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We examined the cytotoxic effects of chaetocin on clear cell renal cell carcinoma (ccRCC) cells and the possibility to combine the effects of chaetocin with the effects of cytokine-induced killer cells (CIK) assayed by MTT assay and FACS analysis. Chaetocin is a thiodioxopiperazine produced by fungi belonging to the chaetomiaceae family. In 2007, it was first reported that chaetocin shows potent and selectiveanti-cancer activity by inducing reactive oxygen species. CIK cells are generated from CD3+/CD56- T lymphocytes with double negative phenotype that are isolated from human blood. The addition of distinct interleukins and antibodies results in the generation of CIK cells that are able to specifically target and destroy renal carcinoma cells. The results of this research state that the anti-ccRCC activity of chaetocin is weak and does not show a high grade of selectivity on clear cell renal cell carcinoma cells. Although the CIK cells show a high grade of selective anti-ccRCC activity, this effect could not be improved by the addition of chaetocin. So chaetocin seems to be no suitable agent for specific targeting ccRCC cells or for the combination therapy with CIK cells in renal cancer.

[english] We analysed the typical features of primary small cell carcinoma of the esophagus (SCCE) with emphasis on occurrence, behaviour, outcome and treatment options. This metaanalysis was aimed at collecting and analyzing information from international studies about handling this disease. This seems necessary due to the rarity of this disease. Studies were acquired from electronic databases and reference lists. We finally analysed 313 patient cases from the literature with oesophageal SCC. A data extraction was accomplished referring to 13 evaluable features that are described in the “methods”, whereof 7 were analyzed with univariate and multivariate tests. Three hundred thirteen cases were analyzed, 109 patients (35%) had limited stage (LS), whereas 167 (54%) had extensive stage (ES). There is no information about the remaining 35 patients concerning the stage. Univariate and multivariate analysis showed only age (50 years, HR 1.024; 95% CI 1.000–1.041, 50 years) and therapy are independent significant predictors of prognosis.[german] Gegenstand unserer Untersuchungen war die Erhebung typischer Eigenschaften des kleinzelligen Ösophaguskarzinoms mit Berücksichtigung des Auftretens, des Verlaufs, der Auswirkung und der Behandlungsoptionen. Ziel unserer Metaanalyse bestand darin, Informationen aus internationalen Studien, die sich mit dieser Krankheit befassten, zu sammeln und auszuwerten. Dies scheint notwendig aufgrund der Seltenheit der Krankheit. Die verwendeten Studien wurden von elektronischen Datenbanken und Referenzlisten ermittelt. Insgesamt wurden 313 Patientenfälle mit einem kleinzelligen Ösophaguskarzinom aus der Literatur ausgewertet. Die erhobenen Daten beziehen sich auf 13 auswertbare Kriterien, die in den „Methoden“ beschrieben sind, wovon sieben Kriterien mit univariaten und multivariaten Tests untersucht worden sind. Von 313 analysierten Patientenfällen waren 109 (35%) Patienten im limitierten Stadium der Erkrankung und 167 (54%) im ausgedehnten Stadium. Über die übrigen 35 Patienten sind keine Informationen bezüglich des Stadiums bekannt. Univariate und multivariate Analysen zeigten nur das Alter (50 Jahre, HR 1.024; 95% CI 1.000–1.041, 50 Jahre) und die Therapie als Kriterien eigenständige, signifikante Anzeichen für eine Prognose sind.

Immunotherapeutic strategies may be a treatment option in patients with refractory acute myelogenous leukemia (AML) or, in cases of complete remission after conventional therapy regimens, may help to reduce disease recurrence or delay time to progression. Evidence suggests a key role of dendritic cells (DCs) in cancer immunotherapy due to their capacity to present tumour antigens to effector cells. We generated cytokine-induced killer (CIK) cells from healthy donors and examined their responses in vitro in an LDH release assay against three cell lines and allogeneic HLA non-matched blasts from three patients with de novo AML after coincubation with autologous peripheral blood monocyte-derived DCs. Although DCs were unable to enhance CIK cell effects against all three cell lines tested, the cytotoxic activity against the patients’ AML cells increased after coculture with mature DCs, which was significant in two of three patients. However, neither prior pulsing of the DCs with blast cell lysates nor with leukemic cell-derived total RNA further enhanced the lytic capacity of the CIK cells. On the contrary, pulsing reduced or even reversed the cytotoxic activity of the effector cells. This decrease of allogeneic cytotoxicity led us to conclude that monocyte-derived DCs may be useful in autologous or allogeneic vaccine strategies for the treatment of AML or in priming donor lymphocytes in vitro, but unfractionated antigens as pulsing agents may have inhibitory effects on T cell efficiency and their employment in immunotherapeutic strategies for AML seems questionable.

We analyzed clinical outcome of patients with an isolated central nervous system lymphoma (CNSL) relapse after systemic non-Hodgkin’s lymphoma (NHL). All 23 patients with an isolated secondary CNSL (SCNSL) treated at two institutions from 04/2003–12/2007 were included into this analysis. At cerebral relapse, 15/23 patients were treated with a regimen consisting of high-dose methotrexate (Bonn protocol). After a median follow-up of 6.5 months (range 1–68), 15/23 (65%) patients with SCNSL had relapsed or progressed. HD (high-dose)- methotrexate (MTX) chemotherapy according to the Bonn protocol is effective concerning response rates; however, overall survival of patients with SCNSL seems to be impaired in comparison to relapses in primary CNSL (PCNSL).

Purpose: Introduction of lenalidomide has expanded the therapeutic options for refractory and recurrent multiple myeloma (MM) patients. However, the application of the approved doses may be difficult in some patients due to adverse effects. Experimental design: Therefore, we evaluated the efficacy and safety of lenalidomide in 10 patients with relapsed and refractory MM who received a reduced dose due to leukopenia (4), polyneuropathy (1), muscle cramps (1), thrombocytopenia (1), renal insufficiency (1), at the request of patient (1), as continuous therapy (1), either from the beginning (2) or during treatment (8). They received lenalidomide at a mean (median) daily dose of 14 (15) mg/d once a day (days 1–21 every 28 days) in combination with dexamethasone at a mean (median) dose of 17.6 (28) mg per day (4–40 mg) on days 1–4, 9–12 and 17–20. Results: Mean (median) duration of treatment with lenalidomide was 15.1 (15) months. Partial response or better was reported in seven and minimal response or better was reported in eight patients. Mean (median) values for time-to-progression (TTP) and for progression-free survival (PFS) were 8.7 (4) months. Mean overall survival (OS) has not been reached, all patients are still alive. Conclusion: In conclusion, dose-reduced lenalidomide is an effective and well tolerated treatment for patients with recurrent or refractory MM who cannot tolerate full doses.

Background: The highly vascular nature of renal carcinoma cells suggests that inhibition of angiogenesis may be beneficial in this disease. Thalidomide has been described as inhibitor of the fibroblast growth factor (FGF) and the vascular endothelial growth factor (VEGF). Therefore and in consideration of the promising response rates of the combination of IL-2, IFN-alpha and 5-FU [1] in metastatic renal cancer, we found it reasonable to test the combination of 5-FU and thalidomide. Thus, we conducted a phase I trial to determine safety, side effects and responses to such a treatment. Methods: Patients with metastasized renal cell cancer after nephrectomy and progress after IL-2 and interferon treatment, received oral 5-FU at a dose of 1250 mg/qm2 twice a day for two weeks, then after pausing a week, the oral application was restarted. In addition, oral thalidomide was applied constantly at a maximum dose of 400 mg/d. The combined therapy was given for three months. The primary endpoint was duration until disease progression, the secondary endpoint the response to treatment. Response was determined by CT scans three months after the end of treatment. Results: In total, 12 male patients participated in the trial and received the combined oral therapy. Concerning clinical response, one mixed response (8%), a stable disease in 4/12 patients (33%) and progression was seen in 7 patients (58%). The survival from the start of the therapy showed a median of 21 months with three patients being alive. At present, the longest survival after the therapy is 51 months. Conclusions: The combination of oral 5-FU and thalidomide showed clinical response with tolerable side effects. Further studies will be required to assess the outcome of this treatment regimen.

Background: Until now, cytokine-induced killer (CIK) cells were assumed to be part of the type I natural killer T (NKT) cell population, but it was not yet investigated if this is correct. Methods: For analysis, CIK cells were generated by various culture conditions. Human type I NKT cells express a T cell receptor (TCR) composed of an invariant Vα24-JαQ chain combined with one of several Vβ chains. The Vα24 is a reliable marker for the presence of these TCRs. Results: While comparing cultures stimulated with different substances, we observed the lack of any Vα24 on the surface of CIK culture cells. Conclusion: We conclude that CIK cells do not belong to the type I NKT cells.

Background: High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) plays an important role in the treatment of aggressive non-Hodgkin’s lymphoma (NHL). We report on a retrospective analysis of all patients with diffuse large B-cell lymphoma who were consecutively treated with HDT followed by ASCT at the University Hospital of Bonn, Germany, between 1996 and 2004. Methods: A total of 25 patients were transplanted for biopsy-proven diffuse large B-cell lymphoma (DLBCL). Eight patients received up-front HDT as first-line therapy, four patients received HDT due to incomplete response to conventional induction chemotherapy, and six patients were treated for primary refractory disease. Seven patients had recurrent lymphoma. Results: A complete remission (CR) was achieved in 14 of 25 patients (56%). Estimated 3-year survival for patients treated with upfront HDT, chemosensitive patients with incomplete response to first line therapy, and patients with chemosensitive relapsed disease was 87.5%, 50.0% and 60.0%, respectively. In contrast, no patient with primary refractory disease or relapsed disease lacking chemosensitivity lived longer than 8 months. Chemosensitivity was the only significant prognostic factor for overall survival (OS) in multivariate analysis. Conclusions: Our results confirm that HDT and ASCT is a highly effective therapy in patients with DLBCL leading to long-term survival in a substantial proportion of patients. Patients treated upfront for high-risk disease, incomplete response to conventional first-line therapy, or for chemosensitive relapse have a good prognosis. In contrast, patients with primary chemorefractory disease and patients with relapsed disease lacking chemosensitivity do not benefit from HDT with ASCT.

Objective: Therapeutic vaccination with dendritic cells (DC) showed promising results in first clinical trials in cases of metastatic renal cell carcinoma (RCC). Human telomerase reverse transcriptase (hTERT) could be a potential target because it is detectable in more than 85% of human tumors including RCC. Design: 10 patients with progressive metastatic RCC were enrolled in a clinical phase I/II trial using DC pulsed with hTERT-peptide. Beside toxicity and feasibility aspects, a complex immune monitoring including in vitro data were evaluated. In addition to detection of tumor-specific effector cells we investigated their functionality like IFN-γ secretion and cytotoxic activity against tumor cells. Results: The vaccine was well tolerated. Two patients showed a mixed response (MR) and one patient a stable disease (SD). Interestingly, responders showed cytotoxic activity already before start of therapy and there was a significant increase in cytotoxic activity of effector cells from all responders (SD and MR patients) after the first vaccination. In contrast non-responders showed no cytotoxic activity before and during treatment. Therefore, cytotoxic activity might be used as a predictive marker in the future. Tetramer staining detected higher amounts of tumor-specific cytotoxic cells in responding patients compared to non-responders. Also, responders possessed increasing amounts of IFN-γ producing immunological effector cells. Conclusion: Telomerase-pulsed DC could enhance a tumor-specific immune response against RCC.

We report of a 34-year old man with second intracranial relapse of a suprasellar germinoma. Despite of extensive pretreatment with radiation and conventional chemotherapy relapse occurred and was treated with sequential high-dose chemotherapy followed by transfusion of autologous peripheral stem cells. The high-dose chemotherapy course was complicated by refractory derailment of pineal gland insufficiency. The patient achieved a complete remission after high dose chemotherapy which lasted for 13 months. Subsequently, he developed a third relapse and died.

Background: Transitions of care after cancer treatment pose a major challenge for patient safety as adverse events and unplanned healthcare utilization occur frequently. At this point, patient and family engagement (PFE) is particularly valuable since patients and their families experience various challenges along this pathway, such as changing roles and recurrent needs to navigate across structural gaps between different services. However, there is currently a lack of evidence on the impact of PFE on patient safety in transitions after cancer treatment. Objective: To systematically review and synthesize evidence on effects of different PFE interventions on patient safety in the transition of care after cancer treatment. Methods: This protocol for a systematic review with meta-analysis follows PRISMA-P guidelines. A comprehensive database search will be conducted in MEDLINE, EMBASE, CENTRAL, CINAHL, and APA PsycInfo. Trial registries and grey literature will be searched, forward and backward citation tracking will be performed. Trials with prospective, longitudinal, interventional study designs will be included if they evaluate PFE interventions on patient safety outcomes (primary outcomes: healthcare utilization, patient harm, adherence, patient experience; secondary: quality of life, distress); eligible studies need to survey patients with any oncological disease during or after transition following cancer treatment. Results will be synthesized narratively and meta-analytically using a random-effects model. Risk of bias will be assessed using the Cochrane RoB-2 and revised JBI critical appraisal tool. The certainty of evidence will be judged according to the GRADE approach. Discussion: Robust evidence of effectiveness is needed to establish PFE interventions for patient safety in care transitions for oncological patients. This review will allow evidence-based conclusions about types and effects of different PFE interventions for transitional safety in oncology care and inform stakeholders in designing sustainable PFE activities. Trial registration: PROSPERO (CRD42024546938), OSF (doi.org/10.17605/OSF.IO/9XAMU). [ABSTRACT FROM AUTHOR]

Cancer, being the most formidable ailment, has had a profound impact on the human health. The disease is primarily associated with genetic mutations that impact oncogenes and tumor suppressor genes (TSGs). Recently, growing evidence have shown that X‐linked TSGs have specific role in cancer progression and metastasis as well. Interestingly, our genome harbors around substantial portion of genes that function as tumor suppressors, and the X chromosome alone harbors a considerable number of TSGs. The scenario becomes even more compelling as X‐linked TSGs are adaptive to key epigenetic processes such as X chromosome inactivation. Therefore, delineating the new paradigm related to X‐linked TSGs, for instance, their crosstalk with autosome and involvement in cancer initiation, progression, and metastasis becomes utmost importance. Considering this, herein, we present a comprehensive discussion of X‐linked TSG dysregulation in various cancers as a consequence of genetic variations and epigenetic alterations. In addition, the dynamic role of X‐linked TSGs in sex chromosome–autosome crosstalk in cancer genome remodeling is being explored thoroughly. Besides, the functional roles of ncRNAs, role of X‐linked TSG in immunomodulation and in gender‐based cancer disparities has also been highlighted. Overall, the focal idea of the present article is to recapitulate the findings on X‐linked TSG regulation in the cancer landscape and to redefine their role toward improving cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Introduction: A multitude of findings from cell cultures and animal studies are available to support the anti-cancer properties of cannabidiol (CBD). Since CBD acts on multiple molecular targets, its clinical adaptation, especially in combination with cancer immunotherapy regimen remains a serious concern. Methods: Considering this, we extensively studied the effect of CBD on the cytokine-induced killer (CIK) cell immunotherapy approach using multiple nonsmall cell lung cancer (NSCLC) cells harboring diverse genotypes. Results: Our analysis showed that, a) The Transient Receptor Potential Cation Channel Subfamily V Member 2 (TRPV2) channel was intracellularly expressed both in NSCLC cells and CIK cells. b) A synergistic effect of CIK combined with CBD, resulted in a significant increase in tumor lysis and Interferon gamma (IFNg) production. c) CBD had a preference to elevate the CD25+CD69+ population and the CD62L_CD45RA+terminal effector memory (EMRA) population in NKTCIK cells, suggesting early-stage activation and effector memory differentiation in CD3+CD56+ CIK cells. Of interest, we observed that CBD enhanced the calcium influx, which was mediated by the TRPV2 channel and elevated phosphor-Extracellular signal-Regulated Kinase (p-ERK) expression directly in CIK cells, whereas ERK selective inhibitor FR180204 inhibited the increasing cytotoxic CIK ability induced by CBD. Further examinations revealed that CBD induced DNA double-strand breaks via upregulation of histone H2AX phosphorylation in NSCLC cells and the migration and invasion ability of NSCLC cells suppressed by CBD were rescued using the TRPV2 antagonist (Tranilast) in the absence of CIK cells. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. Conclusions: Taken together, CBD holds a great potential for treating NSCLC with CIK cell immunotherapy. In addition, we utilized NSCLC with different driver mutations to investigate the efficacy of CBD. Our findings might provide evidence for CBD-personized treatment with NSCLC patients. [ABSTRACT FROM AUTHOR]

A firm link between endoplasmic reticulum (ER) stress and tumors has been wildly reported. Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α), an ER-resident thiol oxidoreductase, is confirmed to be highly upregulated in various cancer types and associated with a significantly worse prognosis. Of importance, under ER stress, the functional interplay of ERO1α/PDI axis plays a pivotal role to orchestrate proper protein folding and other key processes. Multiple lines of evidence propose ERO1α as an attractive potential target for cancer treatment. However, the unavailability of specific inhibitor for ERO1α, its molecular inter-relatedness with closely related paralog ERO1β and the tightly regulated processes with other members of flavoenzyme family of enzymes, raises several concerns about its clinical translation. Herein, we have provided a detailed description of ERO1α in human cancers and its vulnerability towards the aforementioned concerns. Besides, we have discussed a few key considerations that may improve our understanding about ERO1α in tumors. [ABSTRACT FROM AUTHOR]

Background: Despite major advances in medicine, blood-borne biomarkers are urgently needed to support decision-making, including polytrauma. Here, we assessed serum-derived extracellular vesicles (EVs) as potential markers of decision-making in polytrauma. Objective: Our Liquid Biopsy in Organ Damage (LiBOD) study aimed to differentiate polytrauma with organ injury from polytrauma without organ injury. We analysed of blood-borne small EVs at the individual level using a combination of immunocapture and high-resolution imaging. Methods: To this end, we isolated, purified, and characterized small EVs according to the latest Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines from human blood collected within 24 h post-trauma and validated our results using a porcine polytrauma model.Results: We found that small EVs derived from monocytes CD14+ and CD14+CD61+ were significantly elevated in polytrauma with organ damage. To be precise, our findings revealed that CD9+CD14+ and CD14+CD61+ small EVs exhibited superior performance compared to CD9+CD61+ small EVs in accurately indicating polytrauma with organ damage, reaching a sensitivity and a specificity of 0.81% and 0.97%, respectively. The results in humans were confirmed in an independent porcine model of polytrauma.Conclusion: These findings suggest that these specific types of small EVs may serve as valuable, non-invasive, and objective biomarkers for assessing and monitoring the severity of polytrauma and associated organ damage. [ABSTRACT FROM AUTHOR]