Comparison of patient-reported need of psycho-oncologic support and the doctor's perspective: how do they relate to disease severity in melanoma patients?

OBJECTIVE: Psycho-neuro-immune research suggests an association between cancer outcomes and psychosocial distress. Objective criteria to determine patients' levels of distress are important to establish potential links to disease outcomes. METHODS: We compared three patient-reported with one doctor-reported measures of psycho-oncologic distress frequently used in routine cancer care and investigated associations with standard disease severity parameters in melanoma patients. We enrolled n = 361 patients, successively seen at two outpatient university clinics in Germany. In the naturalistic study, n = 222 patients had been diagnosed <180 days and were seen for the first time (Group I); n = 139 had been diagnosed >180 days and were in after-care (Group II). RESULTS: Across groups, only moderate associations were seen between patient- reported and doctor-reported measures. Regarding clinical variables, disease severity and perceived need of psycho-oncologic support reported by patients or doctors showed hardly any association. After subgroup stratification, in patients of Group II, patient-reported and doctor-reported instruments showed some small associations with disease parameters commonly linked to more rapid cancer progression in patients who are in cancer after-care. CONCLUSIONS: Overall, the few and low associations suggest that need of psycho-oncologic support and clinical variables were largely independent of each other and doctors' perception may not reflect the patient's view. Therefore, the assessment of the patient perspective is indispensable to ensure that melanoma patients receive appropriate support, as such need cannot be derived from other disease parameters or proxy report. More research is needed applying psychometrically robust instruments that are ideally combined with sensitive biomarkers to disentangle psycho-neuro-immune implications in melanoma patients. Copyright © 2015 John Wiley & Sons, Ltd.

Inhibition of anti-apoptotic signals by Wortmannin induces apoptosis in the remote myocardium after LAD ligation: evidence for a protein kinase C-δ-dependent pathway.

It has been shown that, in the remote myocardium after infarction (MI), protein kinase C (PKC) inhibition reduces apoptosis both by blocking proapoptotic pathways and by activating antiapoptotic signals including the Akt pathway. However, it was open if vice versa, blockade of antiapoptotic pathways may influence proapoptotic signals. To clarify this, the present study tested the effects of the PI3-kinase blocker Wortmannin on proapoptotic signals and on apoptosis execution in the remote myocardium after infarction. Rats were subjected to MI by LAD ligation in situ. Some were pre-treated with Wortmannin alone or in combination with the PKC inhibitor Chelerythrine. After 24 h, pro- and anti-apoptotic signals (caspase-3, PKC isoforms, p38-MAPK, p42/44-MAPK, Akt, Bad), and marker of apoptosis execution (TUNEL) were quantified in the myocardium remote from the infarction. Wortmannin treatment increased apoptosis in the remote myocardium both at baseline and after MI, together with an activation of the PKC-δ/p38-MAPK-pathway. PKC-ε and p42/44-MAPK were unaffected. Combined treatment with Wortmannin and Chelerythrine fully reversed the pro-apoptotic effects of Wortmannin both at baseline and after MI. The PKC-δ-p38-MAPK-pathway as a strong signal for apoptosis in the non-infarcted myocardium can be influenced by targeting the anti-apoptotic PI3-kinase pathway. This gives evidence of a bi-directional crosstalk of pro- and anti-apoptotic signals after infarction.

Deacetylase inhibitors modulate proliferation and self-renewal properties of leukemic stem and progenitor cells.

Acute myeloid leukemia (AML) is a highly malignant disease that is not curable in the majority of patients. Numerous non-random genetic abnormalities are known, among which several translocations such as PLZF/RARα or AML1/ETO are known to aberrantly recruit histone deacetylases. Deacetylase inhibitors (DACi) are promising drugs leading to growth inhibition, cell cycle arrest, premature senescence and apoptosis in malignant cells. It is believed that DACi may have clinical efficacy by eradicating the most primitive population of leukemic stem and progenitor cells, possibly by interfering with self-renewal. The aim of the study was to investigate the effects of DACi on leukemic stem and progenitor cells using murine transduction-transplantation models of hematopoietic cells harboring the leukemia-associated fusion proteins (LAFP) PLZF/RARα or a truncated AML1/ETO protein (AML1/ETO exon 9). We show that the self-renewal and short-term repopulation capacity of AML1/ETO- or PLZF/RARα-expressing Sca1+/lin- stem and progenitor cells are profoundly inhibited by clinically applicable concentrations of the DACi dacinostat and vorinostat. To further investigate the mechanisms underlying these effects, we examined the impact of DACi on the transcription factor c-MYC and the Polycomb group protein BMI1, which are induced by LAFP and involved in leukemic transformation. In AML1/ETO or PLZF/RARα-positive 32D cells, DACi-mediated antiproliferative effects were associated with downregulation of BMI1 and c-MYC protein levels. Similar effects were demonstrated in primary samples of cytogenetically defined high-risk AML patients. In conclusion, DACi may be effective as maintenance therapy by negatively interfering with signaling pathways that control survival and proliferation of leukemic stem and progenitor cells.

Resonance frequency analysis: a new diagnostic tool for dental ankylosis.

Ankylosed teeth are considered in orthodontic treatment planning; however, diagnostic tools to quantify the rigidity of the tooth-to-bone connection are rare. Resonance frequency analysis (RFA) can quantify the rigidity of the dental implant-to-bone connection and thus may serve as a potential diagnostic tool to identify ankylosed teeth. To test this assumption, we examined 15 and 30 primary mandibular molars, with and without clinical signs of ankylosis, using the Osstell Mentor system. A cut-off implant stability quotient (ISQ) of 43 provided a specificity of 100% and a sensitivity of 53.3% when measured in the mesio-distal direction or a sensitivity of 20% when measured in the bucco-lingual direction. Based on a receiver-operating characteristic (ROC), the area under the curve (AUC) of 0.807 showed the mesio-distal direction of measurement to be a test of moderate discriminatory power. Given its non-invasiveness, RFA may serve as a quantitative diagnostic supplement to the clinical examination of potentially ankylosed primary molars.

Transport of polycyclic aromatic hydrocarbons in highly vulnerable karst systems.

Fluxes of polycyclic aromatic hydrocarbons (PAHs) were investigated along the route of transport in a south German karst system. Atmospheric deposition, seepage water in caves and spring water at the outlet of the catchment were monitored continuously over 1.5 years allowing the establishment of an input/output mass balance at the catchment scale. The results reveal that, even in the highly vulnerable karst catchment, PAHs are effectively retained in the soils. Only during high discharge events, such as snowmelt in spring, increasing PAH concentrations at the outlet of the catchment indicates a mobilization of the pollutants. These events are typically correlated with increasing particle concentrations. Based on our results, we conclude that particle-facilitated transport is the dominating cause of PAH mobilization. In summary, PAHs accumulate over time in soils and only occasionally high discharge events cause a short concentration pulse to be flushed through the karst system.

The deacetylase inhibitor LAQ824 induces notch signalling in haematopoietic progenitor cells.

AML progenitor cells (AML-PC) undergo significant apoptosis in response to the deacetylase inhibitor (DACi) LAQ824 and lose the replating capacity which was not observed with the DACi valproic acid. Treatment of normal hematopoietic progenitor cells (HPC) with LAQ824 resulted in (i) inhibition of differentiation, (ii) an G2/M cell cycle arrest exclusively in multipotent CD34(+) HPC and (iii) induction of apoptosis predominantly in committed CD34(-) HPC. Gene expression analysis showed induction of coactivator and target genes of the notch pathway as well as cell cycle arrest-inducing genes in the most primitive CD34(+) CD38(-) HPC population which may in part be responsible for the considerable, but reversible haematotoxicity of this drug.

The effect of the dual Src/Abl kinase inhibitor AZD0530 on Philadelphia positive leukaemia cell lines.

BACKGROUND: Imatinib mesylate, a selective inhibitor of Abl tyrosine kinase, is efficacious in treating chronic myeloid leukaemia (CML) and Ph+ acute lymphoblastic leukaemia (ALL). However, most advanced-phase CML and Ph+ ALL patients relapse on Imatinib therapy. Several mechanisms of refractoriness have been reported, including the activation of the Src-family kinases (SFK). Here, we investigated the biological effect of the new specific dual Src/Abl kinase inhibitor AZD0530 on Ph+ leukaemic cells. METHODS: Cell lines used included BV173 (CML in myeloid blast crisis), SEM t(4;11), Ba/F3 (IL-3 dependent murine pro B), p185Bcr-Abl infected Ba/F3 cells, p185Bcr-Abl mutant infected Ba/F3 cells, SupB15 (Ph+ ALL) and Imatinib resistant SupB15 (RTSupB15) (Ph+ ALL) cells. Cells were exposed to AZD0530 and Imatinib. Cell proliferation, apoptosis, survival and signalling pathways were assessed by dye exclusion, flow cytometry and Western blotting respectively. RESULTS: AZD0530 specifically inhibited the growth of, and induced apoptosis in CML and Ph+ ALL cells in a dose dependent manner, but showed only marginal effects on Ph- ALL cells. Resistance to Imatinib due to the mutation Y253F in p185Bcr-Abl was overcome by AZD0530. Combination of AZD0530 and Imatinib showed an additive inhibitory effect on the proliferation of CML BV173 cells but not on Ph+ ALL SupB15 cells. An ongoing transphosphorylation was demonstrated between SFKs and Bcr-Abl. AZD0530 significantly down-regulated the activation of survival signalling pathways in Ph+ cells, resistant or sensitive to Imatinib, with the exception of the RTSupB15. CONCLUSION: Our results indicate that AZD0530 targets both Src and Bcr-Abl kinase activity and reduces the leukaemic maintenance by Bcr-Abl.

Chelerythrine treatment influences the balance of pro- and anti-apoptotic signaling pathways in the remote myocardium after infarction.

OBJECTIVE: Apoptotic processes may be implicated in the molecular pathomechanisms of ventricular remodeling after myocardial infarction (MI). The modulation of apoptosis by pro- and anti-apoptotic pathways in the myocardium remote from the infarction, including its link to protein kinase C (PKC), was focus of the present study. METHODS: Rats were subjected to MI by LAD ligation in situ. Some animals were pretreated with the PKC inhibitor chelerythrine. After 1 h up to 28 days, pro- and anti-apoptotic signals (caspase-3, Bcl-2/Bax ratio, Akt, Bad), and marker of apoptosis execution (DNA laddering, TUNEL) were quantified in the myocardium remote from the infarction. RESULTS: Activation of caspase-3, a pro-apoptotic shift of the Bcl-2/Bax ratio, and DNA fragmentation were observed as early as 3 h after infarction and persisted up to 28 days. Akt- and Bad-phosphorylation was unchanged. Chelerythrine markedly reduced DNA fragmentation. Caspase-3 activation was unchanged. Surprisingly, Bad and Akt phosphorylation were highly increased (180% and 750% of control). CONCLUSION: Chelerythrine influences the balance of pro- and anti-apoptotic pathways in the remote myocardium after infarction, with an inhibition of proapoptotic and an activation of anti-apoptotic signals.

Effect of histone deacetylase inhibitor valproic acid on progenitor cells of acute myeloid leukemia.

Histone deacetylase inhibitor valproic acid (VPA) was recently shown to enhance proliferation and self-renewal of normal hematopoietic stem cells, raising the possibility that VPA may also support growth of leukemic progenitor cells (LPC). Here, VPA maintains a significantly higher proportion of CD34+ LPC and colony forming units compared to control cultures in six AML samples, but selectively reduces leukemic cell numbers in another AML sample with expression of AML1/ETO. Our data suggest a differential effect of VPA on the small population of AML progenitor cells and the bulk of aberrantly differentiated blasts in the majority of AML samples tested.

Ninety percent success in palatal implants loaded 1 week after placement: a clinical evaluation by resonance frequency analysis.

To investigate the behaviour of early loaded palatal implants when observed with resonance frequency analysis (RFA). Twenty patients (seven males and 13 females, mean age 26.4 years) received one palatal implant each (length: 4 mm, diameter: 3.3 mm; Orthosystem) for maximum orthodontic anchorage. The implants' stability was observed by RFA. Measurements were carried out at the time of surgery, after first orthodontic loading and subsequently once a week over a period of 12 weeks. Two palatal implants were lost. The other 18 remained stable. The average period from insertion to first loading was 6.7+/-0.8 days. The mean orthodontic force applied was 272.2+/-73.2 cN. The implant stability quotient (ISQ) value at the time of surgery averaged 69.4+/-3.9. The mean ISQ value 6.7 days after insertion was 69.8+/-3.6. Twelve weeks post-surgery the mean ISQ value was 69.8+/-3.5. A statistically significant decrease in stability was observed after 2 and 3 weeks post-surgery (P=0.005 and 0.04). The behaviour of early loaded palatal implants showed an initial decrease of the ISQ values. From 6 weeks post-surgery onward the ISQ values increased. Within the limitations of this study, the results suggest that the healing time of palatal implants reported in the literature (12 weeks) should be discussed. An orthodontic loading of palatal implants 6 weeks post-surgery with a force up to 400 cN seems to be justified. Yet further investigations are necessary to evaluate the behaviour of early loaded palatal implants considering observation periods of over 12 weeks.

Apoptosis at a distance: remote activation of caspase-3 occurs early after myocardial infarction.

OBJECTIVE: After an acute myocardial infarction, the viable myocardium remote from the infarct zone is subjected to ventricular remodeling. Besides hypertrophy, processes of apoptosis may contribute to these remodeling processes. Reports on apoptosis in this area have been doubted because they were mainly based on in-situ nick-end DNA labeling (TUNEL) measurements, with questionable specifity. Moreover, the time course of initiation of these processes has not been characterized. Therefore the goals of this study were to (1) reliably determine if in the remote area of the infarcted heart apoptosis may be initiated using highly specific biochemical markers and (2) evaluate the time course of such an activation. METHODS: A well-defined model, regional myocardial infarction induced by ligation of the left anterior coronary artery in rats in vivo, was used. Heart and lung wet weights, the left ventricular end-diastolic pressure (LVEDP), and the serum level of the atrial natriuretic propeptide (proANP) were determined from 1 day up to 4 weeks as indicators of developing heart failure. In transmural biopsies from the non-ischemic left ventricular wall of the infarcted heart, the activation of caspase-3, the bcl-2/bax ratio (Western blot analysis), and the DNA laddering (LM-PCR) were determined. RESULTS: Although heart- and lung weights did not increase before 1 week after infarction, proANP levels were elevated already 1 day after myocardial infarction suggesting early sub-clinical heart failure. The activity of caspase-3 increased significantly to 160+/- 20% compared to sham operated controls as early as 1 day after ligation and remained elevated over the entire time course. In parallel, the bcl-2/bax ratio shifted toward the pro-apoptotic bax. Moreover, these clear and specific biochemical indicators of apoptosis in the remote area of the infarcted heart were paralleled by the fragmentation of genomic DNA. CONCLUSION: These data demonstrate that apoptotic markers are activated in the surviving zone of the heart remote from the infarct area as early as 1 day after myocardial infarction with persistence for up to 4 weeks. This activation coincides with early markers of heart failure. The exact regulation of this apoptotic process remains to be elucidated.

Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia.

BACKGROUND: Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, induced in vitro differentiation of primary acute myeloid leukemia (AML) blasts, an effect enhanced by all-trans retinoic acid (ATRA). Clinical responses to VPA were recently observed in patients with myelodysplastic syndrome (MDS). Herein, the authors have described results of a clinical trial with VPA plus ATRA in 26 patients with poor-risk AML. METHODS: VPA (5-10 mg/kg starting dose) and ATRA (45 mg/m(2)) were administered orally. Low-dose AraC or hydroxyurea were permitted to control leukocytosis. Biologic activity of VPA was confirmed by serial analysis of HDAC2 protein levels in peripheral blood (PB) mononuclear cells. RESULTS: Nineteen of 26 patients completed at least 4 weeks of VPA/ATRA treatment; 7 patients were withdrawn prematurely because of rapidly progressive disease (n = 3) or unacceptable neurologic and cardiovascular toxicity (n = 4). Additional cytoreductive treatment was required in 58% of patients enrolled. Median treatment duration was 3 months. No patient achieved complete remission, one with de novo AML had a minor response, and two patients with secondary AML arising from myeloproliferative disorder (MPD) achieved a partial remission and clearance of PB blasts, respectively. The latter responses were accompanied by profound granulocytosis and erythrocytosis in both patients, reminiscent of the response pattern known from ATRA treatment of acute promyelocytic leukemia. However, cytogenetic analysis of isolated CD34(+) cells and granulocytes did not reveal terminal differentiation of leukemic blasts. CONCLUSIONS: Treatment with VPA/ATRA results in transient disease control in a subset of patients with AML that has evolved from a myeloproliferative disorder but not in patients with a primary or MDS-related AML.

Valproic acid stimulates proliferation and self-renewal of hematopoietic stem cells.

Histone deacetylase inhibitors have attracted considerable attention because of their ability to overcome the differentiation block in leukemic blasts, an effect achieved either alone or in combination with differentiating agents, such as all-trans retinoic acid. We have previously reported favorable effects of the potent histone deacetylase inhibitor valproic acid in combination with all-trans retinoic acid in patients with advanced acute myeloid leukemia leading to blast cell reduction and improvement of hemoglobin. These effects were accompanied by hypergranulocytosis most likely due to an enhancement of nonleukemic myelopoiesis and the suppression of malignant hematopoiesis rather than enforced differentiation of the leukemic cells. These data prompted us to investigate the effect of valproic acid on normal hematopoietic stem cells (HSC). Here we show that valproic acid increases both proliferation and self-renewal of HSC. It accelerates cell cycle progression of HSC accompanied by a down-regulation of p21(cip-1/waf-1). Furthermore, valproic acid inhibits GSK3beta by phosphorylation on Ser9 accompanied by an activation of the Wnt signaling pathway as well as by an up-regulation of HoxB4, a target gene of Wnt signaling. Both are known to directly stimulate the proliferation of HSC and to expand the HSC pool. In summary, we here show that valproic acid, known to induce differentiation or apoptosis in leukemic blasts, stimulates the proliferation of normal HSC, an effect with a potential effect on its future role in the treatment of acute myeloid leukemia.

Regulation of the isozymes of protein kinase C in the surviving rat myocardium after myocardial infarction: distinct modulation for PKC-alpha and for PKC-delta.

OBJECTIVE: The goal of this study was to clarify the regulation of the isozymes of protein kinase C (PKC) in the process of remodeling after myocardial infarction. METHODS: An in vivo model of regional myocardial infarction induced by ligation of the left anterior coronary artery in rats was used. Hemodynamic parameters and the heart and lung weights were determined 1 week and 1, 2 and 3 months after operation. In transmural biopsies from the non-ischemic left ventricular wall of the infarcted heart, PKC activity (ELISA) and the expression of its major isozymes, PKC-alpha, PKC-delta and PKC-epsilon (Westernblot analysis) were determined. RESULTS: As early as one week after myocardial infarction, heart weight and left ventricular enddiastolic pressures were significantly increased. Lung weights increased after 2 - 3 months, indicating progressive pulmonary congestion. The activity of PKC was significantly increased about 1.8-fold after 1 week, decreasing progressively in the later time course. Whereas the expression of PKC-epsilon did not change, PKC-alpha was increased after 1 month (157%) and then returned to baseline values. In contrast, PKC-delta expression was significantly augmented after 2 and 3 months of myocardial infarction (187%). CONCLUSIONS: These data demonstrate for the first time that in the remodeling heart after myocardial infarction, a subtype-selective regulation of the PKC isozymes occurs: The upregulation of PKC-alpha coincides with the development of hypertrophy, whereas the extensive upregulation of PKC-delta outlasts the process of developing hypertrophy and persists in the failing heart. The trigger mechanisms for this newly characterized process remains to be elucidated.

Neuroblastoma screening at one year of age.

BACKGROUND: Neuroblastoma is the second most common type of childhood tumor. It is not known whether screening for neuroblastoma at one year of age reduces the incidence of metastatic disease or mortality due to neuroblastoma. METHODS: We offered urine screening for neuroblastoma at approximately one year of age to 2,581,188 children in 6 of 16 German states from 1995 to 2000. A total of 2,117,600 eligible children in the remaining states served as controls. We compared the two groups in terms of the incidence of disseminated disease and mortality from neuroblastoma. RESULTS: A total of 1,475,773 children (61.2 percent of those who were born between July 1, 1994, and October 31, 1999) underwent screening. In this group, neuroblastoma was detected by screening in 149 children, of whom 3 have died. Fifty-five children who had negative screening tests were subsequently given a diagnosis of neuroblastoma; 14 of these children have died. The screened group and children in the control area had a similar incidence of stage 4 neuroblastoma (3.7 cases per 100,000 screened children [95 percent confidence interval, 2.7 to 4.7] and 3.8 per 100,000 controls [95 percent confidence interval, 2.9 to 4.6]) and a similar rate of death among children with neuroblastoma (1.3 deaths per 100,000 screened children [95 percent confidence interval, 0.7 to 1.8] and 1.2 per 100,000 controls [95 percent confidence interval, 0.7 to 1.7]). Comparison of the screened group and the children in the control area revealed substantial overdiagnosis in the former group (an estimated rate of 7 cases per 100,000 children [95 percent confidence interval, 4.6 to 9.2]); the overdiagnosis rate represents children who had neuroblastoma that was diagnosed by screening but who would not benefit from earlier diagnosis and treatment. CONCLUSIONS: The present findings do not support the usefulness of general screening for neuroblastoma at one year of age.