BACKGROUND:Colorectal cancer (CRC) accounts for 10% of cancer cases worldwide; however, pediatric CRC is extremely rare, with an annual incidence of one to two cases per million. Microsatellite instability (MSI) has been shown to play a relevant prognostic role in adult CRC. Corresponding data for pediatric CRC are lacking. This study examines MSI in pediatric CRC. PROCEDURE:Patient-, tumor-, and treatment-related data of patients less than 18 years with CRC enrolled in the German Registry for Rare Pediatric Tumors (STEP) between 2005 and 2023 were analyzed and compared with data on patients less than 30 years with CRC and known MSI status from the Surveillance, Epidemiology, and End Results Program (SEER). RESULTS:Forty-one patients with CRC were recorded in STEP. Cancer predisposition syndromes were identified in 52% of tested cases, especially in CRC with MSI (84.6%). The SEER cohort included 803 CRC patients under 30 years, 52 of whom were under 20 years. Most cases were at an advanced stage at diagnosis, with localized disease being rare (STEP: 4.9%, SEER: 16.4%). The 5-year overall survival (OS) of STEP patients was 47.9% ± 9.7%. MSI was observed in 37.5% (STEP) and 32.7% (SEER <20 years) of patients. CRCs with MSI had lower rates of distant metastases and were associated with a significantly better survival (STEP 5-year OS: MSI 85.1% ± 9.7% vs. no-MSI 28.3% ± 11.2%, p = 0.007). CONCLUSIONS:While pediatric CRCs overall more often demonstrate advanced stages, unfavorable histology, and a poorer prognosis than adult CRC, MSI is more common in pediatric CRC and is associated with superior survival.

BACKGROUND & AIMS:Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome. The choice of extended or partial colectomy in patients with LS with primary CRC may influence the risk of metachronous CRC. This study aimed to identify factors associated with metachronous CRC risk and evaluate their potential implications for surgical decision-making. METHODS:We analyzed data from the German Consortium for Familial Intestinal Cancer of patients with LS who underwent either extended or partial colectomy for primary CRC. Cox regression models were used to assess the risk of metachronous CRC, adjusting for sex, age, tumor location, surveillance adherence, and gene. RESULTS:Among 852 LS carriers, 21.1% developed metachronous CRC over a median follow-up of 7.9 years. Among high-risk patients with LS, partial colectomy was associated with a borderline nonsignificant increased risk of metachronous CRC of 3.78 (95% confidence interval, 0.93-15.34; P = .063) compared with extended colectomy. Male sex (hazard ratio [HR], 2.16; P < .001), older age at primary CRC diagnosis (HR, 1.03; P < .001), and left-sided tumor location (HR, 1.53; P = .037) were additional risk factors. Surveillance adherence was not significantly associated with metachronous CRC risk. CONCLUSIONS:This study identifies important risk factors for metachronous CRC in patients with LS, which may support personalized counseling regarding surgical strategies. The findings highlight the complexity of surgical decision-making and the need for individualized approaches. Further studies are required to refine risk stratification and evaluate long-term outcomes to optimize patient care.

BACKGROUND:Primary lung carcinomas are extremely rare in childhood, resulting in limited knowledge of their biology and potential therapeutic targets. METHODS:Whole genome sequencing analysis was performed on 14 patients, thereof 13 pediatric patients. The cohort was grouped into pulmonary mucoepidermoid carcinoma (PMEC) and lung adenocarcinoma (LUAD) with an additional sample being adenosquamous carcinoma (ASC). DNA of tumor and normal tissue were isolated from FFPE and sequenced on a high-throughput sequencer. Data analysis was performed with an in-house validated data analysis pipeline. RESULTS:In the group of pediatric LUAD and ASC, ALK::EML4 fusions were confirmed in three of six tumors, prompting ALK-targeted treatment. We also found mutations frequently occurring in adult LUAD, such as TP53 (n = 3), KRAS and EGFR (each n = 1), but not other established druggable alterations. No smoking-related signatures were observed. One LUAD sample had a homologous recombination deficiency with a high amount of copy number alterations. In the PMEC group (n = 7), we found MAML2 fusions in all patients. Pathogenic germline variants and elevated polygenic risk scores for lung cancer were not detected in both groups. CONCLUSIONS:This study provides crucial insights into the genomic landscape across different types of pediatric lung cancer. We observed frequent presence of ALK fusions in pediatric LUAD + ASC, which are less common in adult LUAD. Other alterations in this subgroup showed resemblance with adult LUAD findings. In pediatric PMEC, we demonstrated the ubiquitous presence of MAML2 translocations. However, the conclusions of the study are limited due to the small sample size and potential artifacts from formalin-fixed paraffin-embedded samples. In summary, the results provide better understanding of the development of rare pediatric tumors and approaches for targeted therapies.

Background: The use of fresh umbilical cord blood (UCB) CD34+ hematopoietic stem cell (HSC)-derived allogeneic natural killer (NK) cells has shown favorable safety in a phase I clinical trial in patients with acute myeloid leukemia (AML). Methods: In a multicenter, open-label, phase I study (NCT04632316) we evaluated the safety and efficacy of cryopreserved UCB CD34+ HSC-derived NK cells, inaleucel (oNKord®), after lymphodepleting conditioning regimen of cyclophosphamide/fludarabine (Cy/Flu) (for cohorts A1, A2, A3, A5), or azacitidine/venetoclax (Aza/Ven) (A4) followed by 1, 2 or 3 NK cell infusions in AML patients. Patients had to be in morphologic complete remission (CR) (including CR with incomplete hematologic recovery [CRi]) with measurable residual disease (MRD), who were not proceeding to allogeneic hematopoietic cell transplantation (alloHCT). MRD was assessed by flow-cytometry and ultrahigh-sensitivity NGS. NK cell persistence was assessed by ultra-high sensitivity molecular chimerism analysis. Results: The intention-to-treat population included 16 AML patients (10 male, 6 female) with a median age of 74.5 years (range 45-82). Patients were in first or second CR after intensive (n=6) or non-intensive (n=10) chemotherapy. The distribution of ELN risk groups varied across cohorts, with a notable enrichment of favorable-risk patients in Cohort A3 (3/4) and A5 (2/3), whereas intermediate and adverse risk groups were more evenly represented in Cohorts A1, A2, and A4. Two patients had a TP53 mutation (A1 and A4) and one patient in group A3 had t(8;21)(q22;q22.1). Three cohorts (A1-3) of 3 patients each received escalating doses of NK cells (3 × 325 – 1,000 × 106 viable NK cells) on D0, D4 and D8 after Cy/Flu conditioning. Additionally, the fourth cohort (A4) received the same dose as the third cohort (A3), but followed an adjusted conditioning strategy with Aza/Ven, while the fifth cohort (A5) received the same cumulative total dose of NK cells as A3 but as a single infusion on D0. The NK cell therapy was well-tolerated and safe, with no adverse events related to the NK cells reported in A1, A2, A4 and A5, and one grade 1 cytokine-release syndrome observed in a patient of A3, which was attributable to pneumonia. This correlated well with the detection of low levels of cytokine IL-6 in patient sera. Unlike previous observations, in this cohort, patient sera analysis did not show any increase in IL-15 levels after cyclophosphamide (300 mg/m2/day at day -5 to -3) and fludarabine (30 mg/m2/day at day -5 to -3) conditioning, and IL-2 levels were overall low. Despite the lack of intrinsic or extrinsic cytokine support, NK cells were detectable for up to 14 days post infusion. MRD dynamics assessed by multiparameter flow cytometry (MFC) showed that patients with baseline MRD positivity had a median burden of 0.26% of BM CD45⁺ cells (range up to 2.3%). Notably, MRD negativity was achieved in 41% (5/12) of Cy/Flu-preconditioned patients whereas none (0/3) of the Aza/Ven-preconditioned patients reached MRD-negativity status by Day 30 post-oNKord infusion. Those who maintained MRD negativity (n=3) demonstrated sustained clinical benefit and completed the study, highlighting a strong association between early MRD clearance and improved outcomes. Furthermore, to assess early treatment efficacy, we monitored variant allele frequencies (VAFs) of all known mutations using NGS-MRD analysis. Among 16 patients, 7 (44%) exhibited >50% reduction in VAFs for all detected variants between baseline and 3 months post-treatment. In 5 additional patients (31%), at least one mutation showed >50% reduction in VAF, while other mutations persisted. The remaining 4 patients (25%) demonstrated persistent VAFs for all detected mutations, including IDH2 and TP53. The one-year survival was 50% for all patients (n=16) and 61.5% for Cy/Flu preconditioned patients. After a median follow-up of 33.4 months, including the patients that also participated in the follow up ReKORD study NCT05290662, the median overall survival of the total cohort was 13.1 months since study entry (n=15) and 14.9 months for Cy/Flu preconditioned patients (n=13).Conclusions: One to three infusions of cryopreserved UCB CD34+ HSC-derived NK cells, inaleucel, in MRD positive AML patients were determined safe and well tolerated. Based on these promising signs of safety and efficacy dose expansion with Cy/Flu pre-conditioning is planned for the near future.

PURPOSE The CLL12 trial reassesses the watch-and-wait consensus for early-stage chronic lymphocytic leukemia (CLL) in the context of targeted therapies. METHODS The German CLL Study Group conducted a randomized, double-blind, placebo-controlled phase III trial with 363 patients with asymptomatic, treatment-naïve Binet stage A CLL at increased risk of progression to receive ibrutinib (n = 182) at a daily dose of 420 mg or placebo (n = 181). Additionally, 152 low-risk patients were allocated to the watch-and-wait group. The final analysis included event-free survival, progression-free survival, time to next treatment, overall survival, and safety assessments. RESULTS Ibrutinib significantly delayed progression to symptomatic disease ( P < .001; hazard ratio, 0.276 [95% CI, 0.188 to 0.407]), but no survival benefit was observed with 26 death cases ( P = .562) at a median observation time of 69.3 months. Five-year survival rates were excellent: 93.3% (95% CI, 89.3 to 97.3) in the ibrutinib group, 93.6% (95% CI, 89.5 to 97.7) in the placebo group, and 97.9% (95% CI, 95.6 to 100) in the watch-and-wait cohort. Estimated 10-year survival rates from diagnosis were 86.5% (95% CI, 78.7 to 94.3, placebo), 89.8% (95% CI, 83.3 to 96.3, ibrutinib), and 95.3% (95% CI, 91.1 to 99.4, watch and wait). In the ibrutinib group, one of 12 deaths was CLL-associated, compared with four of 14 fatal cases of CLL progression or Richter transformation in the placebo group. Adverse and serious adverse events occurred in 99.4% and 60% of both treatment groups, respectively. The safety profile indicated increased cardiovascular toxicity in the ibrutinib group. CONCLUSION Ibrutinib treatment in early-stage CLL delayed disease progression compared with placebo. However, with the given observation time and few deaths, no survival benefit was demonstrated. In the era of targeted therapies, watch and wait remains the standard of care irrespective of risk factors.

Die Chirurgie der Milz bei hämatologischen Erkrankungen erfordert eine gut abgewogene Indikationsstellung, da sich die Therapie aufgrund vieler neuer medikamentöser Ansätze in den letzten Jahren sehr verändert hat. Zusammenfassung der Indikationen, Operationsverfahren und perioperatives Management bei operativen Eingriffen an der Milz bei hämatologischen Erkrankungen. Selektive Literaturrecherche und Darstellung von Übersichtsarbeiten und Leitlinienempfehlungen. Bei hämatologischen Erkrankungen zählt die Chirurgie der Milz (Splenektomie und partielle Splenektomie) zum fundamentalen Repertoire der Therapie. In den letzten Jahren hat sich aufgrund neuer medikamentöser Therapien die Indikationsstellung weiter fokussiert; insbesondere bei der hereditären Sphärozytose, der Immunothrombozytopenie, bei symptomatischer Splenomegalie und Hypersplenismus hat sie ihren Stellenwert. Goldstandard ist die minimal-invasive Splenektomie. Aufgrund der Immun- und Sequestrierungsfunktion der Milz gilt es, prä- und postoperativ besonders auf infektiöse und thromboembolische Ereignisse zu achten und diesen vorzubeugen. Eine enge interdisziplinäre Zusammenarbeit mit der Hämatologie ist für das optimale Outcome der Patienten essenziell. Die minimal-invasive (partielle) Splenektomie gehört zum chirurgischen Repertoire in der Diagnostik und Therapie hämatologischer Erkrankungen. Aufgrund neuartiger medikamentöser Ansätze verändert sich die Therapie laufend. Eine enge Kooperation mit der Hämatologie ist für die optimale Indikationsstellung und das perioperative Management wichtig.

Introduction: We present the final analysis of the phase 3, double-blind, placebo-controlled CLL12 trial evaluating ibrutinib in patients with early stage CLL at increased risk of progression defined by a comprehensive score (NCT02863718). Methods: We randomly assigned patients with asymptomatic, treatment-naïve Binet stage A CLL at increased risk of progression in a 1:1 ratio to receive ibrutinib (n = 182) or placebo (n = 181) at a dose of 420 mg daily. Patients with low risk CLL were allocated to the watch and wait group (W&W; n = 152). The final analysis evaluated event-free survival (EFS; defined as time to symptomatic progression, CLL treatment or death), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). Results: At a median observation time of 69.3 months the overall response rate was 72.5% in the ibrutinib group. PFS, EFS and TTNT were not reached in the ibrutinib group as compared to 14 months (p < 0.001; HR 0.174, 95% CI 0.122–0.246), 51.6 months (p < 0.001; HR 0.276, 95% CI 0.188–0.407), and 68.5 months (p < 0.001; HR 0.244, 95% CI 0.156–0.380) in the placebo group. A total of 29 (15.9%), 79 (43.6%), and 25 (16.4%) subsequent treatment lines were administered in the ibrutinib, placebo and W&W group, respectively. The median overall survival was not reached in neither treatment group (p = 0.562, HR 0.791, 95% CI 0.358–1.748) with 12 (6.6%) deaths in the ibrutinib and 14 (7.7%) deaths in the placebo group. The estimated survival rate at 5 years for patients treated with ibrutinib and placebo was 93.3% and 93.6%, respectively. A total of 6 (3.9%) deaths occurred in the W&W group with median survival from CLL diagnosis not reached, as compared to 258 months for the placebo and not reached for the ibrutinib group. Causes of death were progressive disease (1x ibrutinib), Richter Transformation (3x placebo), treatment-related adverse event (1x ibrutinib, subdural hematoma), infection (2x ibrutinib, 1x placebo, 1x W&W), concomitant disease (4x ibrutinib, 5x placebo, 4x W&W), and other (4x ibrutinib, 5x placebo, 1x W&W). Adverse events were documented in 99.4% of ibrutinib and placebo treated patients, with 71.8% and 66.1% of patients experiencing CTC grade 3–5 events, respectively. More bleeding events (36.5% vs. 14.9%), cardiac arrhythmias (22.4% vs. 9.5%), other cardiac events (17.6% vs. 15.5%), diarrhoea (40.6% vs. 28.6%), and hypertensive disorders (19.4% vs. 8.3%) occurred in ibrutinib as compared to placebo-treated patients. Encore Abstract - previously submitted to EHA 2023 The research was funded by: Janssen Keyword: molecular targeted therapies Conflicts of interests pertinent to the abstract P. Langerbeins Consultant or advisory role: Janssen, AbbVie, AstraZeneca, Beigene, Roche Honoraria: Janssen, AbbVie, AstraZeneca, Beigene, Roche Research funding: Janssen P. Cramer Consultant or advisory role: AbbVie, Acerta, AstraZeneca Honoraria: AbbVie, AstraZeneca, Janssen, Roche Research funding: AbbVie, AstraZeneca, BeiGene, Gilead, Janssen, Novartis/ GSK, Roche Educational grants: AbbVie, AstraZeneca, Gilead, Janssen, Roche M. Fürstenau Honoraria: Abbvie Research funding: Abbvie, AstraZeneca, Beigene, Janssen, Roche O. Al-Sawaf Consultant or advisory role: AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Eli Lilly, Gilead, Janssen, Roche Honoraria: AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Eli Lilly, Gilead, Janssen, Roche Research funding: AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Eli Lilly, Gilead, Janssen, Roche A. Fink Honoraria: AstraZeneca Research funding: AstraZeneca and Celgene Educational grants: AbbVie K. Kreuzer Consultant or advisory role: Mundipharma, Roche, Janssen Honoraria: Mundipharma, Roche, Janssen Research funding: Mundipharma, Roche, Janssen E. Tausch Consultant or advisory role: Roche, Abbvie, Beigene and AstraZeneca Honoraria: Roche, Abbvie, Beigene and AstraZeneca Research funding: Roche, Abbvie and Gilead C. Schneider Consultant or advisory role: AstraZeneca und AbbVie Honoraria: AstraZeneca und AbbVie M. Reiser Consultant or advisory role: Jannsen-Cilag, Abbvie, Amgen, Roche, Novartis, Beigene Honoraria: Jannsen-Cilag, Abbvie, Amgen, Roche, Novartis, Beigene M. Hensel Consultant or advisory role: AbbVie, Janssen, Roche, Beigene Honoraria: AbbVie, Janssen, Roche Educational grants: AbbVie, Janssen, Roche H. Hebarth Consultant or advisory role: AbbVie, AstraZeneca, Beigene, Celgene, Janssen, and Roche Honoraria: AbbVie, AstraZeneca, Beigene, Celgene, Janssen, and Roche Educational grants: AbbVie, AstraZeneca, Beigene, Celgene, Janssen, and Roche C. Wendtner Consultant or advisory role: Janssen-Cilag, Hoffmann-La Roche, GSK, Gilead, AbbVie, AstraZeneca, BeiGene Honoraria: Janssen-Cilag, Hoffmann-La Roche, GSK, Gilead, AbbVie, AstraZeneca, BeiGene Research funding: Janssen-Cilag, Hoffmann-La Roche, GSK, Gilead, AbbVie, AstraZeneca, BeiGene Educational grants: Janssen-Cilag, Hoffmann-La Roche, GSK, Gilead, AbbVie, AstraZeneca, BeiGene K. Fischer Consultant or advisory role: AstraZeneca Honoraria: AbbVie, Roche S. Stilgenbauer Consultant or advisory role: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis Honoraria: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis Research funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis Educational grants: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis B. Eichhorst Consultant or advisory role: Janssen-Cilag, Roche, Abbvie, Beigene, Gilead, Novartis, Celgene, ArQule, AstraZeneca and Oxford Biomedica (UK) Honoraria: Janssen-Cilag, Roche, Abbvie, Beigene, Gilead, Novartis, Celgene, ArQule, AstraZeneca and Oxford Biomedica (UK) Research funding: Janssen-Cilag, Roche, Abbvie, Beigene and Gilead M. Hallek Consultant or advisory role: Roche, Gilead, Janssen, Bristol Myers Squibb, AbbVie, AstraZeneca Honoraria: AbbVie, Celgene, Gilead Sciences, Janssen, Mundipharma, Pharmacyclics, Roche Research funding: Roche, Gilead, Janssen, Bristol Myers Squibb, AbbVie, AstraZeneca.

(1) Background: Gastric carcinoma is an exceptionally rare tumor in childhood. Little is known about the etiology, epidemiology, and clinical features of pediatric gastric carcinomas. This analysis aimed to fill this gap by increasing knowledge about the occurrence of gastric carcinoma in childhood. (2) Material and methods: Data from gastric carcinoma cases diagnosed between 2000 and 2017/2018 were retrieved from the Surveillance, Epidemiology, and End Results Program (SEER) and the German Center for Cancer Registry Data. Data from patients <20 years of age were analyzed for patient- and tumor-related characteristics. In addition, clinical data from patients with gastric carcinoma registered in the German Registry for Rare Pediatric Tumors (STEP) were analyzed for diagnostics, therapy, and outcome. (3) Results: Ninety-one cases of gastric carcinoma, mainly in adolescents, were identified in the epidemiologic cancer registries. Among patients with recorded staging data, advanced tumor stages were common (66.7%). Within the follow-up period covered, 63.7% of patients with clinical follow-up data died. Eight pediatric patients with gastric carcinoma were enrolled in the STEP registry, among whom two were patients with hereditary CDH1 mutations and another was a patient with Peutz−Jeghers syndrome. Three patients were found to have distinctly decreased immunoglobulin concentrations. All four patients in whom complete resection was achieved remained in remission. Three of the other four patients died despite multimodal therapy. (4) Conclusions: A combination of Helicobacter pylori infection and tumor predisposition and/or immunodeficiency appears to promote the development of gastric carcinoma in childhood. While patients with localized disease stages have a good chance of achieving durable remission through complete resection, patients with stage IV carcinomas face a dismal prognosis, highlighting the need to develop new strategies such as mutation-guided treatments.

Engineering immune cells to treat hematological malignancies has been a major focus of research since the first resounding successes of CAR-T-cell therapies in B-ALL. Several diseases can now be treated in highly therapy-refractory or relapsed conditions. Currently, a number of CD19- or BCMA-specific CAR-T-cell therapies are approved for acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma (MM), and follicular lymphoma (FL). The implementation of these therapies has significantly improved patient outcome and survival even in cases with previously very poor prognosis. In this comprehensive review, we present the current state of research, recent innovations, and the applications of CAR-T-cell therapy in a selected group of hematologic malignancies. We focus on B- and T-cell malignancies, including the entities of cutaneous and peripheral T-cell lymphoma (T-ALL, PTCL, CTCL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), classical Hodgkin-Lymphoma (HL), Burkitt-Lymphoma (BL), hairy cell leukemia (HCL), and Waldenström’s macroglobulinemia (WM). While these diseases are highly heterogenous, we highlight several similarly used approaches (combination with established therapeutics, target depletion on healthy cells), targets used in multiple diseases (CD30, CD38, TRBC1/2), and unique features that require individualized approaches. Furthermore, we focus on current limitations of CAR-T-cell therapy in individual diseases and entities such as immunocompromising tumor microenvironment (TME), risk of on-target-off-tumor effects, and differences in the occurrence of adverse events. Finally, we present an outlook into novel innovations in CAR-T-cell engineering like the use of artificial intelligence and the future role of CAR-T cells in therapy regimens in everyday clinical practice.

Current therapeutic approaches for colorectal cancer (CRC) focus on the suppression of oncogenic kinase signaling. Here, we test the hypothesis that targeted hyperactivation of the PI3K/AKT-signaling may lead to trigger CRC cell death. Recently we found that hematopoietic SHIP1 is ectopically expressed in CRC cells. Here we show that SHIP1 is more strongly expressed in metastatic cells than in the primary cancer cells, which allows for an increase in AKT signaling in metastatic cells, giving them an advantage from an evolutionary point of view. Mechanistically, the increased SHIP1 expression reduces the activation of the PI3K/ AKT signaling to a value that is below the threshold that leads to cell death. This mechanism gives the cell a selection advantage. We show that genetic hyperactivation of PI3K/AKT-signaling or blocking the activity of the inhibitory phosphatase SHIP1, induces acute cell death in CRC cells, because of excessive accumulation of reactive oxygen species. Our results demonstrate that CRC cells critically depend on mechanisms to fine-tune PI3K/AKT activity and show SHIP1 inhibition as an unexpectedly promising concept for CRC therapy.

Einleitung Pathogene Keimbahnvarianten in CDH1 oder CTNNA1 gehen mit einem hohen Risiko für ein diffuses Magenkarzinom (DGC) und bei weiblichen CDH1-Anlageträgerinnen auch für ein lobuläres Mammakarzinom (LBC) einher. Anlageträger zeigen oft schon in jungen Jahren multiple Herde eines Siegelringzellkarzinoms des Magens (SRCC) und bekommen eine prophylaktische totale Gastrektomie (PTG) angeboten, vor allem, wenn die Familienanamnese (FA) positiv für ein DGC ist.

Background: Measurable residual disease (MRD) is a predictor of adverse prognosis in patients with Acute Myeloid Leukemia (AML). Elimination of MRD in patients having reached complete remission (CR) could therefore improve their long-term outcomes. Aims: In the WiNK trial (NCT04632316), AML patients, who are in CR/CRi with MRD positivity, but are not undergoing allogeneic hematopoietic stem cell transplantation and who have signed informed consent, are treated with an “off-the-shelf” (readily available), allogeneic (unmatched), cryopreserved NK cell preparation (GTA002), which is generated from CD34+ hematopoietic stem and progenitor cells derived from umbilical cord blood. Methods: The WiNK trial is an ongoing, prospective, open-label, single arm, multicenter Phase I/IIa trial to evaluate the safety and efficacy of GTA002. The Phase I portion follows a 3 + 3 dose escalation design with 3 cohorts testing 1, 2 or 3 infusions (dose levels (DL) 1 to 3) with up to 1 x 109 viable NK cells/dose, spaced 4 days apart, resulting in a cumulative dose range of 1 (lowest) to 3 x 109 (highest) viable NK cells. GTA002 is infused after a conditioning regimen of cyclophosphamide (Cy) and fludarabine (Flu) from day -5 to -3 at 300 and 30 mg/m2, respectively, with no subsequent planned antileukemic treatment. MRD is assessed by multiparametric flowcytometry (MRD-MFC) and error corrected next generation sequencing (MRD-NGS), while chimerism analysis is assessed by duplex qPCR. Results: To date, three patients have been treated at DL1 and two at DL2. Median age of all 5 patients was 73 years (range 69 to 81) with an ELN risk category of favorable in one, intermediate in three and adverse in one patient. Infusions with GTA002 were well tolerated at DL1, with no serious adverse events (SAE) or adverse events (AEs) related to the IMP. One SAE Grade (G) 3 febrile neutropenia related to the conditioning was reported, resulting in a protocol change to a lower dose of Cy/Flu. No ICANS, CRS or GvHD was reported. Severe AEs were almost all (8 of 9) related to the conditioning regimen: anemia G3 (2x), leukopenia G4 (2x), neutropenia G3 (1x) and G4 (1x), thrombocytopenia G4 (1x), febrile neutropenia G3 (1x), lactic acidosis G3 (1x). At DL2, no SAE or dose limiting toxicity was reported up to the date of data cut off. At DL1, all three patients achieved changes of their MRD levels with MRD negativity of 9, 1 and 2 months (ongoing) by MRD-MFC. MRD-NGS showed MRD negativity for 6 (NPM1), 4 (PTPN11 clone only, out of 3 clones: PTPN11, IDH2, SRSF2) and 0 months (mutated TP53). At DL1, GTA002 could be detected by chimerism analysis in peripheral blood at levels up to 2.4% with trace amounts present up to 4 weeks after infusion. Summary/Conclusion: GTA002 treatment of AML patients in CR/CRi with MRD was well tolerated with manageable side effects of the conditioning therapy. Even at the lowest dose level, periods of MRD negativity could be documented by MFC and NGS adding to the excitement of the evaluation of allogeneic, off the shelf NK cell-based immunotherapies in hematological malignancies.

Extravasation of circulating tumor cells (CTCs) is critical for metastasis and is initiated by adhesive interactions between glycoligands on CTCs and E-selectin on endothelia. Here, we show that the clinically approved proteasome inhibitor bortezomib (BZM; Velcade) counteracts the cytokine-dependent induction of E-selectin in the lung mediated by the primary tumor, thereby impairing endothelial adhesion and thus spontaneous lung metastasis in vivo. However, the efficacy of BZM crucially depends on the tumor cells' E-selectin ligands, which determine distinct adhesion patterns. The canonical ligands sialyl-Lewis A (sLeA) and sLeX mediate particularly high-affinity E-selectin binding so that the incomplete E-selectin-reducing effect of BZM is not sufficient to disrupt adhesion or metastasis. In contrast, tumor cells lacking sLeA/X nevertheless bind E-selectin, but with low affinity, so that adhesion and lung metastasis are significantly diminished. Such low-affinity E-selectin ligands apparently consist of sialylated MGAT5 products on CD44. BZM no longer has anti-metastatic activity after CD44 knockdown in sLeA/X-negative tumor cells or E-selectin knockout in mice. sLeA/X can be determined by immunohisto-chemistry in cancer samples, which might aid patient stratification. These data suggest that BZM might act as a drug for inhibiting extravasation and thus distant metastasis formation in malignancies expressing low-affinity E-selectin ligands.

Objective Although there has been much conceptual work on patient-centredness (PC), patients‘ perspectives on PC were neglected. In a previous study, participating patients rated the relevance of 16 dimensions of an integrative model of PC as high to very high. However, it remained unclear which specific behaviours described in the dimensions were considered most relevant. Thus, the aim of the current study was to further explore which of the specific behaviours described in the model are especially relevant for the high ratings in the previous study. Methods and design We conducted semistructured interviews with 20 patients with chronic diseases (16 females, 4 males, mean age: 52 years). Patients answered questions regarding their experiences in the German healthcare system and how optimal healthcare would look like from their perspective. Furthermore, patients were asked to reflect on the most important aspects which they had mentioned in the interview before. Data were analysed via content analysis. Results Participants addressed many different aspects of PC, but mostly focused on three major themes: (1) time appropriate access to care, (2) competence, empathy and being taken seriously by HCPs, (3) HCPs’ individual consideration of each patient’s situation (eg, wishes and needs). Minor themes were: (1) taking a holistic perspective of the patient, (2) patient-centred communication, (3) integration of multidisciplinary treatment elements, (4) transparency regarding waiting time and (5) reduction of unequal access to care. Conclusion This study enriches the construct of PC by depicting essential aspects of PC from the patients’ perspective. The results allow prioritising strategies to implement patient-centred care. Thus, this study helps to pursue the ultimate goal of fostering patient-centred healthcare delivery in Germany.

Background: Pre-therapeutic analysis of threedimensional spheroid cultures of primary tumour samples is a promising approach of assessing susceptibility to potential treatment. The phosphatidylinositol-3-kinase/AKT serine/ threonine kinase/mammalian target of rapamycin (PI3K/ AKT/mTOR) signalling pathway is frequently activated in colorectal cancer (CRC). In previous work, we showed combined inhibition of AKT and mTOR to be highly synergistic in cell lines from patients with hepatocellular carcinoma and cholangiocarcinoma in vitro as well as in vivo in murine xenograft tumour models. Materials and Methods: Patientderived xenograft colorectal carcinoma cell lines HROC80 T1 M1, HROC147 T0 M1, HROC147Met, HROC277 T0 M1 and HROC277Met2 were treated with AKT inhibitor MK2206, mTOR inhibitor RAD001 or the combination of both drugs. The sensitivity of these cell lines to inhibition was evaluated by calculation of combinatory indices after bromodeoxyuridine assays and analysis of the respective pathways by western blotting. Furthermore, the dual inhibition of AKT and mTOR was confirmed in vivo in a xenograft mouse model. Additionally, primary CRC samples of four patients were embedded in a three-dimensional matrix and the sensitivity of these samples was analyzed by measurement of the spheroid area. Results: In this study, we demonstrate that combined treatment with MK2206 and RAD001 resulted in strong synergistic effects on growth of several primary CRC cell lines and reduced the growth of a patient-derived CRC xenograft in a xenotransplantation mouse model in vivo. Interestingly, the response to treatment varied between cell lines derived from the primary lesion and a liver metastasis of the same patient. In addition, combined treatment with AKT and mTOR inhibitors resulted in a synergistic inhibition of tumouroid growth in all four of the primary patient samples, analyzed in a three-dimensional spheroid model in vitro. Conclusion: Our data demonstrate that combined treatment with AKT and mTOR inhibitors exhibits synergistic effects on proliferation of cell lines and primary tumour cells from patients with CRC and may be a promising approach for the treatment of CRC.

Tumor transplantation studies, the development of inbred mouse strains, and new diagnostic procedures give evidence that a broad variety of cancers in humans as well as in animal models induce host immune response. Cytokine gene therapy is the transduction of either tumor cells or immune cells involved in the antitumoral host response. Tumor antigens are encoded by normal cellular genes, mutant cellular genes, or viral genes. It has been shown that normal genes, absolutely silent in nonmalignant cells, can be activated in malignant cells. Tumor cells can be transformed to produce significant amounts of certain cytokines. Expression of cytokines within the tumor cells to induce or enhance host immune response is appealing and simple in concept. Granulocyte macrophage colony stimulating factor has a broad range of functions as a growth and survival factor as well as an enhancer of the function of mature blood cells.