Medizinische Klinik und Poliklinik II
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- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (2)
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- Department of Hematology and Oncology, Sana Hospital Hof, Hof, Germany (1)
- Department of Laboratory Medicine and Medicine Huddinge, Karolinska Institutet and University Hospital, Stockholm, Sweden (1)
- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
- Early Clinical Trial Unit, Comprehensive Cancer Center Mainfranken (1)
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- N-2030-2015 (1)
Objectives
To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease.
Methods
In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation.
Results
In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy.
Conclusions
Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding follow-up procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms.
Clinical trial registration number
This study is registered in the Deutsches Register Klinischer Studien (DRKS00003231) and ClinicalTrials.gov (NCT02485483).
Background & aims
Current non-invasive scores for the assessment of severity of non-alcoholic fatty liver disease (NAFLD) and identification of patients with non-alcoholic steatohepatitis (NASH) have insufficient performance to be included in clinical routine. In the current study, we developed a novel machine learning approach to overcome the caveats of existing approaches.
Methods
Non-invasive parameters were selected by an ensemble feature selection (EFS) from a retrospectively collected training cohort of 164 obese individuals (age: 43.5±10.3y; BMI: 54.1±10.1kg/m2) to develop a model able to predict the histological assessed NAFLD activity score (NAS). The model was evaluated in an independent validation cohort (122 patients, age: 45.2±11.75y, BMI: 50.8±8.61kg/m2).
Results
EFS identified age, γGT, HbA1c, adiponectin, and M30 as being highly associated with NAFLD. The model reached a Spearman correlation coefficient with the NAS of 0.46 in the training cohort and was able to differentiate between NAFL (NAS≤4) and NASH (NAS>4) with an AUC of 0.73. In the independent validation cohort, an AUC of 0.7 was achieved for this separation. We further analyzed the potential of the new model for disease monitoring in an obese cohort of 38 patients under lifestyle intervention for one year. While all patients lost weight under intervention, increasing scores were observed in 15 patients. Increasing scores were associated with significantly lower absolute weight loss, lower reduction of waist circumference and basal metabolic rate.
Conclusions
A newly developed model (http://CHek.heiderlab.de) can predict presence or absence of NASH with reasonable performance. The new score could be used to detect NASH and monitor disease progression or therapy response to weight loss interventions.
Background
A significant number of oncological patients are heavily burdened by psychosocial stress. Doctors recommending or referring their patients to psycho-oncologists in the course of routine consultations can positively influence psycho-oncological care. The aim of this study was to analyze the frequency and predictors of such recommendations and to examine the use of these services by patients.
Methods
4,020 cancer patients (mean age 58 years; 51% women) were evaluated in a multicenter, cross-sectional study in Germany. Data was gathered about doctors’ referral practices, patients’ utilization of psycho-oncological care services, and disease-related symptoms. The PHQ-9 depression scale and the GAD-7 anxiety scale were used to measure psychological burden. Descriptive data analysis was conducted on the basis of subgroup comparisons and multivariable analysis was done using binary logistical regression.
Results
21.9% of the respondents reported having been given a recommendation or referral for psycho-oncological care by a doctor within the course of their cancer diagnosis and treatment. This comprises 29.5% of the patients identified by screening as being psychologically burdened. Nearly half of the patients who received a recommendation or referral (49.8%) acted on it. Predictors for seeking out psycho-oncological care included: patient desire (OR = 2.0), previous experience with psycho-oncological care (OR = 1.59), and female gender (OR = 1.57). Multivariable analysis indicated that patients’ level of psychological burden (depression, anxiety) had no effect on whether doctors gave them a recommendation or referral.
Conclusions
Along with examining the degree to which patients are burdened (e.g. using screening instruments), determining whether or not patients would like to receive psycho-oncological care is an important aspect of improving referral practices and, by extension, will allow important progress in the field of psycho-oncological care to be made.
According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and <60%, and absence of any myeloma-defining event. Active multiple myeloma is preceded by SMM, with a median time to progression of approximately 5 years. Cases of SMM range from the extremes of “monoclonal gammopathy of undetermined significance-like”, in which patients never progress during their lifetimes, to “early multiple myeloma”, in which transformation into symptomatic disease, based on genomic evolution, may be rapid and devastating. Such a “split personality” makes the prognosis and management of individual patients challenging, particularly with regard to the identification and possible early treatment of high-risk SMM. Outside of clinical trials, the conventional approach to SMM generally remains close observation until progression to active multiple myeloma. However, two prospective, randomized trials have recently demonstrated a significant clinical benefit in terms of time to progression, and of overall survival in one of the two studies, for some patients with higher-risk SMM treated with lenalidomide ± dexamethasone, raising the question of whether such an approach should be considered a new standard of care. In this paper, experts from the European Myeloma Network describe current biological and clinical knowledge on SMM, focusing on novel insights into its molecular pathogenesis, new prognostic scoring systems proposed to identify SMM patients at higher risk of early transformation, and updated results of completed or ongoing clinical trials. Finally, some practical recommendations for the real-life management of these patients, based on Delphi consensus methodology, are provided.
The advances in cancer immunotherapy come with several obstacles, limiting its widespread use and benefits so far only to a small subset of patients. One of the underlying challenges remains to be the lack of representative nonclinical models that translate to human immunity and are able to predict clinical efficacy and safety outcomes. In recent years, immunocompetent Cancer-on-Chip models emerge as an alternative human-based platform that enables the integration and manipulation of complex tumor microenvironment. In this review, we discuss novel opportunities offered by Cancer-on-Chip models to advance (mechanistic) immuno-oncology research, ranging from design flexibility to multimodal analysis approaches. We then exemplify their (potential) applications for the research and development of adoptive cell therapy, immune checkpoint therapy, cytokine therapy, oncolytic virus, and cancer vaccines.
Background
In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status.
Patients and Methods
Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients.
Results
Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10−5)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%).
Conclusion
Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status.
Zusammenfassend lässt sich sagen, dass diese prospektive Studie sowohl den prognostischen als auch den prädiktiven Nutzen eines Tumormarker-Abfalls von CA19- 9 auf eine Induktionschemotherapie bei Patienten mit LAPC bestätigt. Nicht die Ausgangswerte des Tumormarkers vor Therapie sollten zur Planung des weiteren Vorgehens herangezogen werden, sondern die Werte nach Abschluss der Induktionschemotherapie bzw. der Abfall unter der Induktionschemotherapie. Das biochemische Ansprechen von CA19-9 ist ein bedeutender Indikator für den Behandlungserfolg und verbessert die diagnostische Genauigkeit bei der Auswahl von Patienten für eine chirurgische Exploration. Sowohl die Betrachtung des biochemischen Ansprechens allein als auch in Kombination mit dem radiologischen Ansprechen verbessert Sensitivität und Spezifität hinsichtlich einer möglichen R0-Resektion. Kombiniert man bei Patienten mit einer SD in Woche 16 ein gutes biochemisches Ansprechen (Rückgang von CA19-9 > 55%), so wird eine Sensitivität von 100% hinsichtlich der möglichen R0-Resektion erreicht. Zur Abschätzung des Gesamtüberlebens von Patienten mit LAPC sollten dagegen eher die absoluten Werte von CA19-9 nach Induktionschemotherapie verwendet werden und nicht der relative Rückgang des Markers. So zeigen Patienten, welche in Woche 16 einen CA19-9 Wert < 50 U/ml aufweisen mit 27,8 Monaten das beste mediane Gesamtüberleben.
Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy.
Background
Gastric pull-up (GPU) procedures may be complicated by leaks, fistulas, or stenoses. These complications are usually managed by endoscopy, but in extreme cases multidisciplinary management including reoperation may be necessary. Here, we report a combined endoscopic and surgical approach to manage a failed secondary GPU procedure.
Case summary
A 70-year-old male with treatment-refractory cervical esophagocutaneous fistula with stenotic remnant esophagus after secondary GPU was transferred to our tertiary hospital. Local and systemic infection originating from the infected fistula was resolved by endoscopy. Hence, elective esophageal reconstruction with free-jejunal interposition was performed with no subsequent adverse events.
Conclusion
A multidisciplinary approach involving interventional endoscopists and surgeons successfully managed severe complications arising from a cervical esophago-cutaneous fistula after GPU. Endoscopic treatment may have lowered the perioperative risk to promote primary wound healing after free-jejunal graft interposition.
The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients.