognostic value of tumor staging and hemoglobin, our data suggest that a risk adapted approach for early transplantation is feasible.

The Treatment of Metastatic Renal Cell Carcinoma.

BACKGROUND: Approximately 15 000 people receive a diagnosis of renal cell carcinoma (RCC) in Germany each year; in 20-30% of cases, metastatic RCC (mRCC) is already present at the time of diagnosis. This disease in the metastatic stage is still mainly treated palliatively, yet the multimodal therapeutic landscape has changed markedly over the past 15 years, with the approval of many new treatments for patients with mRCC. METHODS: This review is based on prospective studies retrieved by a selective search in PubMed and the ASCO and ESMO databases and on the German and European oncological and urological guidelines for RCC. RESULTS: Drugs are the mainstay of treatment. mRCC can be treated with a combination of two immune checkpoint inhibitors (CPIs), a CPI and a tyrosine-kinase inhibitor (TKI) (evidence level IA), or a TKI as monotherapy (evidence level IIC-IC). With prognosis-based sequential drug treatment, a mean progression-free survival of 12 to 24 months and an overall survival of approximately 50 months can be achieved from the time of initiation of first-line therapy. Aside from pharmacotherapy, the multidisciplinary tumor board should evaluate the indications for local treatments such as cytoreductive nephrectomy, metastasectomy, and radiotherapy, depending on the individual prognostic constellation and the patient's present condition. CONCLUSION: Optimal individualized decisions require a high level of expertise and the collaboration of a multidisciplinary tumor board. Older prognostic parameters currently play a leading role in decision-making, while predictive parameters and molecular markers are not yet adequately validated.

Langerhans cell histiocytosis involving the temporal bone with destruction and subsequent reossification of the bony labyrinth boundaries.

PURPOSE: With an incidence between 1-9/100 000 per year, Langerhans cell histiocytosis (LCH) is a rather rare disease from the hemato-oncologic disease spectrum (Hayes et al. 2009). The tumorlike disease with proliferation of histiocytic cells may manifest as localized to one organ or disseminated with infiltration of a wide variety of organs. Approximately 25-30 % of these cases show involvement of the temporal bone (Ni et al. 2017). CASE DESCRIPTION: With vertigo persisting for three years, chronic mastoiditis, and acute progressive hearing loss bilaterally (r > l) for three weeks, a 41-year-old woman presented at an emergency department. The DVT showed extensive bony destruction of large parts of the temporal bone on both sides, involving the vestibular organ, the cochlea, and the internal auditory canal. To confirm the suspicion of a systemic inflammatory process, a PE was performed from the mastoid with bioptic confirmation of an LCH. Systemic therapy was initiated. Post-therapeutic imaging showed almost complete remission with reossification of the preexisting defect zones and the internal auditory canal and labyrinth structures again showed bony margins. Clinically, there was an improvement of the vegetative symptoms with remaining bilateral sensorineural hearing loss. DISCUSSION: LCH of the temporal bone is a rare and often misdiagnosed disease due to its nonspecific clinical presentation. Awareness of temporal bone LCH and its occurrence in adults is essential for accurate and consistent diagnosis. KEY POINTS: · LCH is a rather rare disease from the hemato-oncological spectrum. · Affection of the temporal bone, especially such an extensive one (as in this case report), is rather atypical in adulthood. · Use of systemic therapy resulted in remission. · There was complete reossification of the osseous structures post-therapy. · A cochlear implant was able to be implanted to compensate for hearing loss.

Cabozantinib Plus Nivolumab in Adult Patients with Advanced or Metastatic Renal Cell Carcinoma: A Retrospective, Non-Interventional Study in a Real-World Cohort/GUARDIANS Project.

INTRODUCTION: Combinations of immune-checkpoint inhibitors (ICIs) are the standard of care (SOC) for treatment-naive metastatic renal cell carcinoma (mRCC) patients. In this multicenter study, we evaluated the RW safety and efficacy of cabozantinib plus nivolumab in mRCC patients. METHODS: Data were retrospectively collected from twelve cancer centers in Germany, Switzerland, and Austria. Patients with advanced or mRCC were eligible. The investigator-based objective response rate (ORR) and progression free survival (PFS) were calculated from the start of the treatment to progression or death. Descriptive statistics and Kaplan-Meier (KM) plots were utilized where appropriate. RESULTS: In total, 96 eligible patients (66.6% male) with a median age of 66.0 years were included. The most common histology was clear-cell RCC (ccRCC) in 63.4% (n = 61). A prior nephrectomy was performed in 60.4% (n = 58). ECOG 0-1 was 68.8% (n = 66). A partial response was documented in 43.8% of patients (n = 42), a stable disease in 32.3% (n = 31), and a progressive disease in 8.3% (n = 8) as the best overall response. Response data were not evaluable in 13.5% (n = 13). The median follow-up time was 12.7 months (95% CI, 10.0-15.3). The PFS rate at 6 months was 89.8% in the overall population (86.8% for ccRCC; 90.0% for non-ccRCC). Adverse events (AEs) were reported in 82.3% (n = 79) for all grades and 41.7% (n = 40) for grades 3-5. Elevated liver enzymes (34.4%), diarrhea (31.3%), and hand-foot syndrome (29.2%) were the three most frequent AEs of any grade and causality. DISCUSSION/CONCLUSIONS: In this real-world cohort of mRCC patients, the application of cabozantinib plus nivolumab was shown to be safe and feasible. Our data support the use of cabozantinib plus nivolumab as a first-line standard therapy in mRCC patients. Major limitations were the retrospective data capture and short follow-up time of our study.

NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer.

PURPOSE: The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. MATERIALS AND METHODS: We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non-EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. RESULTS: NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup (P < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. CONCLUSION: NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

Reconstitution and phenotype of Tregs in CMV reactivating patients following allogeneic hematopoietic stem cell transplantation.

In experimental and clinical settings Tregs prevent graft-versus-host disease (GvHD) by inhibiting the proliferation and function of conventional T cells (Tconv). The suppressive potency of Tregs might also lead to the inhibition of protective antiviral T cell responses. As the control of CMV reactivation is important to improve the clinical outcome in allogeneic HSCT, we analyzed the Treg reconstitution in CMV reactivating patients with and without GvHD (n=47) in the first 6 months following transplantation. Most importantly, CMV reactivation does not correlate with the numerical reconstitution of CD4(+)CD25(high)CD127(-) Tregs. During CMV reactivation the proportion of Tregs within the CD4(+) T cell population decreased significantly independent of GvHD manifestation. A comprehensive FACS analysis was performed in order to characterize the phenotype of Tregs and Tconv cells in greater detail for activation, co-stimulation, proliferation, suppressive function and migratory capability. Interestingly, Tregs of patients with CMV reactivation showed a significantly higher CXCR3 expression. CD4(+) Tconv cells expressed significantly higher protein levels of the proliferation marker Ki67 correlating with a numerical increase of CD4(+) T cells. Our results indicate that Tregs are not inhibiting pathogen clearance by Tconv following HSCT, which is of high relevance for future Treg cell-based clinical trials in allogeneic HSCT.

A Podcast Discussion on the Current Treatment Landscape for Renal Cell Carcinoma.

During the last 15 years, tremendous efforts have been made in the medical treatment of metastatic renal cell carcinoma (mRCC). Immune-oncological (IO) combinations are the current standard of care in the first-line setting of mRCC. Here, the current phase 3 trials CM214 (nivolumab/ipilimumab vs. sunitinib), KN426 (axitinib/pembrolizumab vs. sunitinib), Javelin-ren-101 (axitinib/avelumab vs. sunitinib), CM9ER (cabozantinib/nivolumab vs. sunitinib), and CLEAR (lenvatinib/pembrolizumab vs. sunitinib) were discussed. In the mentioned phase 3 trials, primary and secondary endpoints were discussed. Strengths and weaknesses of each trial were reflected in terms of overall survival, progression-free survival, objective remission, health quality of life, and safety. Reflecting on the data, as well as the current ESMO guidelines, we discuss choosing the appropriate medical treatment for patients' individualized treatment journey and relay the strength and weaknesses of each combination-starting with the appropriate first-line therapy.

First Line Medical Treatment of Metastatic Renal Cell Carcinoma: A Podcast on Choosing Wisely and Managing Safely.

During the last 15 years, tremendous efforts have been made toward medical treatment of metastatic renal cell carcinoma (mRCC). Checkpoint inhibitors (CPI) and tyrosine kinase inhibitors (TKI) dominate the therapeutic armamentarium, as a combination of either CPIs or CPI/TKI, while the value of TKI monotherapy is decreasing. With increasing efficiency, however, toxicity also increases. Appropriate management of adverse events is therefore pivotal. Recognizing adverse events, judging their etiology and appropriate management, and sometimes expanding the diagnostics of adverse events are mandatory and demand experience and vigilance. Ultimately, appropriate safety management achieves optimal oncological outcomes and maintains patient quality of life.

Enfortumab vedotin as a salvage option as 5th line therapy for metastatic urothelial bladder cancer.

A 67-year-old female patient with a muscle-invasive, non-metastatic urothelial bladder cancer (UC) (pT2 G3 cN0 cM0) developed metachronous metastases within 6 months after radical cystectomy with ileal conduit urinary diversion. After a good primary response to platinum-based chemotherapy, treatment was switched to the immune checkpoint inhibitor (ICI) pembrolizumab due to progressive disease. Subsequently the patient underwent selective internal radiotherapy (SIRT) of the liver and received vinflunine as well as a re-challenge with pembrolizumab. Two years after the initial diagnosis, rapid disease progression ultimately led to a switch to 5th line therapy with enfortumab vedotin (EV), which had only been approved in the United States at that time. The antibody-drug conjugate was well tolerated by the patient after dose reduction to 1.0 mg/ kg body weight. Simultaneous irradiation of newly occurring precardiac, hepatic and cerebral metastases were necessary. After 10 months of therapy with EV, tumour regression was observed accompanied with good symptom control. The presented case illustrates the efficacy and tolerability of EV in a heavily pre-treated patient with metastatic UC (mUC).

Valuing vicinity: Memory attention framework for context-based semantic segmentation in histopathology.

The segmentation of histopathological whole slide images into tumourous and non-tumourous types of tissue is a challenging task that requires the consideration of both local and global spatial contexts to classify tumourous regions precisely. The identification of subtypes of tumour tissue complicates the issue as the sharpness of separation decreases and the pathologist's reasoning is even more guided by spatial context. However, the identification of detailed tissue types is crucial for providing personalized cancer therapies. Due to the high resolution of whole slide images, existing semantic segmentation methods, restricted to isolated image sections, are incapable of processing context information beyond. To take a step towards better context comprehension, we propose a patch neighbour attention mechanism to query the neighbouring tissue context from a patch embedding memory bank and infuse context embeddings into bottleneck hidden feature maps. Our memory attention framework (MAF) mimics a pathologist's annotation procedure - zooming out and considering surrounding tissue context. The framework can be integrated into any encoder-decoder segmentation method. We evaluate the MAF on two public breast cancer and liver cancer data sets and an internal kidney cancer data set using famous segmentation models (U-Net, DeeplabV3) and demonstrate the superiority over other context-integrating algorithms - achieving a substantial improvement of up to 17% on Dice score. The code is publicly available at https://github.com/tio-ikim/valuing-vicinity.

Monocyte chemoattractant protein 1 as a potential biomarker for immune checkpoint inhibitor-associated neurotoxicity.

BACKGROUND: Oncological patients can benefit substantially from treatment with immune checkpoint inhibitors (ICI). However, there is a growing awareness of immune-related adverse events (irAE). Especially ICI-mediated neurological adverse events (nAE(+)), are tough to diagnose and biomarkers to identify patients at risk are missing. METHODS: A prospective register with prespecified examinations was established for ICI treated patients in December 2019. At the time of data cut-off, 110 patients were enrolled and completed the clinical protocol. Herein, cytokines and serum neurofilament light chain (sNFL) from 21 patients were analyzed. RESULTS: nAE of any grade were observed in 31% of the patients (n = 34/110). In nAE(+) patients a significant increase in sNFL concentrations over time was observed. Patients with higher-grade nAE had significantly elevated serum-concentrations of monocyte chemoattractant protein 1 (MCP-1) and brain-derived neurotrophic factor (BDNF) at baseline compared to individuals without any nAE (p < 0.01 and p < 0.05). CONCLUSION: Here, we identified nAE to occur more frequently than previously reported. Increase of sNFL during nAE confirms the clinical diagnosis of neurotoxicity and might be a suitable marker for neuronal damage associated with ICI therapy. Furthermore, MCP-1 and BDNF are potentially the first clinical-class nAE predictors for patients under ICI therapy.