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Forming the inner layer of the vascular system, endothelial cells (ECs) facilitate a multitude of crucial physiological processes throughout the body. Vascular ECs enable the vessel wall passage of nutrients and diffusion of oxygen from the blood into adjacent cellular structures. ECs regulate vascular tone and blood coagulation as well as adhesion and transmigration of circulating cells. The multitude of EC functions is reflected by tremendous cellular diversity. Vascular ECs can form extremely tight barriers, thereby restricting the passage of xenobiotics or immune cell invasion, whereas, in other organ systems, the endothelial layer is fenestrated (e.g., glomeruli in the kidney), or discontinuous (e.g., liver sinusoids) and less dense to allow for rapid molecular exchange. ECs not only differ between organs or vascular systems, they also change along the vascular tree and specialized subpopulations of ECs can be found within the capillaries of a single organ. Molecular tools that enable selective vascular targeting are helpful to experimentally dissect the role of distinct EC populations, to improve molecular imaging and pave the way for novel treatment options for vascular diseases. This review provides an overview of endothelial diversity and highlights the most successful methods for selective targeting of distinct EC subpopulations. [ABSTRACT FROM AUTHOR]

Simple Summary: Genetic disposition to malignancies represents a significant factor in the diagnosis and treatment of cancer patients, as well as for pre- and post-treatment care of patients and their relatives. In our work, we point out the specific distribution of malignancies in adolescents and young adult patients (AYAs), highlighting the association with an increased risk of genetic predisposition. Genetic disposition requires special attention, especially for AYA patients. Knowledge of an underlying inherited cancer susceptibility facilitates individualized therapies and targeted efforts in cancer surveillance and prevention. With our work, we seek to contribute to a more consistent integration of the screening of AYAs for hereditary cancer predisposition into daily practice in the future. The knowledge of inherited cancer susceptibility opens a new field of cancer medicine. We conducted a retrospective single-center cohort study. Data of AYA cancer patients registered between January 2014 and December 2018 were analyzed. The median age at cancer diagnosis of 704 patients (343 males, 361 females) was 32 years (range, 15–39 years), median follow-up was 181 days (range, 1–1975 days). Solid tumors were diagnosed in 575 (81.7%) patients, hematologic malignancies in 129 (18.3%) patients. Multiple primary cancers were reported in 36 (5.1%) patients. Malignancies that may be indicators of inherited cancer susceptibility were diagnosed in 2.6% of patients with cancers of the endocrine system, in 73% of cancers of the gastrointestinal system, in 88% of tumors of the central nervous system, in 92% of cancers of the urinary tract, and in 59% of head and neck tumors. In addition, all patients with breast cancer, sarcoma, and peripheral nerve sheath tumor were in need of genetic counselling. In sum, at least 181 of 704 (25.7%) AYA cancer patients presented with malignancies suspicious of harboring pathogenic germline variants. Evaluation of AYA cancer patients for hereditary cancer predisposition needs to be integrated into daily practice. [ABSTRACT FROM AUTHOR]

Stimulation of the B cell antigen receptor (BCR) triggers signaling pathways that promote the differentiation of B cells into plasma cells. Despite the pivotal function of BCR in B cell activation, the organization of the BCR on the surface of resting and antigen-activated B cells remains unclear. Here we show, using STED super-resolution microscopy, that IgM-containing BCRs exist predominantly as monomers and dimers in the plasma membrane of resting B cells, but form higher oligomeric clusters upon stimulation. By contrast, a chronic lymphocytic leukemia-derived BCR forms dimers and oligomers in the absence of a stimulus, but a single amino acid exchange reverts its organization to monomers in unstimulated B cells. Our super-resolution microscopy approach for quantitatively analyzing cell surface proteins may thus help reveal the nanoscale organization of immunoreceptors in various cell types. Signalling of the B cell receptor (BCR) is pivotal for survival and activation of naïve B cells. Here the authors show, using super-resolution microscopy techniques, that BCRs exist primarily as monomers and dimers in resting B cells, and oligomerize only on stimulation, thereby implicating a function of BCR clustering patterns on B cell biology. [ABSTRACT FROM AUTHOR]

Biomarkers in chronic lymphocytic leukemia (CLL) allow assessment of prognosis. However, the validity of current prognostic biomarkers based on a single assessment point remains unclear for patients who have survived one or more years. Conditional survival (CS) studies that address how prognosis may change over time, especially in prognostic subgroups, are still rare. We performed CS analyses to estimate 5-year survival in 1-year increments, stratified by baseline disease characteristics and known risk factors in two community-based cohorts of CLL patients (Freiburg University Hospital (n = 316) and Augsburg University Hospital (n = 564)) diagnosed between 1984 and 2021. We demonstrate that 5-year CS probability is stable (app. 75%) for the entire CLL patient cohort over 10 years. While age, sex, and stage have no significant impact on CS, patients with high-risk disease features such as non-mutated IGHV, deletion 17p, and high-risk CLL-IPI have a significantly worse prognosis at diagnosis, and 5-year CS steadily decreases with each additional year survived. Our results confirm that CLL patients have a stable survival probability with excess mortality and that the prognosis of high-risk CLL patients declines over time. We infer that CS-based prognostic information is relevant for disease management and counseling of CLL patients. [ABSTRACT FROM AUTHOR]

Background: Tumour-associated fat cells without desmoplastic stroma reaction at the invasion front (Stroma AReactive Invasion Front Areas (SARIFA)) is a prognostic biomarker in gastric and colon cancer. The clinical utility of the SARIFA status in oesophagogastric cancer patients treated with perioperative chemotherapy is currently unknown. Methods: The SARIFA status was determined in tissue sections from patients recruited into the MAGIC (n = 292) or ST03 (n = 693) trials treated with surgery alone (S, MAGIC) or perioperative chemotherapy (MAGIC, ST03). The relationship between SARIFA status, clinicopathological factors, overall survival (OS) and treatment was analysed. Results: The SARIFA status was positive in 42% MAGIC trial S patients, 28% MAGIC and 48% ST03 patients after pre-operative chemotherapy. SARIFA status was related to OS in MAGIC trial S patients and was an independent prognostic biomarker in ST03 trial patients (HR 1.974, 95% CI 1.555–2.507, p < 0.001). ST03 patients with lymph node metastasis (ypN +) and SARIFA-positive tumours had poorer OS than patients with ypN+ and SARIFA-negative tumours (plogrank < 0.001). Conclusions: The SARIFA status has clinical utility as prognostic biomarker in oesophagogastric cancer patients irrespective of treatment modality. Whilst underlying biological mechanisms warrant further investigation, the SARIFA status might be used to identify new drug targets, potentially enabling repurposing of existing drugs targeting lipid metabolism. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown origin, with a median patient survival time of ~3 years after diagnosis without anti-fibrotic therapy. It is characterized by progressive fibrosis indicated by increased collagen deposition and high numbers of fibroblasts in the lung. It has been demonstrated that CCL18 induces collagen and αSMA synthesis in fibroblasts. We aimed to identify the CCL18 receptor responsible for its pro-fibrotic activities. Methods: We used a random phage display library to screen for potential CCL18-binding peptides, demonstrated its expression in human lungs and fibroblast lines by PCR and immunostaining and verified its function in cell lines. Results: We identified CCR6 (CD196) as a CCL18 receptor and found its expression in fibrotic lung tissue and lung fibroblast lines derived from fibrotic lungs, but it was almost absent in control lines and tissue. CCL18 induced receptor internalization in a CCR6-overexpressing cell line. CCR6 blockade in primary human lung fibroblasts reduced CCL18-induced FGF2 release as well as collagen-1 and αSMA expression. Knockdown of CCR6 in a mouse fibroblast cell line abolished the induction of collagen and α-smooth muscle actin expression. Conclusion: Our data indicate that CCL18 triggers pro-fibrotic processes via CCR6, highlighting its role in fibrogenesis. [ABSTRACT FROM AUTHOR]

Chemotherapy is still the backbone of systemic treatment in the majority of cancers. However, immunotherapies, especially those based on checkpoint inhibition, are additional therapy options for many. For this, functional T cells are a mandatory requirement. The aim of this prospective study was to investigate the influence of chemotherapy on the cellular immune status of individual patients. Peripheral blood samples of 26 patients with solid malignancies undergoing chemotherapy were analyzed for lymphocyte populations and their subsets in a longitudinal approach. Chemotherapy decreased total B lymphocyte counts [median value (25–75 percentile): before chemotherapy 76/µl (39–160) vs. after chemotherapy 49/µl (24–106); p = 0.001]. Among B cells, specific subsets decreased particularly [naïve B cells (49/µl (21–111) vs. 25/µl (13–56); p = 0.001], memory B cells [3/µl (2–8) vs. 2/µl (1–4); p = 0.001], and class-switched B cells [11/µl (6–20) vs. 6/µl (3–12); p = 0.011]. In contrast, chemotherapy had no influence on the total numbers of CD4 + and CD8 + T lymphocytes or on their subsets (T helper cells 1, 2, and 17 as well as cytotoxic T cells in early, intermediate, late, terminal effector and exhausted status as well as both T-cell types with naïve, center memory, effector memory, activated, or regulatory phenotype). Furthermore, the count of natural killer (NK) lymphocytes showed no significant change before and after chemotherapy. In summary, this study shows a decrease of B lymphocytes during systemic chemotherapy, but no relevant effect on T lymphocytes, NK lymphocytes and their subsets. This could support the idea of an effective additive T-cell-dependent immunotherapy to chemotherapy. [ABSTRACT FROM AUTHOR]

The article discusses the use of molecular imaging in a 73-year-old male with chronic lymphocytic leukemia and melanoma to visualize tumor biology. The study highlights the effectiveness of non-invasive chemokine receptor imaging using positron emission tomography (PET) in detecting tumor growth and metastasis. The findings suggest that CXCR-directed imaging can provide valuable insights into disease phenotyping and tumor biology, showcasing the potential of molecular imaging in oncology research. [Extracted from the article]

Purpose: SARS‐CoV‐2 vaccines cause acute ipsilateral lymph node swelling in an important proportion of vaccines. Thus far, no malignant lymphadenopathies have been reported in temporal context to vaccination in the ipsilateral draining lymph node areas. Experimental design: Prompted by two cases with unilateral axillary lymphomas that occurred ipsilaterally to prior SARS‐CoV‐2 vaccination, we systematically retrieved all B‐cell non‐Hodgkin lymphomas at two German University Medical Centers diagnosed before and after introduction of SARS‐CoV‐2 vaccines in Germany. Available lymphoma tissue (n=19) was subjected to next‐generation immunosequencing of the IGH locus. Malignant clonotypes were mined in the CoVabDab database and published data sets from 342 uninfected individuals, 55 individuals 28 days after anti‐SARS‐CoV‐2 vaccination and 139 individuals with acute COVID‐19 together encompassing over 1 million CDR3 sequences in total. Results: Of 313 newly diagnosed cases in the two centers and observation periods, 27 unilateral manifestations in the defined deltoid draining regions were identified. The majority thereof were diffuse large B‐cell lymphomas (18 of 27 cases). Eleven unilateral cases were diagnosed in the era of SARS‐CoV‐2 vaccination and 16 in the control period before introduction of such vaccines. Of the 11 unilateral lymphomas that occurred during the vaccination period, ten had received a SARS‐CoV‐2 vaccine prior to lymphoma diagnosis. These cases were further evaluated. While left‐sided were more frequent than right‐sided lymphomas (19 vs 8 cases), no statistically significant association of vaccination site and laterality of the lymphoma manifestation was found. The unilateral lymphomas showed a normal range of B‐cell receptors typically found in these lymphoma subtypes with no evidence for anti‐SARS‐CoV‐2 sequences in the malignant clonotype. Conclusions: Together, we found no evidence that the current SARS‐CoV‐2 vaccines could serve as a trigger for lymphomagenesis in the draining lymph node areas of the deltoid region used for vaccination. [ABSTRACT FROM AUTHOR]

Purpose: Radioligand therapy is an increasingly important option for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Radiohybrid ligands targeting prostate-specific membrane antigen (PSMA) are a novel group of theranostic radioligand therapy agents for which higher tumour absorbed radiation doses have been demonstrated compared to established PSMA ligands. Here, we report data from ten patients who were treated within a compassionate use program with the radiohybrid PSMA-ligand [177Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [177Lu]Lu-PSMA-I&T.Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [177Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [177Lu]Lu-rhPSMA-10.1 (7.4–8.1 GBq per cycle). Efficacy (PSA response according to PCWG3 and RECIP) and overall survival were evaluated. Adverse events were recorded from first application.Despite progression with [177Lu]Lu-PSMA-I&T, after the first cycle of [177Lu]Lu-rhPSMA-10.1 rescue therapy, five patients (50%) showed a decrease in serum PSA level. In imaging, three of the ten patients (30%) showed a partial radiologic response. Four of the five patients with a decrease of serum PSA under [177Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [177Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [177Lu]Lu-PSMA-I&T therapy but showed an immediate response to [177Lu]Lu-rhPSMA-10.1. The additional treatment with [177Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients.Patients showing tumour progression while receiving [177Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [177Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [177Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance.Methods: Radioligand therapy is an increasingly important option for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Radiohybrid ligands targeting prostate-specific membrane antigen (PSMA) are a novel group of theranostic radioligand therapy agents for which higher tumour absorbed radiation doses have been demonstrated compared to established PSMA ligands. Here, we report data from ten patients who were treated within a compassionate use program with the radiohybrid PSMA-ligand [177Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [177Lu]Lu-PSMA-I&T.Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [177Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [177Lu]Lu-rhPSMA-10.1 (7.4–8.1 GBq per cycle). Efficacy (PSA response according to PCWG3 and RECIP) and overall survival were evaluated. Adverse events were recorded from first application.Despite progression with [177Lu]Lu-PSMA-I&T, after the first cycle of [177Lu]Lu-rhPSMA-10.1 rescue therapy, five patients (50%) showed a decrease in serum PSA level. In imaging, three of the ten patients (30%) showed a partial radiologic response. Four of the five patients with a decrease of serum PSA under [177Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [177Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [177Lu]Lu-PSMA-I&T therapy but showed an immediate response to [177Lu]Lu-rhPSMA-10.1. The additional treatment with [177Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients.Patients showing tumour progression while receiving [177Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [177Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [177Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance.Results: Radioligand therapy is an increasingly important option for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Radiohybrid ligands targeting prostate-specific membrane antigen (PSMA) are a novel group of theranostic radioligand therapy agents for which higher tumour absorbed radiation doses have been demonstrated compared to established PSMA ligands. Here, we report data from ten patients who were treated within a compassionate use program with the radiohybrid PSMA-ligand [177Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [177Lu]Lu-PSMA-I&T.Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [177Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [177Lu]Lu-rhPSMA-10.1 (7.4–8.1 GBq per cycle). Efficacy (PSA response according to PCWG3 and RECIP) and overall survival were evaluated. Adverse events were recorded from first application.Despite progression with [177Lu]Lu-PSMA-I&T, after the first cycle of [177Lu]Lu-rhPSMA-10.1 rescue therapy, five patients (50%) showed a decrease in serum PSA level. In imaging, three of the ten patients (30%) showed a partial radiologic response. Four of the five patients with a decrease of serum PSA under [177Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [177Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [177Lu]Lu-PSMA-I&T therapy but showed an immediate response to [177Lu]Lu-rhPSMA-10.1. The additional treatment with [177Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients.Patients showing tumour progression while receiving [177Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [177Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [177Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance.Conclusions: Radioligand therapy is an increasingly important option for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Radiohybrid ligands targeting prostate-specific membrane antigen (PSMA) are a novel group of theranostic radioligand therapy agents for which higher tumour absorbed radiation doses have been demonstrated compared to established PSMA ligands. Here, we report data from ten patients who were treated within a compassionate use program with the radiohybrid PSMA-ligand [177Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [177Lu]Lu-PSMA-I&T.Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [177Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [177Lu]Lu-rhPSMA-10.1 (7.4–8.1 GBq per cycle). Efficacy (PSA response according to PCWG3 and RECIP) and overall survival were evaluated. Adverse events were recorded from first application.Despite progression with [177Lu]Lu-PSMA-I&T, after the first cycle of [177Lu]Lu-rhPSMA-10.1 rescue therapy, five patients (50%) showed a decrease in serum PSA level. In imaging, three of the ten patients (30%) showed a partial radiologic response. Four of the five patients with a decrease of serum PSA under [177Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [177Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [177Lu]Lu-PSMA-I&T therapy but showed an immediate response to [177Lu]Lu-rhPSMA-10.1. The additional treatment with [177Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients.Patients showing tumour progression while receiving [177Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [177Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [177Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance.Graphical Abstract: Radioligand therapy is an increasingly important option for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Radiohybrid ligands targeting prostate-specific membrane antigen (PSMA) are a novel group of theranostic radioligand therapy agents for which higher tumour absorbed radiation doses have been demonstrated compared to established PSMA ligands. Here, we report data from ten patients who were treated within a compassionate use program with the radiohybrid PSMA-ligand [177Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [177Lu]Lu-PSMA-I&T.Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [177Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [177Lu]Lu-rhPSMA-10.1 (7.4–8.1 GBq per cycle). Efficacy (PSA response according to PCWG3 and RECIP) and overall survival were evaluated. Adverse events were recorded from first application.Despite progression with [177Lu]Lu-PSMA-I&T, after the first cycle of [177Lu]Lu-rhPSMA-10.1 rescue therapy, five patients (50%) showed a decrease in serum PSA level. In imaging, three of the ten patients (30%) showed a partial radiologic response. Four of the five patients with a decrease of serum PSA under [177Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [177Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [177Lu]Lu-PSMA-I&T therapy but showed an immediate response to [177Lu]Lu-rhPSMA-10.1. The additional treatment with [177Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients.Patients showing tumour progression while receiving [177Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [177Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [177Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance. [ABSTRACT FROM AUTHOR]

Monoclonal B-cell lymphocytosis (MBL) and monoclonal gammopathy of undetermined significance (MGUS) result from clonal expansions of mature B or plasma cells. Here, we set out to determine the immunophenotypic/monoclonal immunoglobulin ( M protein) features and co-prevalence of MBL and MGUS in a hospital-based cohort of 1909 non-hematooncological patients. Of the evaluable cases, 3.8 % showed evidence for MBL by immunophenotyping, while 9.8 % were screened positive for M protein by immunofixation. With six concomitant cases (0.4 %), MBL and MGUS were not statistically associated. At least in two of these coincident cases, MBL and MGUS were of different clonal origin since both clones had divergent light chain restriction. CD5 MBL (57.1 %) and IgM+ MGUS (24.7 %) were strikingly overrepresented compared to population-based screenings and did not progress to overt lymphoma or myeloma during the observation period (mean follow-up of 117 weeks or 110 weeks, respectively). Prevalence and phenotypes suggest that a substantial proportion of incidental MBL and MGUS in hospitalized patients may be attributed to transiently expanded B-cell clones in the context of disease-related immune stimulation rather than reflecting veritable precursors of clonal B-cell malignancies. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is characterized by progressive obstruction of pulmonary arteries owing to inflammatory processes, cellular proliferation, and extracellular matrix deposition and vasoconstriction. As treatment options are limited, we studied gene transfer of an inducible nitric oxide synthase (iNOS) using adeno-associated virus (AAV) vectors specifically targeted at endothelial cells of pulmonary vessels in a murine model of PH. Adult mice were intravenously injected with AAV vectors expressing iNOS. Mice were subjected to hypoxia for 3 weeks and killed afterward. We found elevated levels of iNOS both in lung tissue and pulmonary endothelial cells in hypoxic controls that could be further increased by AAV-mediated iNOS gene transfer. This additional increase in iNOS was associated with decreased wall thickness of pulmonary vessels, less macrophage infiltration, and reduced molecular markers of fibrosis. Taken together, using a tissue-targeted approach, we show that AAV-mediated iNOS overexpression in endothelial cells of the pulmonary vasculature significantly decreases vascular remodeling in a murine model of PH, suggesting upregulation of iNOS as promising target for treatment of PH. [ABSTRACT FROM AUTHOR]

Scurvy is ancient disease caused by low or depleted levels of vitamin C (ascorbic acid, VITC) and described throughout history. With VITC supplementation, the prognosis is excellent and symptoms resolve within a short time, whereas scurvy is usually fatal if untreated.2 Literature describes cases of pancytopeniaand bone marrow abnormalities in scurvy.3-6 MDS (myelodysplastic syndrome)-like bone marrow manifestations haven't been reported, yet. Transfusion-refractory pancytopenia with MDS-like morphologic alterations of the bone marrow in a 29-year old man: A mimicry manifestation caused by scurvy. [Extracted from the article]

Purpose: We report a case of a large three-level spinal osteosarcoma infiltrating the adjacent aorta. This is the first case in which a combined modified three-level en bloc corpectomy with resection and replacement of the adjacent aorta was successful as a part of interdisciplinary curative treatment.Methods: Case report.Results: The surgical procedure was performed as a two-step treatment. A heart lung machine (HLM) was not used, in order to avoid cerebral and spinal ischemia and to decrease the risk of hematogenous tumor metastases. Instead, a bypass from the left subclavian artery the distal descending aorta was used. We modified the en bloc corpectomy procedure, leaving a dorsal segment of the vertebral bodies to enable rapid surgery. The procedure was successful and the en bloc resection of the vertebral body with aortal resection could be achieved. Except for pallhypesthesia in the left dermatomes Th7-Th10, the patient does not have any postoperative neurologic deficits.Conclusion: Combined corpectomy with aortic replacement should be considered as a reasonable option in the curative treatment of osteosarcoma with consideration of the immense surgical risks. The use of an HLM is not necessary, especially considering the inherent risk of hematogenous tumor metastases. Modified corpectomy leaving a dorsal vertebral body segment was considered a reasonable variation since tumor-free margins could still be expected. [ABSTRACT FROM AUTHOR]

Abstract: Cell-mediated immunity may impact prostate cancer progression and has great therapeutic potential. Here, we investigated the clinical significance of the numeric density of regulatory T cells (Tregs) in prostate cancer as the presence of such cells in the tumour microenvironment has been linked to clinical outcome in other tumour entities. We detected Tregs by FOXP3 immunohistochemistry in 88.8% of 2002 prostate cancer specimens in tissue microarray format, the largest cohort so far in which Tregs have been quantified. The density of Tregs in tumour tissue was compared with pathological parameters and clinical outcome. The number of Tregs identified per 0.6mm tissue spot ranged from 1 to 10 in normal and 1 to 103 FOXP3+ cells in tumour samples. Prostate-specific antigen (PSA) recurrence-free survival was significantly reduced in patients with higher numbers of Tregs (p =0.0151). Further, a higher number of intratumoural FOXP3+ Tregs was associated with a more advanced tumour stage (p =0.0355) and higher Ki67 labelling index (p <0.0001). The tissue density of Tregs was unrelated to other clinical parameters such as spread to lymph nodes, preoperative PSA level and Gleason score. Our study suggests that the intratumoural presence of regulatory T cells may have substantial functional impact and may confer an adverse clinical course in prostate cancer. [Copyright &y& Elsevier]

Spontaneous complete remission (CR) is a rare, poorly understood phenomenon in acute myeloid leukemia (AML). We describe the 10-year follow-up of a patient with MLL-AF9-positive AML (Müller et al. Eur J Haematol 73:62-66, ), including ex vivo antileukemic immune responses which may contribute to the long-lasting spontaneous CR (tantamount to cure). We could demonstrate strong in vitro cytotoxic activity mediated by the patient's serum (cryopreserved at diagnosis 2001) against myeloid cell lines. We also addressed cellular cytotoxic activity against myeloid leukemia cells. When the patient's natural killer (NK) cells (obtained in 2007) were tested against the K562 cell line, upregulation of CD107 occurred, implying that long-term CR in this patient could be due to NK cell-mediated disease control. [ABSTRACT FROM AUTHOR]

Molecules differentially expressed in blood vessels among organs or between damaged and normal tissues, are attractive therapy targets; however, their identification within the human vasculature is challenging. Here we screened a peptide library in cancer patients to uncover ligand-receptors common or specific to certain vascular beds. Surveying ∼2.35 × 106 motifs recovered from biopsies yielded a nonrandom distribution, indicating that systemic tissue targeting is feasible. High-throughput analysis by similarity search, protein arrays, and affinity chromatography revealed four native ligand-receptors, three of which were previously unrecognized. Two are shared among multiple tissues (integrin a4/annexin A4 and cathepsin B/apolipoprotein E3) and the other two have a restricted and specific distribution in normal tissue (prohibitin/annexin A2 in white adipose tissue) or cancer (RAGE/leukocyte proteinase-3 in bone metastases). These findings provide vascular molecular markers for biotechnology and medical applications. [ABSTRACT FROM AUTHOR]

Background/objectives: Locally advanced rectal cancer is treated with neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME). As this approach achieves complete pathologic remissions (pCR) in approximately 30% of patients, it raises the question of whether surgery is always necessary. Non-surgical strategies, such as "watch and wait" (W&W), have shown similarly promising outcomes. However, there is an unmet need for reliable biomarkers predicting pCR. Analysis of circulating tumor DNA (ctDNA) has shown potential for monitoring treatment response and detecting minimal residual disease. We hypothesized that monitoring ctDNA changes during nCRT might facilitate the identification of individuals who achieve pCR., Methods: In the prospective single-center NEORECT trial, the plasma of forty rectal cancer patients was collected before, during, and after nCRT and before TME. Informative somatic mutations were identified in tissue biopsies by NGS and subsequently used for ctDNA quantification by dPCR., Results: The results identified three distinct ctDNA patterns: increase, decrease, and absence. Remarkably, undetectable DNA was observed in good responders, while a tenfold ctDNA increase was associated with the emergence of new metastases. Despite these insights, ctDNA alone demonstrated low specificity, with no significant correlation to pCR or long-term prognosis. A multimodal approach incorporating routinely available clinical parameters remains inadequate for accurately predicting pCR prior to TME., Conclusions: In conclusion, the NEORECT trial establishes the feasibility of ctDNA-based personalized monitoring for rectal cancer patients undergoing nCRT. However, the utility of ctDNA in enhancing pCR prediction for a W&W strategy warrants further investigation. Larger studies integrating multi-gene analyses and expanded clinical datasets are essential in the future.

Not available.

Background: Local ablative therapies (LAT) are increasingly used in patients with metastatic soft tissue sarcoma (STS), yet evidence-based standards are lacking. This study aimed to assess the impact of LAT on survival of metastatic STS patients and to identify prognostic factors., Methods: In this retrospective multicenter study, 246 STS patients with metastatic disease who underwent LAT on tumor board recommendation between 2017 and 2021 were analyzed. A mixed effects model was applied to evaluate multiple survival events per patient., Results: Median overall survival (OS) after first metastasis was 5.4 years with 1-, 2- and 5-year survival rates of 93.7, 81.7, and 53.1 %, respectively. A treatment-free interval ≥12 months and treatment of liver metastases were positively correlated with progression-free survival (PFS) after LAT (HR = 0.61, p = 0.00032 and HR = 0.52, p = 0.0081, respectively). A treatment-free interval ≥12 months and treatment of metastatic lesions in a single organ site other than lung and liver were positive prognostic factors for OS after first LAT (HR = 0.50, p = 0.028 and HR = 0.40, p = 0.026, respectively) while rare histotypes and LAT other than surgery and radiotherapy were negatively associated with OS after first LAT (HR = 2.56, p = 0.020 and HR = 3.87, p = 0.025). Additional systemic therapy was independently associated with a PFS benefit in patients ≤60 years with ≥4 metastatic lesions (for max. diameter of treated lesions ≤2 cm: HR = 0.32, p = 0.02 and >2 cm: HR = 0.20, p = 0.0011, respectively)., Conclusion: This multicenter study conducted at six German university hospitals underlines the value of LAT in metastatic STS. The exceptionally high survival rates are likely to be associated with patient selection and treatment in specialized sarcoma centers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Providing patient access to precision oncology (PO) is a major challenge of clinical oncologists. Here, we provide an easily transferable model from strategic management science to assess the outreach of a cancer center., Methods: As members of the German WERA alliance, the cancer centers in Würzburg, Erlangen, Regensburg and Augsburg merged care data regarding their geographical impact. Specifically, we examined the provenance of patients from WERA´s molecular tumor boards (MTBs) between 2020 and 2022 (n = 2243). As second dimension, we added the provenance of patients receiving general cancer care by WERA. Clustering our catchment area along these two dimensions set up a four-quadrant matrix consisting of postal code areas with referrals towards WERA. These areas were re-identified on a map of the Federal State of Bavaria., Results: The WERA matrix overlooked an active screening area of 821 postal code areas - representing about 50 % of Bavaria´s spatial expansion and more than six million inhabitants. The WERA matrix identified regions successfully connected to our outreach structures in terms of subsidiarity - with general cancer care mainly performed locally but PO performed in collaboration with WERA. We also detected postal code areas with a potential PO backlog - characterized by high levels of cancer care performed by WERA and low levels or no MTB representation., Conclusions: The WERA matrix provided a transparent portfolio of postal code areas, which helped assessing the geographical impact of our PO program. We believe that its intuitive principle can easily be transferred to other cancer centers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The blood-brain barrier (BBB) protects the central nervous system from infections or harmful substances 1 ; its impairment can lead to or exacerbate various diseases of the central nervous system 2-4 . However, the mechanisms of BBB disruption during infection and inflammatory conditions 5,6 remain poorly defined. Here we find that activation of the pore-forming protein GSDMD by the cytosolic lipopolysaccharide (LPS) sensor caspase-11 (refs. 7-9 ), but not by TLR4-induced cytokines, mediates BBB breakdown in response to circulating LPS or during LPS-induced sepsis. Mice deficient in the LBP-CD14 LPS transfer and internalization pathway 10-12 resist BBB disruption. Single-cell RNA-sequencing analysis reveals that brain endothelial cells (bECs), which express high levels of GSDMD, have a prominent response to circulating LPS. LPS acting on bECs primes Casp11 and Cd14 expression and induces GSDMD-mediated plasma membrane permeabilization and pyroptosis in vitro and in mice. Electron microscopy shows that this features ultrastructural changes in the disrupted BBB, including pyroptotic endothelia, abnormal appearance of tight junctions and vasculature detachment from the basement membrane. Comprehensive mouse genetic analyses, combined with a bEC-targeting adeno-associated virus system, establish that GSDMD activation in bECs underlies BBB disruption by LPS. Delivery of active GSDMD into bECs bypasses LPS stimulation and opens the BBB. In CASP4-humanized mice, Gram-negative Klebsiella pneumoniae infection disrupts the BBB; this is blocked by expression of a GSDMD-neutralizing nanobody in bECs. Our findings outline a mechanism for inflammatory BBB breakdown, and suggest potential therapies for diseases of the central nervous system associated with BBB impairment., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

We recently published the first dosimetry data, to our knowledge, for the radioligand therapy agent 177 Lu-rhPSMA-10.1, providing an intrapatient comparison with 177 Lu-PSMA-I&T in patients with metastatic prostate cancer. Here, we report efficacy and safety findings from these patients. Methods: Four consecutive patients with prostate-specific membrane antigen (PSMA)-positive metastatic prostate cancer received up to 6 cycles of 177 Lu-rhPSMA-10.1 (7.4-7.7 GBq per cycle). Efficacy (prostate-specific antigen response according to Prostate Cancer Working Group 3 criteria and the Response Evaluation Criteria in PSMA PET/CT), progression-free survival, and overall survival were evaluated. Adverse events were recorded from the first dose until 16-24 mo after treatment. Results: The patients received a total activity of 29.6-59.4 GBq (4-6 cycles). Prostate-specific antigen was reduced by 100%, 99%, 88%, and 35%. Progression-free survival was not reached for 2 patients at 24 and 18 mo of follow-up and was 15 and 12 mo for the other 2 patients. One patient had a sustained complete response with 2 y of follow up. All patients were alive at the last time point of data collection. No serious adverse events were reported. Conclusion: 177 Lu-rhPSMA-10.1 demonstrated encouraging preliminary efficacy and was well tolerated. Formal clinical trials are now under way to evaluate its potential prospectively (NCT05413850)., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Objectives: Lung cancer (LC) accounts for the largest number of cancer deaths worldwide, with smoking being the leading cause for its development. While quality of life (QoL) is a crucial factor in the treatment of patients with LC, the impact of smoking status on QoL remains unclear. This systematic review aims to provide a comprehensive overview of available evidence on the relationship between smoking status and QoL among patients with LC., Methods: A systematic search of Embase, Medline and Web of Science was conducted. Studies reporting the impact of smoking status on QoL among patients with LC were eligible for inclusion. Two reviewers independently assessed the eligibility of studies, extracted data and evaluated the risk of bias using the Critical Appraisal Skills Programme appraisal tool for cohort studies. A descriptive synthesis was performed due to the heterogeneity of the studies., Results: A total of 23 studies met the inclusion criteria (17 studies providing cross-sectional and 6 longitudinal data). The studies included a total of 10 251 participants. The results suggested a tendency towards lower QoL among smokers compared with non-smokers. The effect of smoking cessation on QoL was insufficiently investigated in the included studies and therefore remains inconclusive., Conclusions: The findings of this review suggest that current smokers may experience worse QoL than former and never smokers. The results of this systematic review should, however, be viewed in the context of the difficulty of data collection in this patient group given the low survival rates and low performance status, among other factors and in light of the large variety of different QoL measures used. Future research requires uniform QoL measures, a holistic representation of all patients with LC as well as a comprehensive consideration of all potential determinants of QoL. The potential benefits of smoking cessation on QoL among patients with LC require investigation., Competing Interests: Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. AH is coeditor of the German (DGPPN) Schizophrenia treatment guidelines and first author of the WFSBP Schizophrenia treatment guidelines. AH has received paid speakerships from Janssen, Otsuka, Rovi, Recordati, Advanz and AbbVie. He was member of Rovi, Recordati, Otsuka, Lundbeck and Janssen advisory boards. MG is chair person of the German Federal Association of Sexualized Substance Use (BISS) and received honorariums for talks from several HIV and drug counselling centers. Furthermore he received honorariums from Gilead sciences and travel expenses for a conference journey and is medical consultant of the district of Swabia for addiction issues. TR received travel expenses and congress fees from the Sanofi company. SR received travel support and congress fees from MedXpert. Within the past 5 years, MT has received speakers or advisory honoraria and travel support from Novartis, Amgen, Roche, Celgene, Janssen, Klinikum Stuttgart, ConEvent, MedUpdate, Sirtex, COCS, FOMF, Klinikum Esslingen, VHS Stadtbergen., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)