Outcome and feasibility of radiotherapy bridging in large B-cell lymphoma patients receiving CD19 CAR T in the UK.

Radiotherapy (RT) has potential synergistic effects with chimeric antigen receptor (CAR) T but is not widely used as bridging therapy due to logistical challenges and lack of standardised protocols. We analysed RT bridging in a multicentre national cohort of large B-cell lymphoma patients approved for 3L axicabtagene ciloleucel or tisagenlecleucel across 12 UK centres. Of 763 approved patients, 722 were leukapheresed, 717 had data available on bridging therapy. 169/717 (24%) received RT bridging, 129 as single modality and 40 as combined modality treatment (CMT). Of 169 patients, 65.7% had advanced stage, 36.9% bulky disease, 86.5% elevated LDH, 41.7% international prognostic index (IPI) ≥3 and 15.2% double/triple hit at the time of approval. Use of RT bridging varied from 11% to 32% between centres and increased over time. Vein-to-vein time and infusion rate did not differ between bridging modalities. RT-bridged patients had favourable outcomes with 1-year progression-free survival (PFS) of 56% for single modality and 47% for CMT (1-year PFS 43% for systemic bridging). This is the largest cohort of LBCL patients receiving RT bridging prior to CAR T reported to date. Our results show that RT bridging can be safely and effectively used even in advanced stage and high-risk disease, with low dropout rates and excellent outcomes.

Improved outcomes of large B-cell lymphoma patients treated with CD19 CAR T in the UK over time.

The success of CD19 Chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off-the-shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the 'standard-of-care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020-2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression-free survival (1-year PFS 50% vs. 32%, p < 0.001) and overall survival (1-year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high-grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up-to-date clinical data when comparing CAR T against new treatment options for r/r LBCL.

CAR T in patients with large B-cell lymphoma not fit for autologous transplant.

Large B-cell lymphoma (LBCL) patients with comorbidities and/or advanced age are increasingly considered for treatment with CD19 CAR T, but data on the clinical benefit of CAR T in the less fit patient population are still limited. We analysed outcomes of consecutive patients approved for treatment with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) by the UK National CAR T Clinical Panel, according to fitness for autologous stem cell transplant (ASCT). 81/404 (20%) of approved patients were deemed unfit for ASCT. Unfit patients were more likely to receive tisa-cel versus axi-cel (52% vs. 48%) compared to 20% versus 80% in ASCT-fit patients; p < 0.0001. The drop-out rate from approval to infusion was significantly higher in the ASCT-unfit group (34.6% vs. 23.5%; p = 0.042). Among infused patients, response rate, progression-free and overall survival were similar in both cohorts. CAR T was well-tolerated in ASCT-unfit patients with an incidence of grade ≥3 cytokine release syndrome and neurotoxicity of 2% and 11%, respectively. Results from this multicentre real-world cohort demonstrate that CD19 CAR T can be safely delivered in carefully selected older patients and patients with comorbidities who are not deemed suitable for transplant.

[Operative treatment of diabetics with vascular complications : Secondary data analysis of diagnosis-related groups statistics from 2005 to 2014 in Germany]. / Operative Versorgung von Diabetikern mit vaskulären Komplikationen : Sekundärdatenanalyse der DRG-Statistik von 2005 bis 2014 in Deutschland.

BACKGROUND: In Germany approximately 40,000 amputations per year are performed on patients with diabetes mellitus, often with accompanying vascular complications. OBJECTIVE: The aim of this study was to present the various degrees of severity of the vascular complications and the temporal changes of the treatment options in diabetics with vascular complications in Germany. MATERIAL AND METHODS: The microdata of the diagnosis-related groups (DRG) statistics of the Federal Statistical Office were analyzed over the period from 2005 to 2014. All cases were included in which the main or secondary diagnosis of diabetes mellitus with concurrent vascular complications (diabetic angiopathy and peripheral arterial disease) was encrypted. RESULTS: The median age of the 1,811,422 cases was 73 years and 62% were male. While the total number of amputations remained stable over time, there was a 41% reduction in knee-preserving and a 31% reduction in non-knee preserving major amputations with an 18% increase in minor amputations. Revascularization increased by 33% from 36 procedures in 2005 to 48 procedures per 100,000 inhabitants. The increase in revascularization was evident in the area of endovascular therapy alone where there was an increase of 78%. CONCLUSION: Due to the significant increase in endovascular revascularization measures, there was a significant increase in the proportion of diabetes patients with vascular pathologies in whom revascularization was carried out. As a result, improved limb preservation was achieved despite equally high amputation rates due to increasing minor amputation rates.

Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial.

BACKGROUND: There is an on-going debate whether 2- or 3-weekly administration of R-CHOP is the preferred first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). The UK NCRI R-CHOP14v21 randomized phase 3 trial did not demonstrate a difference in outcomes between R-CHOP-14 and R-CHOP-21 in newly diagnosed DLBCL patients aged 19-88 years, but data on elderly patients have not been reported in detail so far. Here, we provide a subgroup analysis of patients ≥60 years treated on the R-CHOP14v21 trial with extended follow-up. PATIENTS AND METHODS: Six hundred and four R-CHOP14v21 patients ≥60 years were included in this subgroup analysis, with a median follow-up of 77.7 months. To assess the impact of MYC rearrangements (MYC-R) and double-hit-lymphoma (DHL) on outcome in elderly patients, we performed a joint analysis of cases with available molecular data from the R-CHOP14v21 (N = 217) and RICOVER-60 (N = 204) trials. RESULTS: Elderly DLBCL patients received high dose intensities with median total doses of ≥98% for all agents. Toxicities were similar in both arms with the exception of more grade ≥3 neutropenia (P < 0.0001) and fewer grade ≥3 thrombocytopenia (P = 0.05) in R-CHOP-21 versus R-CHOP-14. The elderly patient population had a favorable 5-year overall survival (OS) of 69% (95% CI: 65-73). We did not identify any subgroup of patients that showed differential response to either regimen. In multivariable analysis including individual factors of the IPI, gender, bulk, B2M and albumin levels, only age and B2M were of independent prognostic significance for OS. Molecular analyses demonstrated a significant impact of MYC-R (HR = 1.96; 95% CI: 1.22-3.16; P = 0.01) and DHL (HR = 2.21; 95% CI: 1.18-4.11; P = 0.01) on OS in the combined trial cohorts, independent of other prognostic factors. CONCLUSIONS: Our data support equivalence of both R-CHOP application forms in elderly DLBCL patients. Elderly MYC-R and DHL patients have inferior prognosis and should be considered for alternative treatment approaches. TRIAL NUMBERS: ISCRTN 16017947 (R-CHOP14v21); NCT00052936 (RICOVER-60).

Epidemiology and inpatient treatment of vascular diseases in Germany: English Version.

BACKGROUND: Non-cardiac vascular diseases account for approximately 10 % of the total burden of disease in the German population as measured in disability-adjusted life years (DALY). Thus, from the social perspective, much attention should be paid to optimization of the provision of vascular services especially in elderly people. OBJECTIVES: This article describes the structure of inpatient care and the provision of vascular treatment as well as age- and gender-specific hospital incidence rates of vascular diseases in Germany between 2005 and 2013. MATERIALS AND METHODS: Secondary data analysis is based on basic data from German hospitals as well as nationwide aggregated data from the diagnosis-related groups' statistics from the Federal Statistical Office. RESULTS: Since 2005, the incidence of non-cardiac vascular diseases has increased and showed a significant dependency on sex and age. In general, men were affected consistently more frequently by vascular diseases. In contrast, hospital admission rates due to varicose veins or acute ischemia of the legs were higher in women. Treatment of arterial diseases was performed predominantly in general surgery units or departments for vascular surgery. From 1991 to 2013, the number of hospitals employing specialists for vascular surgery almost doubled, and the number of vascular surgeons working full-time in German hospitals was nearly tripled. Endovascular approaches were used particularly for revascularization of peripheral arteries as well as aortic aneurysm repair. In contrast, carotid surgery as well as peripheral embolectomy were predominately performed using open surgical techniques. CONCLUSIONS: Since 1991, the increasing need for vascular services for patients has been met by continuously growing structures for the provision of vascular surgical treatment; however, the suitability and efficiency of provision of vascular services could only be assessed in an appropriate way by using more differentiated and disaggregated data. ADDITIONAL MATERIAL AVAILABLE ONLINE: Additional information is available in the online version of this article (doi:10.1007/s00772-015-0095-5).

Patient characteristics and outcomes of carotid endarterectomy and carotid artery stenting: analysis of the German mandatory national quality assurance registry - 2003 to 2014.

AIM: In Germany, every surgical or endovascular procedure on the extracranial carotid artery is documented in a mandatory quality assurance registry. The purpose of this study is to describe the patient characteristics, the indications for treatment, and the short-term outcomes as well as to analyse the corresponding trends from 2003 to 2014. METHODS: Data on demographics, peri-procedural measures, and outcomes were extracted from the annual quality reports published by the Federal Agency for Quality Assurance and the Institute for Applied Quality Improvement and Research in Health Care. Data were available from 2003 to 2014 for carotid endarterectomy (CEA) and from 2012 to 2014 for carotid artery stenting (CAS). The primary outcome event of this study is any stroke or death until discharge from hospital. Temporal trends of categorical variables were statistically analysed using the Cochran-Armitage test for trend. RESULTS: Between 2003 and 2014, 309,405 CEAs and 18,047 CAS procedures were documented in the database; 68.1% of all patients were male. The mean age of patients treated with CEA increased from 68.9 years in 2003 to 70.9 years in 2014. The proportion of patients with ASA stages III to V increased from 65% to 71% in CEA, whereas it decreased from 44% to 41% in CAS patients. 53.1% of all CEAs were performed for asymptomatic patients (group A), 34.4% for symptomatic patients treated electively (group B), and 11.2% a in a collective group including other indications for CEA or CAS (such as recurrent stenosis, carotid aneurysms, emergency treatment due to stroke-in-evolution). The corresponding data for CAS are 49.3%, 26.1% and 26.3% respectively. In group B, the interval between the neurological index event and CEA decreased from 28 to 8 days (P<0.001). In patients treated with CAS, this interval was 9 days in 2012 (no further data available). On average, 67.1% and 48.2% of surgically treated patients as well as 77.8% and 69.8% of CAS patients were neurologically assessed before and after the procedure, respectively. From 2003 to 2014, CEA procedures were performed more frequently in locoregional anesthesia (10.1% to 29.1%, P<0.001). The same trend was observed for the application of the eversion technique (37.0% to 41.6%, P<0.001), the neurophysiological monitoring (49.8% to 61.8%, P<0.001), and the intra-procedural assessment of the treated artery (44.5% to 69.7%, P<0.001). In contrast, shunting was used less frequently (48.1% to 43.0%, P<0.001). Averagely 95.7% of all endovascular procedures were performed using stent-angioplasty. In 54.2% a protection device was used. Nitinol and bare metal stents were used in 74.1% and 21.4% of cases, respectively. The in-hospital rate of any stroke or death decreased from 2.0% to 1.1% in asymptomatic patients treated with CEA without a contralateral stenosis ≥75% or occlusion, P<0.001). In patients treated with CAS this rate did not increase (1.7% to 1.8%, p=0.909). The corresponding rates in CEA and CAS patients with severe contralateral stenosis or occlusion varied between 1.9%-3.1% and 2.2%-2.6%, respectively. In symptomatic patients (group B) with a stenosis of 50 percent or more, the rate of any stroke or death decreased significantly after CEA from 4.2% to 2.4% (P<0.001) and remained stable after CAS (3.9% to 3.5%, P=0.577). CONCLUSION: This report on 327,452 carotid procedures analysed one of the largest quality registries on CEA and CAS worldwide. Data indicate that treated patients became older and sicker, whereas in contrast, the in-hospital rates of stroke or death are decreasing over time.

Stroke risk in the early period after carotid related symptoms: a systematic review.

Current guidelines recommend performing carotid endarterectomy in patients with symptomatic carotid disease as soon as possible after the neurological index event. However, early stroke risk has not been well documented for this patient group. We therefore conducted a systematic analysis of the current literature on the recurrent risk of ischemic events in patients with symptomatic carotid stenosis. Systematic review was performed by searching the MEDLINE® database from 1950 until June 8, 2015 (key words: cerebral ischemia, transient ischemic attack, amaurosis fugax, stroke, symptomatic carotid stenosis, recurrent risk, outcome, prognosis, follow-up, cohort and natural history). All studies reporting stroke risks in patients with symptomatic carotid stenosis after neurologic index events within a period of 7 days were included. Cumulative stroke risks with 95% confidence intervals after a neurologic index event were recalculated at 2-3, 7, 14 and 30 days and a meta-analysis including an analysis of heterogeneity were performed using the statistical package R and Excel for Mac 2003. Ten studies with a total number of 2634 patients were included. Results of an overall stroke risk were as follows: 2.0-17.2% at 2-3 days, 0-22.1% at 7 days, 0-29.6% at 14 days and 0-11.1% at 30 days in patients with a symptomatic extracranial carotid stenosis. The pooled stroke risk in the six studies with active follow-up was 6.0% (95% CI 2.4-14.4) at 2-3 days, 10.9% (6.1-18.7) at 7 days and 17.6% (9.7-29.9) at 14 days. Pooled stroke risk in the three studies with uncensored populations was even higher with 6.4% (1.5-23.8%) at 2-3 days, 19.5% (12.7-28.7) at 7 days and 26.1% (20.6-32.5%) at 14 days. Significant heterogeneity (P<0.001) could be explained by the different inclusion criteria and the study's design. Retrospective studies with passive follow-up had the lowest stroke risk whereas prospective studies with active follow-up and without bias through early intervention by carotid endarterectomy or carotid stenting had the highest stroke risk. The risk of recurrence of cerebrovascular events in patients with symptomatic carotid stenosis within the first days after a neurologic index event is as high as 6.4% (1.5-23.8), 19.5% (12.7-28.7) and 26.1% (20.6-32.5) after 2-3, 7 and 14 days respectively. Patients with a symptomatic carotid stenosis are therefore at a very high risk of a definitive stroke. Recommendations by current guidelines to perform carotid endarterectomy as soon as possible after the neurologic index event are therefore justified.

Characterization of coxsackievirus B3 replication in human umbilical vein endothelial cells.

After successful invasion of susceptible hosts, systemic distribution of coxsackievirus B3 (CVB3) most likely requires interactions with the endothelial system. Thereby, infection of endothelial cells occurs directly or viruses and/or virus-infected leukocytes migrate through the endothelial barrier. Many of these processes have not been studied so far. In order to analyze viral replication in the endothelium, human umbilical vein endothelial cells (HUVEC) were isolated and infected with CVB3. Time-course experiments revealed maximal viral replication at 10-24 h and viral RNA persistence up to 120 h post-infection (p. i.) without the induction of obvious general cytopathic effects or the loss of cellular viability. However, the application of the EGFP-expressing recombinant virus variant CVB3/EGFP revealed shrinkage and death of individual cells. Using infectious center assays, a noticeable CVB3 replication occurred on an average of 20 % of HUVEC at 10 h p. i. This may be in part due to a higher coxsackievirus/adenovirus receptor expression in a small subgroup of HUVEC (5-7 %) as analyzed by flow cytometry. Interestingly, CVB3 replication escalated and cellular susceptibility increased significantly after reversal of cell cycle arrest caused by serum deprivation indicating that reactivation of cellular metabolism may help to promote CVB3 replication. Finally, CVB3-infected HUVEC cultures revealed increased DNA fragmentation, and inhibition of caspase activity caused an accumulation of intracellular virus particles indicating that apoptotic processes are involved in virus release mechanisms. Based on these observations, it is assumed that CVB3 replicates efficiently in human endothelial cells. But how this specific infection of the endothelium may influence viral spread in the infected host needs to be investigated in the future.

Antileukemic activity of the HSP70 inhibitor pifithrin-µ in acute leukemia.

Heat shock protein (HSP) 70 is aberrantly expressed in different malignancies and has emerged as a promising new target for anticancer therapy. Here, we analyzed the in vitro antileukemic effects of pifithrin-µ (PFT-µ), an inhibitor of inducible HSP70, in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cell lines, as well as in primary AML blasts. PFT-µ significantly inhibited cell viability at low micromolar concentrations in all cell lines tested, with IC50 values ranging from 2.5 to 12.7 µ, and was highly active in primary AML blasts with a median IC50 of 8.9 µ (range 5.7-37.2). Importantly, higher IC50 values were seen in normal hematopoietic cells. In AML and ALL, PFT-µ induced apoptosis and cell cycle arrest in a dose-dependent fashion. PFT-µ also led to an increase of the active form of caspase-3 and reduced the intracellular concentrations of AKT and ERK1/2 in NALM-6 cells. Moreover, PFT-µ enhanced cytotoxicity of cytarabine, 17-(allylamino)-17-desmethoxygeldanamycin, suberoylanilide hydroxamic acid, and sorafenib in NALM-6, TOM-1 and KG-1a cells. This is the first study demonstrating significant antileukemic effects of the HSP70 inhibitor PFT-µ, alone and in combination with different antineoplastic drugs in both AML and ALL. Our results suggest a potential therapeutic role for PFT-µ in acute leukemias.

BAALC-associated gene expression profiles define IGFBP7 as a novel molecular marker in acute leukemia.

Over expression of BAALC (brain and acute leukemia, cytoplasmic) predicts an inferior outcome in acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients. To identify BAALC-associated genes that give insights into its functional role in chemotherapy resistance, gene expression signatures differentiating high from low BAALC expressers were generated from normal CD34(+) progenitors, T-acute lymphoblastic leukemia (T-ALL) and AML samples. The insulin-like growth factor binding protein 7 (IGFBP7) was one of the four genes (CD34, CD133, natriuretic peptide receptor C (NPR3), IGFBP7) coexpressed with BAALC and common to the three entities. In T-ALL, high IGFBP7-expression was associated with an immature phenotype of early T-ALL (P<0.001), expression of CD34 (P<0.001) and CD33 (P<0.001). Moreover, high IGFBP7-expression predicted primary therapy resistance (P=0.03) and inferior survival in T-ALL (P=0.03). In vitro studies revealed that IGFBP7 protein significantly inhibited the proliferation of leukemia cell lines (Jurkat cells: 42% reduction, P=0.002; KG1a cells: 65% reduction, P<0.001). In conclusion, IGFBP7 was identified as a BAALC coexpressed gene. Furthermore, high IGFBP7 was associated with stem cell features and treatment failure in T-ALL. In contrast to BAALC, which likely represents only a surrogate marker of treatment failure in acute leukemia, IGFBP7 regulates the proliferation of leukemic cells and might be involved in chemotherapy resistance.

[Systemic therapy of male breast cancer]. / Systemische Behandlung des Brustkrebses des Mannes.

Due to its low incidence there is only few information on optimal systemic therapy of male breast cancer. There are no prospective randomized trials, neither for early breast cancer nor for advanced stages. Retrospective analyses mostly comprise long-term-data from a small number of patients. In terms of epidemiology, cellular receptors or genetics there exist some significant differences between male and female breast cancer. Therefore, the possibility to extrapolate treatment recommendation for male patients from female breast cancer-trials is limited. Despite a high rate of receptor positivity, hormonal therapy seems to be less efficient in men, possibly due to different biological factors. The current standard in endocrine therapy is tamoxifen. It is not known whether tamoxifen therapy is as effective as orchiectomy, but tamoxifen is favoured because of its low side effects. The use of aromatase inhibitors needs to be considered carefully, since aromatization is blocked, but 5-alpha-reductase increases estrogen-like androstanediole. There might be a benefit from additional therapy with GnRH-analoga respectively 5-alpha-reductase inhibitors, but data is not available yet. Combination of GnRH-analoga and antiandrogens does induce tumor remission, but comparison to other endocrine therapies is still lacking. Currently, the efficiency of fulvestrant, an estrogen receptor destructor, is being examined. Cytostatic therapy seems to be as effective as in female breast cancer patients. Nevertheless, convincing prospective trials for the management of early and advanced male breast cancer need to be performed.

[Dental and periodontal sequelae of bulimia nervosa]. / Dentale und parodontale Folgeschäden bei Bulimia nervosa.

Twenty-eight women with established bulimia nervosa according to the US psychiatric diagnostic criteria DSM III R with periods of morbidly increased appetite and vomiting, as well as 35 psychically and somatically healthy women were subjected to dental examination. The bulimic patients revealed a significantly poorer dental status (DMFS rate) than the control group. Within the patient group a deterioration of the DMFS rate was observed parallel with an increase in the frequency of vomiting and bulimic attacks, in sugar consumption and duration of the disease, as well as a decrease in salivary flow. Causes and implications for treatment and prevention are discussed.