Communication patterns in families affected by parental cancer from the healthy parents' perspective-process evaluation of the complex intervention Family-SCOUT.

PURPOSE: Within families affected by parental cancer, open communication impacts the well-being of parents and their children; however, limited research exists on communication patterns in these families. This sub-study addresses this through the Family-SCOUT study, a multicenter, prospective, interventional, and non-randomized investigation with intervention (IG) and control group (CG). The purpose of this sub-study was to identify and compare the differences in communication patterns between the IG and CG as part of the process evaluation. The research question was addressed in both groups: What communication patterns do healthy parents perceive within their families? METHODS: Using a qualitative approach, the study involved interviewing healthy parents as surrogates for their families. The interviews were audio-recorded, transcribed, and coded using a template analysis. The resulting data were analyzed at the group level. RESULTS: Twenty-three interviews were conducted in the IG and 27 interviews in the CG. The analysis of themes centered on communication patterns as seen in the family structure. Both groups exhibited instances of open communication about fears and wishes as well as the use of child-friendly language when discussing cancer. Notable differences were observed: challenges in open communication with children were sorely reported in CG interviews, and "the illness is discussed when necessary" was sorely described in IG interviews. CONCLUSION: This study underscores the need to address and encourage open communication within families with parental cancer.

Practical management of toxicities associated with bosutinib in patients with Philadelphia chromosome-positive chronic myeloid leukemia.

Bosutinib (SKI-606) is an oral, dual Src/Abl tyrosine kinase inhibitor (TKI) approved for treatment of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) that is resistant or intolerant to prior TKI therapy or for whom other TKIs are not appropriate choices. The objective of this review is to provide a longitudinal summary of toxicities that may arise during treatment with second-line or later bosutinib in patients with Ph+ chronic phase CML and to provide strategies for managing these toxicities. As bosutinib is not currently indicated for newly diagnosed CML, toxicities associated with first-line treatment are not reviewed. Recognition and optimal management of these toxicities can facilitate patient compliance and affect treatment outcomes.

[Biobanking requirements from the perspective of the clinician : Experiences in hematology and oncology]. / Biobankinganforderungen aus Sicht des Klinikers : Erfahrungen aus der Hämatologie und Onkologie.

The requirements for optimal biobanking from the point of view of the clinical partner can be highly variable. Depending on the material, processing, storage conditions, clinical data, and involvement of external partners, there will be special requirements for the participating clinician and specialist areas. What they all have in common is that the goal of any biobanking must be to improve clinical, translational, and basic research. While in the past biomaterials often had to be individually stored for each research project, modern biobanking offers decisive advantages: a comprehensive ethics vote fulfilling state-of-the-art data safety requirements, standardized processing and storage protocols, specialized biobank software for pseudonymization and localization, protection against power failures and defects of the equipment, centralized and sustainable storage, easy localization and return of samples, and their destruction or anonymization after completion of an individual project. In addition to this important pure storage function, central biobanking can provide a link to clinical data as well as the anonymous use of samples for project-independent research. Both biobank functions serve different purposes, are associated with specific requirements, and should be pursued in parallel. If successful, central biomaterial management can achieve a sustainable improvement of academic and non-academic biomedical research and the optimal use of resources. The close collaboration between clinicians and non-clinicians is a crucial prerequisite for this.

Health care setting and severity, symptom burden, and complications in patients with Philadelphia-negative myeloproliferative neoplasms (MPN): a comparison between university hospitals, community hospitals, and office-based physicians.

Philadelphia-negative myeloproliferative neoplasms (MPN) comprise a heterogeneous group of chronic hematological malignancies with significant variations in clinical characteristics. Due to the long survival and the feasibility of oral or subcutaneous therapy, these patients are frequently treated outside of larger academic centers. This analysis was performed to elucidate differences in MPN patients in three different health care settings: university hospitals (UH), community hospitals (CH), and office-based physicians (OBP). The MPN registry of the Study Alliance Leukemia is a non-interventional prospective study including adult patients with an MPN according to WHO criteria (2008). For statistical analysis, descriptive methods and tests for significant differences were used. Besides a different distribution of MPN subtypes between the settings, patients contributed by UH showed an impaired medical condition, a higher comorbidity burden, and more vascular complications. In the risk group analyses, the majority of polycythemia vera (PV) and essential thrombocythemia (ET) patients from UH were classified into the high-risk category due to previous vascular events, while for PV and ET patients in the CH and OBP settings, age was the major parameter for a high-risk categorization. Regarding MPN-directed therapy, PV patients from the UH setting were more likely to receive ruxolitinib within the framework of a clinical trial. In summary, the characteristics and management of patients differed significantly between the three health care settings with a higher burden of vascular events and comorbidities in patients contributed by UH. These differences need to be taken into account for further analyses and design of clinical trials.

Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part).

BACKGROUND: Recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN) overexpresses αvß5 integrin. Cilengitide selectively inhibits αvß3 and αvß5 integrins and is investigated as a treatment strategy. PATIENTS AND METHODS: The phase I/II study ADVANTAGE evaluated cilengitide combined with cisplatin, 5-fluorouracil, and cetuximab (PFE) in R/M-SCCHN. The phase II part reported here was an open-label, randomized, controlled trial investigating progression-free survival (PFS). Patients received up to six cycles of PFE alone or combined with cilengitide 2000 mg once (CIL1W) or twice (CIL2W) weekly. Thereafter, patients received maintenance therapy (cilengitide arms: cilengitide plus cetuximab; PFE-alone arm: cetuximab only) until disease progression or unacceptable toxicity. RESULTS: One hundred and eighty-two patients were treated. Median PFS per investigator read was similar for CIL1W + PFE, CIL2W + PFE, and PFE alone (6.4, 5.6, and 5.7 months, respectively). Accordingly, median overall survival and objective response rates were not improved with cilengitide (12.4 months/47%, 10.6 months/27%, and 11.6 months/36%, respectively). No clinically meaningful safety differences were observed between groups. None of the tested biomarkers (expression of integrins, CD31, Ki-67, vascular endothelial growth factor receptor 2, vascular endothelial-cadherin, type IV collagen, epidermal growth factor receptor, or p16 for human papillomavirus) were predictive of outcome. CONCLUSION: Neither of the cilengitide-containing regimens demonstrated a PFS benefit over PFE alone in R/M-SCCHN patients.

Effectiveness of a comprehensive support program for families with parental cancer (Family-SCOUT): results of a multicenter non-randomized controlled trial.

BACKGROUND: Cancer patients with minor children but also their families suffer from significant psychological distress and comorbidity. Protective factors predicting successful coping are well known. Corresponding systematic interventions are rare and limited by access barriers. We developed a comprehensive family-centered intervention for cancer patients with at least one dependent minor. PATIENTS AND METHODS: Family-SCOUT represents a multicentric, prospective, interventional, and controlled study for families with parental cancer and their minor children. In the intervention group (IG), all family members were addressed using a care and case management approach for nine months. Families in the control group (CG) received standard of care. Participating parents were asked to complete the Hospital-Anxiety-Depression-Scale (HADS) questionnaire at enrolment (T0) and after 9 months (T2). The primary outcome was a clinically relevant reduction of distress in at least one parent per family, measured as minimal important difference (MID) of ≥1.6 in the HADS total score. The percentage of families achieving MID is compared between the IG and CG by exact Fisher's test, followed by multivariate confounder analyses. RESULTS: T0-questionnaire of at least one parent was available for 424 of 472 participating families, T2-questionnaire after 9 months was available for 331 families (IG n = 175, CG n = 156). At baseline, both parents showed high levels of distress (HADS total: sick parents IG: 18.7 ± 8.1; CG: 16.0 ± 7.2; healthy partners: IG: 19.1 ± 7.9; CG: 15.2 ± 7.7). The intervention was associated with a significant reduction in parental distress in the IG (MID 70.4% in at least one parent) compared with the CG (MID 55.8%; P = 0.008). Adjustment for group differences from specific confounders retained significance (P = 0.047). Bias from other confounders cannot be excluded. CONCLUSIONS: Parental cancer leads to a high psychosocial burden in affected families. Significant distress reduction can be achieved through an optimized and structured care approach directed at the family level such as family-SCOUT.

Phase I/II trial of cilengitide with cetuximab, cisplatin and 5-fluorouracil in recurrent and/or metastatic squamous cell cancer of the head and neck: findings of the phase I part.

BACKGROUND: Novel therapies are needed to improve the poor prognosis of patients with recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN). METHODS: ADVANTAGE is a phase I/II, multicentre study evaluating the integrin inhibitor cilengitide combined with cetuximab and platinum-based chemotherapy in patients with recurrent and/or metastatic SCCHN. The phase I part tested cilengitide (500, 1000 and 2000 mg) twice weekly with standard doses of cetuximab, cisplatin and 5-fluorouracil. RESULTS: Ten patients (9 male, 1 female; median 56 years old) were included in the phase I part. No dose-limiting toxicities (DLTs: grade 3/4 toxicities in the first 3 weeks as defined per protocol) or deaths occurred. The most common adverse events (AEs) were constipation, rash, nausea, anorexia and fatigue. Cilengitide-related grade 3/4 AEs, all of which occurred after the DLT observation period, were anaemia, angioedema, asthenia, mucosal inflammation, nausea and vomiting (one event per category). Best overall tumour response was partial response (PR) for 4 out of 10 patients and stable disease (SD) for 6 out of 10 patients across all cohorts. Disease control rate (complete response, PR and SD) was 100%. CONCLUSION: Cilengitide combined with cetuximab and platinum-based chemotherapy was well tolerated. No DLTs or unexpected AEs were observed. Cilengitide 2000 mg was considered safe and was selected for the subsequent randomised phase II part assessing progression-free survival.

Asymmetric cell divisions sustain long-term hematopoiesis from single-sorted human fetal liver cells.

Hematopoietic stem cells (HSCs) in adult marrow are believed to be derived from fetal liver precursors. To study cell kinetics involved in long-term hematopoiesis, we studied single-sorted candidate HSCs from fetal liver that were cultured in the presence of a mixture of stimulatory cytokines. After 8-10 d, the number of cells in primary cultures varied from <100 to >10,000 cells. Single cells in slow growing colonies were recloned upon reaching a 100-200 cell stage. Strikingly, the number of cells in subclones varied widely again. These results are indicative of asymmetric divisions in primitive hematopoietic cells in which proliferative potential and cell cycle properties are unevenly distributed among daughter cells. The continuous generation of functional heterogeneity among the clonal progeny of HSCs is in support of intrinsic control of stem cell fate and provides a model for the long-term maintenance of hematopoiesis in vitro and in vivo.

Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood.

To study telomere length dynamics in hematopoietic cells with age, we analyzed the average length of telomere repeat sequences in diverse populations of nucleated blood cells. More than 500 individuals ranging in age from 0 to 90 yr, including 36 pairs of monozygous and dizygotic twins, were analyzed using quantitative fluorescence in situ hybridization and flow cytometry. Granulocytes and naive T cells showed a parallel biphasic decline in telomere length with age that most likely reflected accumulated cell divisions in the common precursors of both cell types: hematopoietic stem cells. Telomere loss was very rapid in the first year, and continued for more than eight decades at a 30-fold lower rate. Memory T cells also showed an initial rapid decline in telomere length with age. However, in contrast to naive T cells, this decline continued for several years, and in older individuals lymphocytes typically had shorter telomeres than did granulocytes. Our findings point to a dramatic decline in stem cell turnover in early childhood and support the notion that cell divisions in hematopoietic stem cells and T cells result in loss of telomeric DNA.

[When only the pathologist may help. Limitation and possibilities of biopsies in Internal Medicine]. / Wenn nur noch der Pathologe hilft. Grenzen und Möglichkeiten der Biopsie in der Inneren Medizin.

Histological evaluation after biopsy remains the gold standard for the diagnosis of numerous diseases in Internal Medicine. The gastrointestinal tract (e. g. esophagus, liver and large intestine), the kidneys or bone marrow are organs, where biopsy-driven diagnosis and evaluation of therapeutic regimens are of major relevance. Improvement in blood analysis, endoscopic techniques and radiology could significantly reduce the number of biopsies. Hence under certain circumstances, the risk of biopsy can be avoided and non-invasive markers can sufficiently substitute the histological evaluation. However, histological evaluation derived from biopsies remains the standard of diagnosis in many cases in Internal Medicine. In the present review the current standards and future developments of pathologic diagnosis through biopsy are illustrated.

Tolerability of high dose chemotherapy and autologous stem cell transplantation in elderly patients with multiple myeloma: A single-center retrospective analysis.

PURPOSE OF THE STUDY: In the past years, high dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT)has more extensively been performed in elderly patients with multiple myeloma (MM). Several studies found a similar survival benefit compared to younger patients. The objective of our retrospective study is to analyse the tolerability of HDT + ASCT in elderly patients. PATIENTS AND METHODS: We compared 26 ASCT performed in MM patients ≥65 years to 127 ASCT in patients <65 years by evaluating treatment-tolerability, length of hospital stay and number of transfusions. RESULTS: There was no significant difference in the duration of hospitalisation (16 days (range 14-47) in the elderly vs. 17 days (range 14-71) days, P = 0.0903), median time of cytopenia (neutrophils<500/µl: 5 days (range 4-24) vs. 6 days (range 3-28) days, P = 0.1091; platelets<30 000/µl: 6 days (range 3-36) vs. 7 days (range 0-53) days, P = 0.274) or incidence of, or degree of complications between the two age-groups. Immediate and day 100 treatment related mortality (TRM) was comparable in both groups (3.85% vs. 1.58%, P = 0.4304). CONCLUSION: our findings support the concept that HDT + ASCT can be safely administered as first-line option for well-selected patients≥65 years.

A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease.

In chronic-phase chronic myeloid leukaemia (CP-CML), residual BCR-ABL1+ leukaemia stem cells are responsible for disease persistence despite TKI. Based on in vitro data, CHOICES (CHlorOquine and Imatinib Combination to Eliminate Stem cells) was an international, randomised phase II trial designed to study the safety and efficacy of imatinib (IM) and hydroxychloroquine (HCQ) compared with IM alone in CP-CML patients in major cytogenetic remission with residual disease detectable by qPCR. Sixty-two patients were randomly assigned to either arm. Treatment 'successes' was the primary end point, defined as ≥0.5 log reduction in 12-month qPCR level from trial entry. Selected secondary study end points were 24-month treatment 'successes', molecular response and progression at 12 and 24 months, comparison of IM levels, and achievement of blood HCQ levels >2000 ng/ml. At 12 months, there was no difference in 'success' rate (p = 0.58); MMR was achieved in 80% (IM) vs 92% (IM/HCQ) (p = 0.21). At 24 months, the 'success' rate was 20.8% higher with IM/HCQ (p = 0.059). No patients progressed. Seventeen serious adverse events, including four serious adverse reactions, were reported; diarrhoea occurred more frequently with combination. IM/HCQ is tolerable in CP-CML, with modest improvement in qPCR levels at 12 and 24 months, suggesting autophagy inhibition maybe of clinical value in CP-CML.

Consequences of telomerase inhibition by BIBR1532 on proliferation and chemosensitivity of chondrosarcoma cell lines.

PURPOSE: Human chondrosarcomas are generally resistant to conventional treatments like chemotherapy and radiotherapy. We investigated the effects of BIBR1532, an inhibitor of telomerase on chondrosarcoma cells in vitro. METHODS: Telomerase activity, telomere lengths, growth kinetics and chemosensitivity were analyzed in chondrosarcoma cell lines treated with BIBR1532. RESULTS: BIBR1532 treatment resulted in telomerase inhibition, decrease of telomere length and reduction of growth capacity of telomerase positive chondrosarcoma cells. Although resistant to cisplatin, telomerase positive cells were sensitive to paclitaxel, which rapidly induced telomere erosion. CONCLUSION: Targeting of telomeres might represent a valid strategy for the (re-)sensitization of chemoresistant chondrosarcomas.

Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML.

This corrects the article DOI: 10.1038/leu.2017.9.

Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.

Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL.

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover.

Telomeres both reflect and limit the replicative lifespan of normal somatic cells. Immature sub-populations of human CD34+38- hematopoietic stem cell (HSC) can be identified in vitro based on their growth kinetics and telomere length. Fluorescence in situ hybridization and flow cytometry (flow-FISH) has been used to characterize telomere length dynamics as a surrogate marker for HSC turnover in vivo. Investigations in normal steady-state hematopoiesis provided the basis for follow-up studies in model scenarios characterized by increased HSC turnover. Disorders with underlying malignant transformation of HSC (e.g., chronic myeloid leukemia (CML)) can be discriminated from disease states with increased HSC turnover rates secondary to depletion of the stem cell compartment, for example, as in defined bone marrow failure syndromes. In some of these model scenarios, the degree of telomere shortening can be correlated with disease duration, disease stage and severity as well as with response to disease-modifying treatment strategies. Whether increased telomere shortening represents a causal link between HSC turnover, replicative senescence and/or the induction of genetic instability in acquired HSC disorders remains to be shown. However, data from congenital disorders, like dyskeratosis congenita (DKC), suggest that disturbed telomere maintenance may play a role for replicative exhaustion of the HSC pool in vivo.

How to build an allogeneic hematopoietic cell transplant unit in 2016: Proposal for a practical framework.

Allogeneic hematopoietic cell transplantation is part of the standard of care for many hematological diseases. Over the last decades, significant advances in patient and donor selection, conditioning regimens as well as supportive care of patients undergoing allogeneic hematopoietic cell transplantation leading to improved overall survival have been made. In view of many new treatment options in cellular and molecular targeted therapies, the place of allogeneic transplantation in therapy concepts must be reviewed. Most aspects of hematopoietic cell transplantation are well standardized by national guidelines or laws as well as by certification labels such as FACT-JACIE. However, the requirements for the construction and layout of a unit treating patients during the acute phase of the transplantation procedure or at readmission for different complications are not well defined. In addition, the infrastructure of such a unit may be decisive for optimized care of these fragile patients. Here we describe the process of planning a transplant unit in order to open a discussion that could lead to more precise guidelines in the field of infrastructural requirements for hospitals caring for people with severe immunosuppression.

Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants.

Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.