Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma.

BACKGROUND: The introduction of rituximab significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), emphasizing the importance of evaluating the long-term consequences of exposure to radiotherapy, alkylating agents and anthracycline-containing (immuno)chemotherapy among DLBCL survivors. METHODS: Long-term risk of subsequent malignant neoplasms (SMNs) was examined in a multicenter cohort comprising 2373 5-year DLBCL survivors treated at ages 15-61 years in 1989-2012. Observed SMN numbers were compared with expected cancer incidence to estimate standardized incidence ratios (SIRs) and absolute excess risks (AERs/10 000 person-years). Treatment-specific risks were assessed using multivariable Cox regression. RESULTS: After a median follow-up of 13.8 years, 321 survivors developed one or more SMNs (SIR 1.5, 95% CI 1.3-1.8, AER 51.8). SIRs remained increased for at least 20 years after first-line treatment (SIR ≥20-year follow-up 1.5, 95% CI 1.0-2.2, AER 81.8) and were highest among patients ≤40 years at first DLBCL treatment (SIR 2.7, 95% CI 2.0-3.5). Lung (SIR 2.0, 95% CI 1.5-2.7, AER 13.4) and gastrointestinal cancers (SIR 1.5, 95% CI 1.2-2.0, AER 11.8) accounted for the largest excess risks. Treatment with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin versus ≤2250 mg/m2/≤150 mg/m2, respectively, was associated with increased solid SMN risk (hazard ratio 1.5, 95% CI 1.0-2.2). Survivors who received rituximab had a lower risk of subdiaphragmatic solid SMNs (hazard ratio 0.5, 95% CI 0.3-1.0) compared with survivors who did not receive rituximab. CONCLUSION: Five-year DLBCL survivors have an increased risk of SMNs. Risks were higher for survivors ≤40 years at first treatment and survivors treated with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin, and may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up for rituximab-treated patients.

Construct validity and reliability of the modified gait efficacy scale for older adults.

PURPOSE: To perform a cross-cultural adaptation of the mGES into Dutch and investigate its construct validity, internal consistency, test-retest reliability and floor and ceiling effects in a large cohort of community-dwelling older adults. MATERIALS AND METHODS: We translated the British version of the mGES into Dutch, back into English, and had a native English speaker review the final version. Next, we included 223 community-dwelling older adults from the 'Veilig in Beweging Blijven' (VIBE) cohort (69.8 [67.6-74.3] years old, 155 (69.5%) female), who filled out both the mGES and the Falls Efficacy Scale-International (FES-I) twice, with a month in between. Construct validity was assessed by Spearman's correlation between the scores on the mGES and the FES-I. Internal consistency was assessed with Cronbach's alpha and test-retest reliability was assessed with the intra class correlation coefficient (ICC(2,1)). RESULTS: Construct validity (rho = -0.81, p < 0.001), internal consistency (α = 0.95), and test-retest reliability (ICC(2,1)=0.90, 95%CI = [0.87-0.92]) were all excellent. Ceiling effect was observed in 44 (19.7%) participants which suggest caution when evaluating the mGES for fit and confident older adults. CONCLUSION: The Dutch mGES is a valid and reliable tool to assess confidence in walking and is suggested as a tool for evaluating self-efficacy after interventions aimed at improving gait.IMPLICATIONS FOR REHABILITATIONAssessment and rehabilitation of gait may be affected by self-efficacy of walking performance.We show that the Dutch translation of the modified gait efficacy scale is a valid and reliable tool for assessing self-efficacy of walking.A ceiling effect was observed that was associated with muscle strength and symptoms of depression.The results of the present study underline the use of the modified gait efficacy scale in the assessment and evaluation of self-efficacy of walking in rehabilitation.

Does misjudgement in a stepping down paradigm predict falls in an older population?

Although measures of actual and perceived physical ability appear to predict falls in older adults, a disparity between these two, also known as misjudgement, may even better explain why some older adults fall, while their peers with similar abilities do not. Therefore, we investigated whether adding a misjudgement term improved prediction of future falls. Besides conventional measures of actual (physical measures) and perceived abilities (questionnaires), we used a stepping down paradigm to quantify behavioural misjudgement. In a sample of 55 older adults (mean age 74.5 (s.d. = 6.6) years, 33 females and 20 fallers over a 10-month follow-up period), we tested the added value of a misjudgement term and of a stepping-down task by comparing experimental Bayesian logistic-regression models to a default null model, which was composed of the conventional measures: Falls Efficacy Scale international and QuickScreen. Our results showed that the default null model fitted the data most accurately; however, the accuracy of all models was low (area under the receiver operating characteristic curve (ROC) ≤ 0.65). This indicates that neither a misjudgement term based on conventional measures, nor on behavioural measures improved the prediction of future falls in older adults (Bayes Factor10 ≤ 0.5).

Consistency and test-retest reliability of stepping tests designed to measure self-perceived and actual physical stepping ability in older adults.

BACKGROUND: Older adults with an incorrect perception of their physical abilities may fall more often, suggesting a need for tests to quantify self-perceived and actual abilities. AIMS: To determine between-test consistency and test-retest reliability of three tests that measure self-perceived and actual stepping ability in older adults. METHODS: Older adults performed three stepping tests, covering high (bar test) and far steps (river and step tests). We studied between-test consistency in the perceived ability and actual ability of 269 participants at each task and in the difference between these two (degree of misjudgment). We also studied test-retest reliability in 21 participants. RESULTS: Perceived ability showed moderate consistency (r = 0.46-0.55, p < 0.001) and moderate-to-strong reliability [ICC(2,1) = 0.42-0.63, p < 0.03] for all tests. Actual ability showed strong consistency (r = 0.77, p < 0.001) and strong-to-excellent reliability [ICC(2,1) = 0.68-0.93, p < 0.001]. Degree of misjudgment was weakly consistent between two stepping far tests (r = 0.32, p < 0.001), but not consistent between stepping far and high tests (r = 0.05 and 0.06, p > 0.3). Test-retest reliability of the degree of misjudgment was poor-to-moderate [ICC(2,1) = 0.38 and 0.50, p < 0.05 on the two stepping far tests and ICC(2,1) = - 0.08, p = 0.63 on the stepping high test]. CONCLUSIONS: Actual and perceived ability can be consistently and reliably measured across tests, whereas the degree of misjudgment is less reliable and consistent within individuals.

Effect of preoperative biliary drainage on cholestasis-associated inflammatory and fibrotic gene signatures in perihilar cholangiocarcinoma.

Preoperative biliary drainage (PBD) is used routinely in the evaluation of patients with potentially resectable perihilar cholangiocarcinoma to relieve cholestasis and improve the liver's resilience to surgery. Little preclinical or translatational data are, however, currently available to guide the use of PBD in this patient group. The effect of PBD on hepatic gene expression profiles was therefore studied by microarray analysis. Drainage affects inflammatory and fibrotic gene signatures.

Self-perceived gait stability modulates the effect of daily life gait quality on prospective falls in older adults.

BACKGROUND: Quality of gait during daily life activities and perceived gait stability are both independent risk factors for future falls in older adults. RESEARCH QUESTION: We investigated whether perceived gait stability modulates the association between gait quality and falling in older adults. METHODS: In this prospective cohort study, we used one-week daily-life trunk acceleration data of 272 adults over 65 years of age. Sample entropy (SE) of the 3D acceleration signals was calculated to quantify daily life gait quality. To quantify perceived gait stability, the level of concern about falling was assessed using the Falls Efficacy Scale international (FES-I) questionnaire and step length, estimated from the accelerometer data. A fall calendar was used to record fall incidence during a six-month follow up period. Logistic regression analyses were performed to study the association between falling and SE, step length or FES-I score, and their interactions. RESULTS: High (i.e., poor) SE in vertical direction was significantly associated with falling. FES-I scores significantly modulated this association, whereas step length did not. Subgroup analyses based on FES-I scores showed that high SE in the vertical direction was a risk factor for falls only in older adults who had a high (i.e. poor) FES-I score. In conclusion, perceived gait stability modulates the association between gait quality and falls in older adults such that an association between gait quality and falling is only present when perceived gait stability is poor. SIGNIFICANCE: The results of the present study indicate that the effectiveness of interventions for fall prevention, aimed at improving gait quality, may be affected by a modulating effect of perceived gait stability. Results indicate that interventions to reduce falls in older adults might sort most effectiveness in populations with both a poor physiological and psychological status.

In vitro detection of cholangiocarcinoma cells using a fluorescent protein-expressing oncolytic herpes virus.

Pathological confirmation is desired prior to high-risk surgery for suspected perihilar cholangiocarcinoma (PHC), but preoperative tissue diagnosis is limited by poor sensitivity of available techniques. This study aimed to validate whether a tumor-specific enhanced green fluorescent protein (eGFP)-expressing oncolytic virus could be used for cholangiocarcinoma (CC) cell detection. Extrahepatic CC cell lines SK-ChA-1, EGI-1, TFK-1 and control cells (primary human liver cells) were exposed to the oncolytic herpes simplex type 1 virus NV1066 for up to 24 h in adherent culture. The technique was validated for cells in suspension and cultured cells that had been exposed to crude patient bile. Optimal incubation time of the CC cells with NV1066 at a multiplicity of infection of 0.1 was determined at 6-8 h, yielding 15% eGFP-expressing cells, as measured by flow cytometry. Cells were able to survive 2-h crude bile exposure and remained capable of producing eGFP following NV1066 infection. Detection of malignant cells was possible at the highest dilution tested (10 CC cells among 2 × 105 control cells), though hampered by non-target cell autofluorescence. The technique was not applicable to cells in suspension due to insufficient eGFP production. Accordingly, as yet the technique is not suitable for standardized clinical diagnostics in PHC.

Adrenocortical carcinoma.

Adrenocortical carcinoma is a rare disease with a poor prognosis. Patients can present with a hormonal syndrome or with general symptoms from an abdominal mass. The pathogenesis is unknown. Sometimes the adrenocortical carcinoma is associated with tumour syndromes such as the Beckwith-Wiedemann and Li-Fraumeni syndrome; however, most tumours are sporadic. Using one of the international classification methods, histopathological research can in almost all cases distinguish between adrenocortical adenoma and carcinoma. complete surgical resection is the treatment of choice for adrenocortical carcinoma. Mitotane is given when surgery is not possible, after incomplete resection or for metastatic disease. Frequently used chemotherapeutic combinations are etoposide, doxorubicin, cisplatin and mitotane (EDP/M) and streptozotocin and mitotane (SZ/M). International and national cooperation has resulted in a randomised trial aimed at determining a standard therapy in advanced adrenocortical carcinoma. The Dutch Adrenal Network is a national cooperation of endocrinologists, pathologists and oncologists from all eight academic centres and Máxima Medical centre. The network combines knowledge and expertise and gives patients the opportunity to receive optimal treatment in their own district.

Modelling the effects of (green) antifungals, droplet size distribution and temperature on mould outgrowth in water-in-oil emulsions.

Prevention of fungal spoilage is a key microbiological issue for the shelf life of fat spreads. Our aim was to assess and model the scope of (natural) antimicrobials for extending shelf life of spreads (water-in-oil emulsions). Production conditions were established to make 60% model fat spreads with reproducible droplet size distributions. The mould vulnerabilities ranged from 1 to 20 weeks. The system allowed feasibility testing of lytic enzymes (Novozym 234) and LMW compounds against Penicillium roqueforti, a key-spoilage mould. The action of Novozym 234, carvacrol, undecanol and dihydrocarveol was benchmarked against sorbate and preservative-free controls under ambient and chilled conditions. Novozym 234 was ineffective to prevent outgrowth of P. roqueforti. Carvacrol, undecanol and dihydrocarveol had limited effects on shelf-life extension compared to sorbate. Fungal growth boundaries of (un-)preserved spreads were modelled. The emulsion droplet size distribution (DSD) was first captured in a mechanistic parameter DSD-I (I = Influence). DSD-I was a move away from the mean droplet diameter D3,3 as sole quantitative droplet-size distribution parameter for mould susceptibility of emulsions. DSD-I is a combination of available water droplets and surface area to initiate and sustain fungal outgrowth. Followup experiments showed that modelling D3,3 and distribution width (e(sigma)) instead of DSD-I gave better results for emulsions with high e(sigma). Empirical predictive models were subsequently developed for the effects of D3,3, e(sigma) and undissociated sorbic acid (HSO) on the shelf life of emulsions.