Challenges in diagnosis and management of neutropenia upon exposure to immune-checkpoint inhibitors: meta-analysis of a rare immune-related adverse side effect.

BACKGROUND: Cancer immunotherapy via immune-checkpoint inhibition (ICI) by antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and cell death protein 1 (PD-1) have significantly improved the outcome of metastasized melanoma and of a rapidly increasing number of other cancer types. The anti-tumor effect is often accompanied by immune-related adverse events (irAE). Hematological irAE, specifically neutropenia, are rarely observed. However, neutropenia is associated with high morbidity and mortality due to infection complications. Thus, early detection and treatment is crucial. METHODS: We present the clinical course of two patients with severe neutropenia after ICI therapy and demonstrate the difficulty of the diagnosis when a comedication of metamizole, a well-known analgesic drug used to treat cancer pain, is present. Further, we provide a comprehensive descriptive and statistical analysis of published data on diagnostics, treatment and infection complication in patients with at least grade 4 neutropenia by a systematic database search. RESULTS: Finally, 34 patients were analyzed, including the two case reports from our cohort. The median onset of neutropenia was 10.5 weeks after first ICI administration (interquartile range: 6 weeks). In 76% (N = 26), a normalization of the neutrophil count was achieved after a median duration of neutropenia of 13 days. In a subsample of 22 patients with detailed data, the infection rate was 13%, proven by positive blood culture in 3 cases, but 68% (N = 15) presented with fever > 38 °C. Treatment regime differed relevantly, but mainly included G-CSF and intravenous corticosteroids. Death was reported in 14 patients (41%), 3 of whom (9%) were associated with hematological irAE but only two directly associated with neutropenia. CONCLUSION: With an increasing number of cancer patients eligible to ICI therapy, the incidence of severe hematological toxicities may rise substantially over the next years. Clinicians working in the field of cancer immune therapies should be aware of neutropenia as irAE to provide immediate treatment.

Impact of a Patient Blood Management monitoring and feedback programme on allogeneic blood transfusions and related costs.

A Patient Blood Management programme was established at the University Hospital of Zurich, along with a monitoring and feedback programme, at the beginning of 2014 with a first analysis reported in 2015. Our study aimed to investigate the further impact of this Patient Blood Management monitoring and feedback programme on transfusion requirements and related costs. We included adult patients discharged between 2012 and 2017. A total of 213,882 patients underwent analysis: 66,659 patients in the baseline period (2012-2013); 35,309 patients in the year after the introduction of the Patient Blood Management monitoring and feedback programme (2014) and 111,914 patients in the continued sustainability period (2015-2017). The introduction of the Patient Blood Management monitoring and feedback programme reduced allogeneic blood product transfusions by 35%, from 825 units per 1000 hospital discharges in 2012 to 536 units in 2017. The most sustained effect was an approximately 40% reduction in red blood cell transfusions, from 535 per 1000 discharges to 319 units. Fewer patients were transfused in the periods after the introduction of the Patient Blood Management monitoring and feedback programme (6251 (9.4%) vs. 2932 (8.3%) vs. 8196 (7.3%); p < 0.001). Compared with 2012, the yearly OR for being exposed to any blood transfusion declined steadily after the introduction of the Patient Blood Management monitoring and feedback programme to 0.64 (95%CI 0.61-0.68; p < 0.001) in 2017. For patients requiring extracorporeal membrane oxygenation, transfusion requirements were also sustainably reduced. This reduction in allogeneic blood transfusions led to savings of 12,713,754 Swiss francs (£ 9,497,000 sterling; EUR 11,100,000; US$ 12,440,000) in blood product acquisition costs over 4 years. In-hospital mortality was not affected by the programme. The Patient Blood Management monitoring and feedback programme sustainably reduced transfusion requirements and related costs, without affecting in-hospital mortality.

Distinct factors determine the kinetics of disease relapse in adults transplanted for acute myeloid leukaemia.

BACKGROUND: Disease recurrence remains the major cause of death in adults with acute myeloid leukaemia (AML) treated using either intensive chemotherapy (IC) or allogenic stem cell transplantation (allo-SCT). AIMS: The timely delivery of maintenance drug or cellular therapies represent emerging strategies with the potential to reduce relapse after both treatment modalities, but whilst the determinants of overall relapse risk have been extensively characterized the factors determining the timing of disease recurrence have not been characterized. MATERIALS AND METHODS: We have therefore examined, using a series of sequential landmark analyses, relapse kinetics in a cohort of 2028 patients who received an allo-SCT for AML in CR1 and separately 570 patients treated with IC alone. RESULTS: In the first 3 months after allo-SCT, the factors associated with an increased risk of relapse included the presence of the FLT3-ITD (P < 0.001), patient age (P = 0.012), time interval from CR1 to transplant (P < 0.001) and donor type (P = 0.03). Relapse from 3 to 6 months was associated with a higher white cell count at diagnosis (P = 0.001), adverse-risk cytogenetics (P < 0.001), presence of FLT3-ITD mutation (P < 0.001) and time interval to achieve first complete remission (P = 0.013). Later relapse was associated with adverse cytogenetics, mutated NPM1, absence of chronic graft-versus-host disease (GVHD) and the use of in vivo T-cell depletion. In patients treated with IC alone, the factors associated with relapse in the first 3 months were adverse-risk cytogenetics (P < 0.001) and FLT3-ITD status (P = 0.001). The factors predicting later relapse were the time interval from diagnosis to CR1 (P = 0.22) and time interval from CR1 to IC (P = 0.012). DISCUSSION AND CONCLUSION: Taken together, these data provide novel insights into the biology of disease recurrence after both allo-SCT and IC and have the potential to inform the design of novel maintenance strategies in both clinical settings.

Association between dental status and food diversity among older Japanese.

OBJECTIVE: To investigate the relationship of dental status to food diversity among older Japanese. DESIGN AND SETTING: A community-based cross-sectional study conducted in the town of Tosa, Kochi Prefecture, Japan. METHODS: The study participants were 252 Japanese (84 men and 168 women, average age 81.2 years) and dentate participants were classified into three groups: 1-9 teeth, 10-19 teeth and 20 or more teeth. Food diversity was assessed as a validated measure of dietary quality using the 11-item Food Diversity Score Kyoto (FDSK-11), which evaluates frequency of consumption of 11 main food groups. Multivariable analysis of the differences in FDSK-11 score ranging from 0 to 11, with a higher score indicating greater food diversity, among the three dental status groups was conducted using general linear models. All the performed analyses were stratified by gender. RESULTS: There was no association between dental status and food diversity score in models for men. In contrast, women with ≤ 9 teeth and with 10-19 teeth had significantly lower FDSK-11 scores than women with ≥ 20 teeth after adjusting for confounders (p < 0.001 and p = 0.009, respectively). Additionally, there was a trend toward lower scores for FDSK-11 with fewer teeth (p = 0.001). CONCLUSION: A less varied diet, as indicated by low FDSK-11 score, was observed in female participants with fewer teeth. Tooth loss was associated with poor diet quality among older Japanese women.

[Analysis of quality of life outcome for nasopharyngeal carcinoma patients after treatment]. / Posttherapeutische Lebensqualität beim Nasopharynxkarzinom.

BACKGROUND: This retrospective study analysed patient characteristics and quality of live (QoL) for patients with nasopharyngeal carcinoma (NPC) after treatment. MATERIAL AND METHODS: A cross-sectional investigation was conducted to assess the QoL of 20 NPC patients with cancer-free survival of more than one year, which were treated with radiotherapy (RT) or chemoradiotherapy (RCT) during the period 2001-2009 at the University Hospital Bonn, Germany. The QoL was assessed by the FACT-NP (functional assessment of cancer therapy-nasopharyngeal) questionnaire. RESULTS: The median age of the patients was 57 ± 13 years and the male/female ratio was 2.33/1.3 (15%) patients were treated with RT and 17 (85%) with RCT. The global QoL was good in our patients. Xerostomia, chewing, decrease of gustatory sense, discontent with sexual life and ear problems were of major concern with the majority of patients and affected the QoL negatively. Pain, lost of working ability, emotional distress, or family problems were no significant factors. CONCLUSION: The expected reduction of QoL after treatment must be explained in detail to the NPC patient. The integration of the family and partner, an antidepressant therapy or psycho-oncological support can be useful and necessary.

[Treatment results of nasopharyngeal carcinoma in adults]. / Ergebnisse beim Nasopharynxkarzinom im Erwachsenenalter.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a rare tumor entity in Germany in contrast to endemic countries in Asia or Africa. This retrospective study investigated patient characteristics and prognostic factors with respect to different NPC treatment strategies. PATIENTS AND METHODS: A total of 63 NPC patients treated during the period 1990-2009 at the University Hospital Bonn, Germany, were included. RESULTS: The median age of the patients was 56.4 years, the male:female ratio was 3.2:1, 23.8% were in Union Internationale Contre le Cancer (UICC) stage I/II and 76.2% were in stage III/IV. Most of the carcinomas were WHO type III (57.1%), followed by World Health Organization (WHO) type II (33.3%) and at last WHO type I (9.6%). The 5-year overall survival rate after concomitant chemoradiotherapy (RCT) was 75% and after radiotherapy (RT) 60%. The mortality rate increased by 3.5 times with each increase in T-stage (p ≤ 0.047). The recurrence rate (RR) after RCT was 34% and after RT alone 68% (p ≤ 0.04). Tumor ablation increased the RR significantly (p ≤ 0.047). CONCLUSION: Combined chemotherapy and RT is an effective treatment of NPC disease and clearly superior to RT alone. Tumor ablation before RCT/RT worsens the prognosis and is now obsolete.

Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome.

Treatment results of AML in elderly patients are unsatisfactory. In an open label randomized phase II study, we investigated whether addition of the XPO1 inhibitor selinexor to intensive chemotherapy would improve outcome in this population. 102 AML patients > 65 years of age (median 69 (65-80)) were randomly assigned to standard chemotherapy (3 + 7) with or without oral selinexor 60 mg twice weekly (both arms n = 51), days 1-24. In the second cycle, cytarabine 1000 mg/m2 twice daily, days 1-6 with or without selinexor was given. CR/CRi rates were significantly higher in the control arm than in the investigational arm (80% (95% C.I. 69-91%) vs. 59% (45-72%; p = 0.018), respectively). At 18 months, event-free survival was 45% for the control arm versus 26% for the investigational arm (Cox-p = 0.012) and overall survival 58% vs. 33%, respectively (p = 0.009). AML and infectious complications accounted for an increased death rate in the investigational arm. Irrespective of treatment, MRD status after two cycles appeared to be correlated with survival. We conclude that the addition of selinexor to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients. (Netherlands Trial Registry number NL5748 (NTR5902), www.trialregister.nl ).

Correction: Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS.

More effective treatment modalities are urgently needed in patients with acute myeloid leukemia (AML) of older age. We hypothesized that adding lenalidomide to intensive standard chemotherapy might improve their outcome. After establishing a safe lenalidomide, dose elderly patients with AML were randomly assigned in this randomized Phase 2 study (n = 222) to receive standard chemotherapy ("3 + 7") with or without lenalidomide at a dose of 20 mg/day 1-21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without lenalidomide (20 mg/day 1-21). The CR/CRi rates in the two arms were not different (69 vs. 66%). Event-free survival (EFS) at 36 months was 19% for the standard arm versus 21% for the lenalidomide arm and overall survival (OS) 35% vs. 30%, respectively. The frequencies and grade of adverse events were not significantly different between the treatment arms. Cardiovascular toxicities were rare and equally distributed between the arms. The results of the present study show that the addition of lenalidomide to standard remission induction chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR2294 in The NederlandsTrial Register (www.trialregister.nl).

Human T cell development and HIV infection in human hemato-lymphoid system mice.

Advances in generation of mice that on human hematopoietic stem and progenitor cell transplantation develop and maintain human hemato-lymphoid cells have fueled an already thriving field of research. We focus here on human T cell development and HIV infection in Rag2 -/- gamma(c) -/- mice transplanted as newborns with human CD34+ cord blood hematopoietic stem and progenitor cells.

Development of CD8alpha-positive dendritic cells from a common myeloid progenitor.

Dendritic cells (DCs) are critical in both initiating adaptive immune responses and maintaining tolerance to self antigens. These apparently contradictory roles have been suggested to depend on different subsets of DCs that arise from either myeloid or lymphoid hematopoietic origins, respectively. Although DC expression of CD8alpha is attributed to a lymphoid origin, here we show that both CD8alpha+ and CD8alpha- DCs can arise from clonogenic common myeloid progenitors in both thymus and spleen. Thus, expression of CD8alpha is not indicative of a lymphoid origin, and phenotypic and functional differences among DC subsets are likely to reflect maturation status rather than ontogeny.

[Bronchogenic cyst: a rare cause of a retroperitoneal mass]. / Bronchogene Zyste: Eine seltene Diagnose bei retroperitonealer Raumforderung.

BACKGROUND: Bronchogenic cysts are developmental abnormalities of the primitive foregut which typically occur in the lung. Subdiaphragmatic and, especially, retroperitoneal locations are rare. The histopathological definition consists of the presence of ciliated epithelium together with cartilage or bronchial mucous glands. CASE PRESENTATION: We report on a 49-year-old patient with the incidental finding of a large cystic mass between the diaphragm and the stomach. Imaging studies suggested an adrenal tumour. Surgical resection and postoperative follow-up were uneventful. Histological examination revealed the surprising diagnosis of a bronchogenic cyst. CONCLUSION: Bronchogenic cysts must be considered in the differential diagnosis of retroperitoneal cystic lesions. Regardless of being asymptomatic most of the time, surgical resection is recommended to obtain definitive histological diagnosis and avoid future complications.

Perceptions and Attitudes toward Data Sharing among Dental Researchers.

INTRODUCTION: Increasing attention is being given to the roles of data management and data sharing in the advancement of research. This study was undertaken to explore opinions and past experiences of established dental researchers as related to data sharing and data management. METHODS: Researchers were recruited from the International Association for Dental Research scientific groups to complete a survey consisting of Likert-type, multiple-choice, and open-ended questions. RESULTS: All 42 respondents indicated that data sharing should be promoted and facilitated, but many indicated reservations or concerns about the proper use of data and the protection of research subjects. Many had used data from data repositories and received requests for data originating from their studies. Opinions varied regarding restrictions such as requirements to share data and the time limits of investigator rights to keep data. Respondents also varied in their methods of data management and storage, with younger respondents and those with higher direct costs of their research tending to use dedicated experts to manage their data. DISCUSSION: The expressed respondent support for research data sharing, with the noted concerns, complements the idea of developing managed data clearinghouses capable of promoting, managing, and overseeing the data-sharing process. KNOWLEDGE TRANSFER STATEMENT: Researchers can use the results of this study to evaluate and improve management and sharing of research data. By encouraging and facilitating the data-sharing process, research can advance more efficiently, and research findings can be implemented into practice more rapidly to improve patient care and the overall oral health of populations.

Lymphocyte development from hematopoietic stem cells.

The recent application of new techniques, such as multi-color cell sorting and the production of transgenic and gene-knockout mice, has contributed to a better understanding of lymphocyte development from hematopoietic stem cells. Now that we can purify progenitors at different maturational stages during lymphocyte development, the challenge is to understand the processes that govern each developmental stage transition.

Comparison of two antacid preparations on intragastric acidity--a two-centre open randomised cross-over placebo-controlled trial.

BACKGROUND: Rennie and Riopan Gel are 2 of the most well-known and popular over-the-counter antacids; for heartburn symptoms, pain relief is fast with both preparations. A direct comparison with respect to intragastric acidity has not been done yet. The aim of our study was therefore to compare the effects of both preparations on intragastric acidity of fasting volunteers. METHODS: The study was conducted as an open, randomised, placebo-controlled, 2-centre cross-over study. On different days, 24 healthy adult volunteers (11 males and 13 females) received equimolar acid-neutralising amounts of either Riopan Gel (800 mg magaldrate) or 2 tablets of Rennie (680 mg calcium carbonate and 80 mg magnesium carbonate) or no drug (control) with a wash-out period of at least 4 days between applications. The intragastric pH was measured for 3 h by intragastric pH-metry. The primary endpoint was the median time lag before intragastric pH >3.0 was reached for 10 consecutive min after drug administration. RESULTS: For both antacids, the median pH during the first 30 min after drug administration was statistically significantly different from placebo (p < 0.05), but there was a statistically significant increase in pH during the first 5 min for Riopan Gel only. CONCLUSION: Compared to placebo, both antacids (Rennie and Riopan Gel) have short-lasting effects on intragastric acidity. There is no statistically significant difference between the 2 preparations, except in the first 5 min, indicating a faster onset of action for Riopan Gel. We conclude that the antacid formulation (tablet or liquid) has little influence on intragastric acidity.

[Pharmacologic treatments of transit disorders]. / Pharmakologische Therapie von Transitstörungen.

The gastrointestinal transit can be disturbed in different situations by increased or decreased motility patterns. Pharmacological treatment of gastrointestinal motility disorders is intended to inhibit or stimulate motility. Prokinetic agents as metoclopramide, domperidone, erythromycin or tegaserod are used in clinical settings. We discuss their use in functional dyspepsia and gastroparesis. Management of chronic constipation consists of increasing fluid and dietary fiber intake and increasing physical activity. Fiber, lubricants, osmotic and stimulative laxatives increase stool frequency and improve symptoms of constipation. Treatment of irritable bowel syndrome (IBS) should focuses on the specific gastrointestinal complaints. In constipation predominant IBS fiber and isoosmotic laxatives are used first line. Tegaserod has an advantage over placebo in constipation-predominant IBS. Pain can be treated with antispasmodic agents and tricyclic antidepressants in low doses. The diarrhea-predominant IBS responds well to a loperamide treatment.

Comparative value of post-remission treatment in cytogenetically normal AML subclassified by NPM1 and FLT3-ITD allelic ratio.

Post-remission treatment (PRT) in patients with cytogenetically normal (CN) acute myeloid leukemia (AML) in first complete remission (CR1) is debated. We studied 521 patients with CN-AML in CR1, for whom mutational status of NPM1 and FLT3-ITD was available, including the FLT3-ITD allelic ratio. PRT consisted of reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (alloHSCT) (n=68), myeloablative conditioning (MAC) alloHSCT (n=137), autologous hematopoietic stem cell transplantation (autoHSCT) (n=168) or chemotherapy (n=148). Favorable overall survival (OS) was found for patients with mutated NPM1 without FLT3-ITD (71±4%). Outcome in patients with a high FLT3-ITD allelic ratio appeared to be very poor with OS and relapse-free survival (RFS) of 23±8% and 12±6%, respectively. Patients with wild-type NPM1 without FLT3-ITD or with a low allelic burden of FLT3-ITD were considered as intermediate-risk group because of similar OS and RFS at 5 years, in which PRT by RIC alloHSCT resulted in better OS and RFS as compared with chemotherapy (hazard ratio (HR) 0.56, P=0.022 and HR 0.50, P=0.004, respectively) or autoHSCT (HR 0.60, P=0.046 and HR 0.60, P=0.043, respectively). The lowest cumulative incidence of relapse (23±4%) was observed following MAC alloHSCT. These results suggest that alloHSCT may be preferred in patients with molecularly intermediate-risk CN-AML, while the choice of conditioning type may be personalized according to risk for non-relapse mortality.

[Water supply for Peking ducks--possible alternatives for bathing]. / Wasserversorgung von Pekingenten--Badeersatzmöglichkeiten.

In order to investigate possible advantages of open water drinkers such as troughs and bells in the intensive husbandry of ducks, we evaluated in this study the effect of open water systems on the behavior and health of peking ducks. In this investigation six fattening trials each with 1152 Cherry Valley Peking ducks were analyzed. The average fattening period was 47 to 49 days. The ducks were kept on straw in six standardized compartments each 32 qm with 192 ducks. 25% of the compartment with perforated grid, with one of the tested water systems. In contrast to pens with nipple-drinkers only, the ducks in pens with open water troughs/showers had the opportunity to exhibit their natural drinking behavior and water associated activities in accordance with the animal welfare requirements. In the free-choice pens the open water systems were significantly preferred, and over a 24-hour period the ducks in watering areas with open water troughs showed higher activity. Limiting the access to the open water systems to eight, four or two hours per day led to an increased use per time unit. Ducks with access to nipple drinkers only showed a significantly higher percentage of plugged up nostrils than animals from pens with open water drinkers. Open water drinkers had also a positive impact on the plumage condition.

Comparative therapeutic value of post-remission approaches in patients with acute myeloid leukemia aged 40-60 years.

The preferred type of post-remission therapy (PRT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1) is a subject of continued debate, especially in patients at higher risk of nonrelapse mortality (NRM), including patients >40 years of age. We report results of a time-dependent multivariable analysis of allogenic hematopoietic stem cell transplantation (alloHSCT) (n=337) versus chemotherapy (n=271) or autologous HSCT (autoHSCT) (n=152) in 760 patients aged 40-60 years with AML in CR1. Patients receiving alloHSCT showed improved overall survival (OS) as compared with chemotherapy (respectively, 57±3% vs 40±3% at 5 years, P<0.001). Comparable OS was observed following alloHSCT and autoHSCT in patients with intermediate-risk AML (60±4 vs 54±5%). However, alloHSCT was associated with less relapse (hazard ratio (HR) 0.51, P<0.001) and better relapse-free survival (RFS) (HR 0.74, P=0.029) as compared with autoHSCT in intermediate-risk AMLs. AlloHSCT was applied following myeloablative conditioning (n=157) or reduced intensity conditioning (n=180), resulting in less NRM, but comparable outcome with respect to OS, RFS and relapse. Collectively, these results show that alloHSCT is to be preferred over chemotherapy as PRT in patients with intermediate- and poor-risk AML aged 40-60 years, whereas autoHSCT remains a treatment option to be considered in patients with intermediate-risk AML.