Impact of chemotherapy on health status and symptom burden of colon cancer survivors: a population-based study

Background

This population-based study assessed the impact of chemotherapy on general and disease-specific health status of resected colon cancer survivors up to 10 years post-diagnosis.

Patients and methods

Colon cancer survivors diagnosed between 1998 and 2007 were selected from the Eindhoven Cancer Registry. Survivors completed the SF-36 and the EORTC colorectal module (EORTC-QLQ-CR38). Comparisons to a normative population were conducted. Multiple linear regression analyses investigated the association between treatment and health status.

Results

Eight hundred and forty eight survivors were evaluated: 29% had chemotherapy (CT); 71% without chemotherapy (nCT). Survivors had similar SF-36 scores and scored better than the normative population on several domains. On the EORTC-QLQ-CR38, male nCT survivors had more sexual problems than CT survivors (p = 0.01). Among the sexually active respondents, the survivors reported sex to be less enjoyable than the normative population (p = 0.02). In multivariate analyses, CT predicted better physical function, and less male sexual dysfunction and weight loss problems than nCT.

Conclusions

Overall, CT survivors have general health status scores comparable to nCT survivors and the normative population up to 10 years since initial diagnosis. Sex-related problems among survivors suggest more attention on this often sensitive issue is required in clinical management.     

Modulation of extracellular matrix protein phosphorylation alters mineralization in differentiating chick limb-bud mesenchymal cell micromass cultures

Protein phosphorylation and dephosphorylation are important regulators of cellular and extracellular events. The purpose of this study was to define how these events regulate cartilage matrix calcification in a cell culture system that mimics endochondral ossification. The presence of casein kinase II (CK2), an enzyme known to phosphorylate matrix proteins, was confirmed by immunohistochemistry. The importance of phosphoprotein phosphorylation and dephosphorylation was examined by comparing effects of inhibiting CK2 or phosphoprotein phosphatases on mineral accretion relative to untreated mineralizing controls. Specific inhibitors were added to differentiating chick limb-bud mesenchymal cell micromass cultures during the development of a mineralized matrix at the times of cell differentiation, proliferation, formation of the mineralized matrix, or proliferation of the mineral crystals. The mineralizing media for these cultures contained 4 mM inorganic phosphate and no organic-phosphate esters; control cultures had 1 mM inorganic phosphate. Mineralization was monitored based on (45)Ca uptake and infrared characterization of the mineral; cell viability was assessed by three independent methods. Treatments that caused cell toxicity were excluded from the analysis. Inhibition of CK2 activity with apigenin or CK2 inhibitor II reduced the rate of mineral deposition, but did not block mineral accretion. Effects were greatest during the time of mineralized matrix formation. Inhibition of phosphoprotein phosphatase activities with okadaic acid, calyculin A, and microcystin-LR, at early time points also markedly inhibited mineral accretion. Inhibition after mineralization had commenced increased the mineral yield. Levamisole, an alkaline phosphatase inhibitor, had no effect on mineral accretion in this system, suggesting the involvement of other phosphatases. Adding additional inorganic phosphate to the inhibited cultures after mineralization had started, but not earlier, reversed the inhibition indicating that the phosphatases were, in part, providing a source of inorganic phosphate. To characterize the roles of specific phosphoproteins blocking studies were performed. Blocking with anti-osteopontin antibody confirmed osteopontin's previously reported role as a mineralization inhibitor. Blocking antibodies to bone sialoprotein added from day 9 or on days 9 and 11 retarded mineralization, supporting its role as a mineralization nucleator. Antibodies to osteonectin slightly stimulated early mineralization, but had no effect after the time that initial mineral deposition occurs. Taken together, the results of this study demonstrate the importance of the phosphorylation state of extracellular matrix proteins in regulating mineralization in this culture system.     

Frequency of abnormal correlation between leptin and the body mass index during first and second generation antipsychotic drug treatment

BACKGROUND: Leptin dysregulation has been implicated in the body weight gain and metabolic dysfunction observed with the second generation antipsychotic drugs (SGAD) olanzapine and clozapine. METHODS: This study quantified the frequency of subjects with abnormal correlation between leptin and the body mass index controlling for gender (defined as being out of the upper or lower 95% confidence interval in the regression line when combining each group with the drug-free subjects) after prolonged treatment with olanzapine (n=126), clozapine (n=62), first generation antiypsychotics (n=91), other SGAD (n=22), other psychotropic drugs (n=65) and drug-free subjects (n=229). RESULTS: None of the analysis was significant (p>0.05). In fact, in 17 out of 20 comparisons, the drug-free group had numerically higher frequencies of outliers than the corresponding treatment group. There were 28 outliers (4.7% of the total sample). In agreement with previous studies, cross-sectional analysis did not report gross alterations in serum leptin levels during olanzapine or clozapine administration. CONCLUSIONS: Longitudinal studies should focus on leptin regulation early on treatment, on the frequency of abnormal leptin receptor sensitivity and/or specific polymorphisms in the leptin allele and on several confounding factors in order to design personalized preventive and therapeutic measures.     

Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion

Vascular development is dependent on various growth factors and certain modifiers critical for providing arterial or venous identity, interaction with the surrounding stroma and tissues, hierarchic network formation, and recruitment of pericytes. Notch receptors and ligands (Jagged and Delta-like) play a critical role in this process in addition to VEGF. Dll4 is one of the Notch ligands that regulates arterial specification and maturation events. In the current study, we have shown that loss of function by either targeted allele deletion or use of a soluble form of Dll4 extracellular domain leads to inhibition of Notch signaling, resulting in increased vascular proliferation but defective maturation. Newly forming vessels have thin caliber, a markedly reduced vessel lumen, markedly reduced pericyte recruitment, and deficient vascular perfusion. sDll4 similarly induced defective vascular response in tumor implants leading to reduced tumor growth. Interference with Dll4-Notch signaling may be particularly desirable in tumors that have highly induced Dll4-Notch pathway.     

Step by step development of clinical care pathways for older cancer patients: Necessary or desirable?

Medical and nursing staff in oncology for older cancer patients are confronted with a range of problems including co-morbidity, poly-pharmacy, cognitive impairments, emotional problems, functional limitations, sensory impairment and a lack of social support. Comprehensive geriatric assessment identifies many of the existing problems and can be used to estimate life expectancy and tolerance of treatment. However, health care providers have to interpret and apply the medical and nursing information and must deal with specific problems and care needs throughout the continuum of cancer care. Imperfect interdisciplinary communication, cooperation and patient-provider communication may further complicate the care actually delivered. A clinical care pathway aims to improve continuity, increase multidisciplinary tuning and deliver appropriate patient education, treatment and care for vulnerable older cancer patients. This paper gives an overview of common problems in older cancer patients and addresses communication barriers through the development of clinical care pathways in geriatric oncology.     

Quantitative in vivo islet potency assay in normoglycemic nude mice correlates with primary graft function after clinical transplantation

Reliable assays are critically needed to monitor graft potency in islet transplantation (IT). We tested a quantitative in vivo islet potency assay (QIVIPA) based on human C-peptide (hCP) measurements in normoglycemic nude mice after IT under the kidney capsule. QIVIPA was initially tested by transplanting incremental doses of human islets. hCP levels in mice were correlated with the number of transplanted islet equivalents (r(2) = 0.6, P<0.01). We subsequently evaluated QIVIPA in eight islet preparations transplanted in type 1 diabetic patients. Conversely to standard criteria including islet mass, viability, purity, adenosine triphosphate content, or glucose stimulated insulin secretion, hCP in mice receiving 1% of the final islet product was correlated to primary graft function (hCP increase) after IT (r(2)=0.85, P<0.01). QIVIPA appears as a reliable test to monitor islet graft potency, applicable to validate new methods to produce primary islets or other human insulin secreting cells.     

Inhibition of neutral endopeptidase by thiorphan does not modify coronary vascular responses to angiotensin I, angiotensin II and bradykinin in the isolated guinea pig heart

Both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) are involved in the regulation of renin-angiotensin and kallikrein-kinin systems. The aim of the present study was to assess the role of NEPand ACE in the regulation of vascular responses to angiotensin I (Ang I), angiotensin II (Ang II) and bradykinin (Bk) in the coronary circulation. For this purpose we used typical inhibitors of ACE and NEP, perindoprilate (1 microM) and thiorphan (1 micromM and 10 microM), respectively, and analyzed their effects on the coronary vasoconstrictor responses to Ang I and Ang II and coronary vasodilator responses to Bk in the isolated guinea pig heart. Perindoprilate abolished coronary vasoconstriction induced by Ang I and potentiated coronary vasodilation evoked by Bk. Thiorphan at a concentration of 1 muM slightly reduced response to Ang I without a significant effect on the responses to Ang II and Bk. However, thiorphan at a concentration of 10 muM abolished coronary vasoconstrictor response to Ang I and enhanced Bk-induced vasodilation. Importantly, in the presence of perindoprilate, addition of thiorphan (10 microM) did not modify further either responses to Ang I, Ang II or to Bk. In conclusion, vascular responses induced by Ang I, Ang II and Bk in the isolated guinea pig heart are regulated by ACE but not by NEP. Moreover, thiorphan is not a perfect tool to asses functional role of NEP as it displays ACE inhibitory activity.     

Antichemical Protective Gear Prolongs Time to Successful Airway Management: A Randomized, Crossover Study in Humans

Background: Airway management is the first step in resuscitation. The extraordinary conditions in mass casualty situations impose special difficulties in airway management, even for experienced caregivers. The authors evaluated whether wearing surgical attire or antichemical protective gear made any difference in anesthetists' success of airway control with either an endotracheal tube or a laryngeal mask airway.

Methods: Fifteen anesthetists with 2-5 yr of residency and wearing either full antichemical protective gear or surgical attire intubated or inserted laryngeal masks in 60 anesthetized patients. The study was performed in a prospective, randomized, crossover manner. The duration of intubation/insertion was measured from the time the device was grasped to the time a normal capnography recording was obtained.

Results: Endotracheal tubes were introduced significantly (P < 0.01) faster when the anesthetist wore surgical attire (31 +/- 7 vs. 54 +/- 24 s for protective gear), but the mean times necessary to successfully insert laryngeal masks were similar (44 +/- 20 s for surgical attire vs. 39 +/- 11 s for protective gear). Neither performance failure nor incidences of hypoxemia were recorded.