Early clinical trial unit tumor board: a real-world experience in a national cancer network.

PURPOSE: Early clinical trials are the first step into clinical therapies for new drugs. Within the six Bavarian university-based hospitals (Augsburg, Erlangen, Regensburg, Munich (LMU and TU), Würzburg) we have enrolled a virtual network platform for patient discussion. METHODS: The virtual Early Clinical Trial Unit Tumor Board (ECTU Tumor Board) is a secured web-based meeting to evaluate early clinical trial options for patients, where representatives from local ECTUs participate. We retrospectively analyzed patient cases discussed between November 2021 and November 2022. RESULTS: From November 2021 to November 2022, a total of 43 patients were discussed in the ECTU Tumor Board. Median age at diagnosis was 44.6 years (range 10-76 years). The median number of previous lines of therapies was 3.7 (range 1-9 therapies) including systemic treatment, surgery, and radiation therapy. A total of 27 different tumor entities were presented and 83.7% (36/43) patients received at least one trial recommendation. In total, 21 different active or shortly recruiting clinical trials were recommended: ten antibody trials, four BiTE (bispecific T cell engager) trials, six CAR (chimeric antigen receptor) T-cell trials, and one chemotherapy trial. Only six trials (28.6%) were recommended on the basis of the previously performed comprehensive genetic profiling (CGP). CONCLUSION: The ECTU Tumor Board is a feasible and successful network, highlighting the force of virtual patient discussions for improving patient care as well as trial recruitment in advanced diseases. It can provide further treatment options after local MTB presentation, aiming to close the gap to access clinical trials.

Cancer of unknown primary (CUP) through the lens of precision oncology: a single institution perspective.

PURPOSE: For patients with cancer of unknown primary (CUP), treatment options are limited. Precision oncology, the interplay of comprehensive genomic profiling (CGP) and targeted therapies, aims to offer additional treatment options to patients with advanced and hard-to-treat cancers. We aimed to highlight the use of a molecular tumor board (MTB) in the therapeutic management of CUP patients. METHODS: In this single-center observational study, CUP patients, presented to the MTB of the Comprehensive Cancer Center Munich LMU, a tertiary care center, were analyzed retrospectively. Descriptive statistics were applied to describe relevant findings. RESULTS: Between June 2016 and February 2022, 61 patients with unfavorable CUP were presented to the MTB, detected clinically relevant variants in 74% (45/61) of patients, of which 64% (29/45) led to therapeutic recommendation. In four out of 29 patients (14%), the treatment recommendations were implemented, unfortunately without resulting in clinical benefit. Reasons for not following the therapeutic recommendation were mainly caused by the physicians' choice of another therapy (9/25, 36%), especially in the context of worsening of general condition, lost to follow-up (7/25, 28%) and death (6/25, 24%). CONCLUSION: CGP and subsequent presentation to a molecular tumor board led to a high rate of therapeutic recommendations in patients with CUP. Recommendations were only implemented at a low rate; however, late GCP diagnostic and, respectively, MTB referral were found more frequent for the patients with implemented treatment. This contrast underscores the need for early implementation of CGP into the management of CUP patients.

Prognosis and tumor biology of pancreatic cancer patients with isolated lung metastases: translational results from the German multicenter AIO-YMO-PAK-0515 study.

BACKGROUND: Pulmonary metastasis (M1-PUL) as first site of dissemination in pancreatic ductal adenocarcinoma (PDAC) is a rare event and may define a distinct biological subgroup. PATIENTS AND METHODS: Arbeitsgemeinschaft Internistische Onkologie-Young Medical Oncologists-Pankreas-0515 study (AIO-YMO-PAK-0515) was a retrospective German multicenter study investigating clinical and molecular characteristics of M1-PUL PDAC patients; 115 M1-PUL PDAC patients from 7 participating centers were included. Clinical characteristics and potential prognostic factors were defined within the M1-PUL cohort. Archival tumor samples were analyzed for Her2/neu, HNF1A and KRT81 expression. Additionally, messenger RNA (mRNA) expression analysis (using a 770-gene immune profiling panel) was carried out in the M1-PUL and in a control cohort (M1-ANY). RESULTS: Median overall survival in the entire M1-PUL cohort was 20 months; the most favorable prognosis (median survival: 28 months) was observed in the subgroup of 66 PDAC patients with metachronous lung metastases after previous curative-intent surgery. The number of metastatic lesions, uni- or bilateral lung involvement as well as metastasectomy were identified as potential prognostic factors. Her2/neu expression and PDAC subtyping (by HNF1A and KRT81) did not differ between the M1-PUL and the M1-ANY cohort. mRNA expression analysis revealed significant differentially expressed genes between both cohorts: CD63 and LAMP1 were among the top 20 differentially expressed genes and were identified as potential mediators of organotropism and favorable survival outcome of M1-PUL patients. CONCLUSION: M1-PUL represents a clinically favorable cohort in PDAC patients. Site of relapse might already be predetermined at the time of surgery and could potentially be predicted by gene expression profiling.

Alterations in regulatory T cells and immune checkpoint molecules in pancreatic cancer patients receiving FOLFIRINOX or gemcitabine plus nab-paclitaxel

Purpose This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). Patients and methods Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. Results Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. Conclusions Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC (AU)

Alterations in regulatory T cells and immune checkpoint molecules in pancreatic cancer patients receiving FOLFIRINOX or gemcitabine plus nab-paclitaxel.

PURPOSE: This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. RESULTS: Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. CONCLUSIONS: Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC.

Afatinib plus gemcitabine versus gemcitabine alone as first-line treatment of metastatic pancreatic cancer: The randomised, open-label phase II ACCEPT study of the Arbeitsgemeinschaft Internistische Onkologie with an integrated analysis of the 'burden of therapy' method.

BACKGROUND: Targeting the epidermal growth factor receptor pathway remains controversial in pancreatic cancer. Afatinib is an oral irreversible ErbB family blocker approved in non-small-cell lung cancer. This open-label, multicenter, randomised phase II trial evaluated gemcitabine plus afatinib (Gem/afatinib) versus gemcitabine (Gem) alone as first-line treatment for metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomised in a 2:1 ratio to either Gem (1000 mg/m2 weekly for three weeks followed by one week of rest, repeated every four weeks) and afatinib (40 mg orally once daily) or Gem alone. Overall survival (OS) was the primary study end-point. The novel BOTh©™ methodology was implemented to derive a quantitative estimate for the 'Burden of Therapy/Toxicity' (BOTh) for each patient on every day during the clinical study. RESULTS: One hundred nineteen patients from 25 centres were randomised, 79 patients for Gem/afatinib and 40 for Gem. Median OS was 7.3 months in the Gem/afatinib arm versus 7.4 months in the Gem-alone arm (hazard ratio [HR]: 1.06, p = 0.80). Median progression-free survival was identical in both arms (3.9 months versus 3.9 months, HR: 0.85, p = 0.43). Adverse events were more frequent in the Gem/afatinib arm, especially diarrhoea (71% vs. 13%) and skin rash (65% vs. 5%). The BOTh©™ analysis revealed a significantly higher burden of toxicity in the combination arm (p = 0.0005). CONCLUSION: The addition of afatinib to Gem did not improve treatment efficacy and was more toxic. The BOTh©™ methodology allowed a detailed insight into the course of treatment-related adverse events over the study period. The trial was registered at clinicaltrials.gov (NCT01728818) and Eudra-CT (2011-004063-77).

[Bone marrow transplantation patients in the intensive care unit]. / Der knochenmarktransplantierte Patient auf der Intensivstation.

Allogeneic hematopoetic stem cell transplantation yields improved long-term survival for patients with high-risk malignant and non-malignant hematologic disease. However, it is associated with high morbidity and mortality. A proportion of patients need intensive care due to infectious, immunological and/or toxic complications. The utility of intensive care unit (ICU) treatments as mechanical ventilation and renal replacement therapy for these patients is uncertain since mortality is high. We describe the most frequent complications and the treatment options concerning the ICU in recipients of allogeneic hematopoetic stem cells.

[The critically ill CAR T-cell patient : Relevant toxicities, their management and challenges in critical care]. / Der kritisch kranke Patient nach CAR-T-Zell-Therapie : Relevante Nebenwirkungen, deren Management und Herausforderungen an die Intensivmedizin.

BACKGROUND: CAR­T cell therapy has been implemented as clinical routine treatment option during the last decade. Despite beneficial outcomes in many patients severe side effects and toxicities are seen regularly that can compromise the treatment success. METHODS: Literature review: CAR T­cell therapy, toxicities and their management RESULTS: The cytokine release syndrome (CRS) and the immune effector cell-associated neurotoxicity syndrome (ICANS) are seen regularly after CAR T­cell treatment. CRS symptoms can range from mild flu-like symptoms to severe organ dysfunction requiring vasopressor therapy, mechanical ventilation and other intensive care support. ICANS symptoms usually develop later and can range from disorientation and aphasia to potentially life-threatening brain edema. IL­6 is a key factor in the pathophysiology of CRS. The pathophysiology of ICANS is not fully understood. The ASTCT consensus grading is recommended to stratify patients for different management options. An interdisciplinary team including hematologist, intensivist, neurologists and other specialties is needed to optimize the treatment. DISCUSSION: Severe and potentially life-threatening toxicities occur regularly after CAR T­cell therapy. Treatment strategies for CRS and ICANS still need to be evaluated prospectively. Due to the increasing number of patients treated with CAR T­cells the number of patients requiring temporary intensive care management due to CRS and ICANS is expected to increase during the next years.

Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling.

T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell leukemia 1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular postthymic T cells. We assessed activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent noncanonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR clonotypes. The highly activated leukemic cells also revealed losses of negative-regulatory TCR coreceptors (eg, CTLA4). TCR stimulation of T-PLL cells evoked higher-than-normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to the marked resistance of T-PLL to activation- and FAS-induced cell death. Enforced TCL1A enhanced phospho-activation of TCR kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or chimeric antigen receptors, these Lckpr-hTCL1Atg T cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR signals and drives the accumulation of death-resistant memory-type cells that use amplified low-level stimulatory input, and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR and survival signaling.

[Prevalence of cancer patients in German intensive care units]. / Prävalenz von Krebspatienten auf deutschen Intensivstationen.

INTRODUCTION: Cancer is one of the leading causes of death worldwide. Due to increasing comorbidities, age and aggressive chemotherapy, care of cancer patients in intensive care units (ICUs) is more and more necessary. So far, little is known about the care structure of cancer patients in German ICUs. The aim of this work is to collect and evaluate the prevalence and care data of cancer patients on two reference dates. METHODS: German ICUs were invited to participate in a 2-day, prospective, multicenter point prevalence study in ICU cancer patients. Participation in the study was voluntary and the study was not funded. An ethics vote was obtained to conduct the study. The data were anonymously entered into an eCRF (electronic case report form) by the participating centers. Identification of the patients is therefore not possible. RESULTS: About one in four patients on the ICU/IMC ward had hematological-oncological (HO) disease (n = 316/1319, 24%). The proportion depended significantly on the number of beds in each hospital. The most frequent reasons for admission to the ICU/IMC station were postoperative monitoring (n = 83/221, 37.6%), respiratory instability (n = 79/221, 35.7%), circulatory instability (n = 52/221; 23.5%) and the severe infection with sepsis (n = 47/221; 21.3%). In all, 66.5% (n = 147/221) of the patients had a solid tumor and 21.7% (n = 48/221) had hematological cancer, 78.3% (n = 173/221) of the documented cancer patients received "full-code" intensive management, while 42.5% (n = 94/221) of the HO patients were ventilated and 40.7% (n = 90/221) required catecholamines. The median (mean; IQR) SAPS II score was 35 (37.79, IQR = 24-48) and the median (mean, IQR) TISS score was 10 (13.26, IQR = 10-15). Through the analysis and evaluation of the data available in the context of the prevalence study, it was possible for the first time to determine the Germany-wide cross-center prevalence and care situation of hematological cancer patients in intensive care and intermediate care stations. About one in four patients on German ICUs and IMC wards have a major or minor cancer diagnosis (n = 316/1319 = 24%). Care management is complex in this patient population and requires close interdisciplinary collaboration.

Management of sepsis in neutropenic cancer patients: 2018 guidelines from the Infectious Diseases Working Party (AGIHO) and Intensive Care Working Party (iCHOP) of the German Society of Hematology and Medical Oncology (DGHO).

Sepsis and septic shock are major causes of mortality during chemotherapy-induced neutropenia for malignancies requiring urgent treatment. Thus, awareness of the presenting characteristics and prompt management is most important. Improved management of sepsis during neutropenia may reduce the mortality of cancer therapies. However, optimal management may differ between neutropenic and non-neutropenic patients. The aim of the current guideline is to give evidence-based recommendations for hematologists, oncologists, and intensive care physicians on how to manage adult patients with neutropenia and sepsis.

Neurotrophic tropomyosin receptor kinase (NTRK) and nerve growth factor (NGF) are not expressed in Caucasian patients with biliary tract cancers: pooled data from three independent cohorts.

BACKGROUND: Neuronal signaling has been implicated in the pathophysiology of multiple malignancies. In biliary tract cancers (BTCs), tumor cell expression of nerve growth factor (NGF) and its receptor neurotrophic tropomyosin receptor kinase (NTRK) has been reported in Asian patients and linked to inferior clinical outcome. Furthermore, NTRK fusions have emerged as a promising target in various cancers. Expression patterns of these markers in Caucasian patients remain unknown. METHODS: In this study, 106 patients with BTCs were included. Immunohistochemistry for pan-NTRK and NGF-beta was performed on > 90 samples of this cohort. Additionally, samples from two independent cohorts, incorporating 254 cases, were used to confirm the findings of the original cohort. RESULTS: While expression of pan-NTRK and NGF-beta was readily detectable in peri-tumoral nerves, these markers were not detectable in malignant epithelial cells in our cohort. CONCLUSIONS: In a large cohort of Caucasian patients with BTC, NTRK and NGF-beta were not detectable, underscoring potential differences between Caucasian and Asian patient populations.

[Antifreeze poisoning : The case of a patient with repeated ethylene glycol poisoning]. / Intoxikation nach Frostschutzmittelaufnahme : Der Fall eines Patienten nach wiederholter Ethylenglykolintoxikation.

Ethylene glycol poisoning of incidental or suicidal intention can cause life-threatening metabolic acidosis, diverse secondary damage, and even lead to death. Beside hemodialysis effective therapy consists of the administration of fomepizole and ethanol. We describe a patient after repeated ethylene glycol poisoning with high anion gap metabolic acidosis and acute renal failure. Using hemodialysis, with dialysate containing a specific amount of ethanol, and intravenous ethanol administration we were able to prevent severe secondary organ damage.

Repeated mutKRAS ctDNA measurements represent a novel and promising tool for early response prediction and therapy monitoring in advanced pancreatic cancer.

Background: The presence of mutated KRAS (mutKRAS ctDNA) in plasma samples has been consistently shown to be a negative prognostic indicator in pancreatic cancer (PC). Only small pilot studies have evaluated the value of serial mutKRAS ctDNA-measurements in PC. Patients and methods: The aim of the present study was to explore the potential of repeated mutKRAS ctDNA measurements for response prediction and therapy monitoring in advanced PC patients. We used the BEAMing technology to determine levels of mutKRAS ctDNA, CA 19-9, CEA and CYFRA 21-1 in 284 plasma samples of 54 patients with advanced PC receiving gemcitabine-based chemotherapy. Absolute levels and kinetics of mutKRAS ctDNA, CA 19-9, CEA and CYFRA 21-1 were correlated to radiological response, progression-free and overall survival. Results: mutKRAS ctDNA was present in a majority of advanced PC patients (n = 36/54, 67%) and indicated tissue KRAS mutation status with a high sensitivity (75%) and specificity (100%). The presence of mutKRAS ctDNA, as well as higher levels of CA 19-9, CEA and CYFRA 21-1 before initiation of the first-line chemotherapy, was significantly correlated to an adverse overall survival. During therapy, changes in mutKRAS ctDNA levels were more rapid and pronounced than changes in protein-based tumor markers. A decrease in mutKRAS ctDNA levels during therapy was an early indicator of response to therapy, while there was no significant correlation between kinetics of CA 19-9, CEA or CYFRA 21-1 and response to chemotherapy during the first four weeks of treatment. Repeated mutKRAS ctDNA measurements during follow-up appeared to be superior to protein-based tumor markers in detecting progressive disease (sensitivity: 83%, specificity: 100%). Conclusion: mutKRAS ctDNA kinetics appear to be a powerful and highly specific tool in early response prediction and therapy monitoring of advanced PC patients receiving chemotherapy.

Consensus statement for cancer patients requiring intensive care support.

This consensus statement is directed to intensivists, hematologists, and oncologists caring for critically ill cancer patients and focuses on the management of these patients.

Prospective Analyses of Circulating B Cell Subsets in ABO-Compatible and ABO-Incompatible Kidney Transplant Recipients.

Immunosuppressive strategies applied in renal transplantation traditionally focus on T cell inhibition. B cells were mainly examined in the context of antibody-mediated rejection, whereas the impact of antibody-independent B cell functions has only recently entered the field of transplantation. Similar to T cells, distinct B cell subsets can enhance or inhibit immune responses. In this study, we prospectively analyzed the evolution of B cell subsets in the peripheral blood of AB0-compatible (n = 27) and AB0-incompatible (n = 10) renal transplant recipients. Activated B cells were transiently decreased and plasmablasts were permanently decreased in patients without signs of rejection throughout the first year. In patients with histologically confirmed renal allograft rejection, activated B cells and plasmablasts were significantly elevated on day 365. Rituximab treatment in AB0-incompatible patients resulted in long-lasting B cell depletion and in a naïve phenotype of repopulating B cells 1 year following transplantation. Acute allograft rejection was correlated with an increase of activated B cells and plasmablasts and with a significant reduction of regulatory B cell subsets. Our study demonstrates the remarkable effects of standard immunosuppression on circulating B cell subsets. Furthermore, the B cell compartment was significantly altered in rejecting patients. A specific targeting of deleterious B cell subsets could be of clinical benefit in renal transplantation.