Refractory or relapsed aggressive B-cell lymphoma failing (R)-CHOP: an analysis of patients treated on the RICOVER-60 trial.

BACKGROUND: The prognosis of elderly patients with aggressive B-non-Hodgkin's lymphoma after first lymphoma-related treatment failure (TF-L) is not well described. METHODS: We analysed patient characteristics including the presence of MYC rearrangements and MYC-expression immunohistochemistry (IHC) at diagnosis and modalities of salvage therapy and their impact on the prognosis of patients between 61 and 80 years who had been treated on the RICOVER-60 trial. RESULTS: TF-L occurred in 301 of the 1222 (24.6%) patients; 297 patients could be analysed. Prognosis was extremely poor in patients with primary progressive disease or early relapse (≤12 months) with median survivals of 3.3 and 6.4 months. Survival after TF-L was significantly lower in patients pretreated with R-CHOP compared with CHOP (23.0% versus 36.4% at 2 years, P = 0.016). In patients with MYC translocation at diagnosis Rituximab reduced the risk of TF-L from 58.8% to 26.3%. Survival after TF-L was significant longer for patients after CHOP without MYC translocations (31.8% versus 0% at 2 years, P < 0.001) or negative MYC-IHC (41.0% versus 16.8% at 2 years, P = 0.017) but not after R-CHOP. 224 patients (75.4%) received salvage therapy. Rituximab was part of salvage therapy in 57.4% and improved 2-year survival rate from 20.7% to 46.8% (P < 0.001). The benefit of R was significant after first-line CHOP [2-year overall survival (OS) 49.6% versus 19.1%, P < 0.001] as well as after R-CHOP (2-year OS 33.1% and 22.5%, P = 0.034). For patients pretreated with R-CHOP long-term survival was below 15% regardless of the treatment chosen. CONCLUSION: MYC rearrangement and IHC are adverse prognostic factors after TF-L for CHOP treated patients, rituximab as part of first-line therapy reduced the effects of MYC-break. Rituximab improves results of any type of salvage therapy; however, survival after progression/relapse of aggressive B-cell lymphoma in elderly patients pretreated with (R)-CHOP is poor regardless of treatment chosen.

The 'Dispersal Rate' - a product dependent characteristic to predict the reliability of the calibrated in vitro SPF on WW5 plates.

OBJECTIVES: The evaluation of the SPF by the measurement of light transmission through a thin film on PMMA plates is an interesting alternative to the conventional in vivo method. However, during the last years an internationally acknowledged in vitro SPF measurement could not be established mainly due to bad reproducibility. With this work, we would like to give new suggestions for an improved reproducibility and to open new space for discussion. METHODS: A total of 22 o/w emulsions with well-established in vivo SPF were measured in vitro close to the international Standard ISO 24443 on two different substrates (PMMA plates: WW5 and HD6). For each product, the ratio 'in vitro SPFraw /in vivo SPF' was calculated. The composition of the products was analysed regarding a parameter that correlates with the aforementioned ratio. Additionally seven suitable calibration products were determined to transfer the in vitro SPFraw to the calibrated in vitro SPFcal . RESULTS: We could show that the results for the SPFcal matched very well for 19 measured o/w emulsions on WW5 plates. However, we found two products where the in vitro SPF was much lower than the in vivo SPF. The Dispersal Rate allows us to identify a product characteristic parameter to predict too low measured in vitro SPFs on WW5 plates. This parameter mainly refers to the ratio of water to lipids in an emulsion. We found that products with few emollients and few emulsifiers are measured too low in vitro. CONCLUSION: We suggest implementing an individual calibration of the in vitro SPF to improve the reproducibility of in vitro SPF measurements between different laboratories. Considering the Dispersal Rate helps to estimate the reliability of the in vitro SPF measured on WW5 plates. In order to evaluate whether those products with a high Dispersal Rate can also be calibrated with special standards, further measurements need to be done. We demonstrate that, besides the known parameter, also the composition of the products should be considered for the interpretation of the in vitro SPF. Our findings could explain some multiple reported problems in correlation between in vitro and in vivo SPF, especially for higher SPFs (Personal Care, November, 2014, 27).

Discrepancies between medical oncologists and surgeons in assessment of resectability and indication for chemotherapy in patients with colorectal liver metastases.

BACKGROUND: Multidisciplinary discussion of the treatment of patients with colorectal liver metastases (CRLM) is advocated currently. The aim of this study was to investigate medical oncologists' and surgeons' assessment of resectability and indication for chemotherapy, and the effect of an educational intervention on such assessment. METHODS: Medical histories of 30 patients with CRLM were presented to ten experienced medical oncologists and 11 surgeons at an initial virtual tumour board meeting (TB1). Treatment recommendations were obtained from each participant by voting for standardized answers. Following lectures on the potential of chemotherapy and surgery, assessment was repeated at a second virtual tumour board meeting (TB2), using the same patients and participants. RESULTS: Overall, 630 answers (21 × 30) were obtained per tumour board meeting. At TB1, resectability was expected more frequently by surgeons. Participants changed 56·8 per cent of their individual answers at TB2. Assessment shifted from potentially resectable to resectable CRLM in 81 of 161 and from unresectable to (potentially) resectable CRLM in 29 of 36 answers. Preoperative chemotherapy was indicated more often by medical oncologists, and overall was included in 260 answers (41·3 per cent) at TB1, compared with only 171 answers (27·1 per cent) at TB2. Medical oncologists more often changed their decision to primary resection in resectable patients (P = 0·006). Postoperative chemotherapy was included in 51·9 and 52·4 per cent of all answers at TB1 and TB2 respectively, with no difference in changes between medical oncologists and surgeons (P = 0·980). CONCLUSION: Resectability and indication for preoperative chemotherapy were assessed differently by medical oncologists and surgeons. The educational intervention resulted in more patients deemed resectable by both oncologists and surgeons, and less frequent indication for chemotherapy.

Metastatic recurrence after complete resection of colorectal liver metastases: impact of surgery and chemotherapy on survival.

PURPOSE: Surgery is the standard of care for resectable colorectal liver metastases (CRC-LM). Unfortunately, 60% of patients develop secondary metastatic recurrence (SMR) after R0-resection of CRC-LM. We investigated the impact of surgical re-intervention and chemotherapy (Ctx) on survival in a consecutive series of patients with SMR. METHODS: From 01/2001 to 11/2011, 104 out of 178 consecutive patients with R0-resection of CRC-LM developed SMR and were evaluated. The impact of surgical and Ctx re-interventions on recurrence free (RFS) and cancer-specific survival (CSS) was analyzed. Median follow-up was 28.0 (95%CI: 19.4-37.4) months. RESULTS: SMR occurred in 81 patients at a single site (49× liver, 18× lung, 14× other) and in 23 patients at multiple sites. Forty-two patients were scheduled for primary surgery. Fifty-three patients were classified as non-resectable and treated with median 5.0 [IQR, 3.0-10.0] cycles of Ctx, combined with an EGFR/VEGF-antibody in 27 patients. Nine patients received best supportive care only. R0/R1 resection could be achieved in 35 patients primarily and even in 8 patients secondarily after Ctx. Surgical morbidity and mortality were 16 and 0%, respectively. The 5-year RFS rates for patients with R0 versus R1-resection were 22 and 24% (p = 0.948). The 5-year CSS rate for R0/R1-resected patients was 38% versus 10% for those patients treated by Ctx alone (p < 0.001). CONCLUSION: In SMR, surgical re-intervention is feasible and safe in a remarkable number of patients and offers significantly longer CSS compared to patients without resection.

Bilobar spreading of colorectal liver metastases does not significantly affect survival after R0 resection in the era of interdisciplinary multimodal treatment.

PURPOSE: Bilobar colorectal liver metastases (CRLM) are often considered incurable or associated with poor prognosis even after R0 resection. In this single-center study, we evaluate the impact of CRLM spreading on recurrence-free survival (RFS) and cancer-specific overall survival (CSS) after R0 resection of CRLM with respect to multimodal treatment strategies including perioperative chemotherapy and multistep resections. METHODS: Between January 2001 and December 2010, R0 resection could be achieved in 70 patients with bilobar and 100 with unilobar CRLM. Extent of disease, perioperative chemotherapy, surgical procedures, adjuvant treatment, histopathological workup, RFS, and CSS were compared between both cohorts. RESULTS: Forty-six (66 %) patients with bilobar and 26 (26 %) patients with unilobar CRLM received preoperative chemotherapy (p < 0.001). For bilobar CRLM, more extended and multistep resection including portal vein occlusion were performed (29 % versus 3 %; p < 0.001). Morbidity (39 % versus 28 %, p = 0.183) and mortality (1 % versus 3 %, p = 0.644) rates were comparable in both patients' cohorts. Postoperative therapy was applied in adjuvant intent to 42 (60 %) versus 51 (51 %) patients (p = 0.275). The 5-year RFS and CSS rates were 24 % versus 31 % (p = 0.169) and 42 % versus 55 % (p = 0.131), respectively. CONCLUSIONS: To our single-center experience, there is no significant effect of CRLM spreading (bilobar versus unilobar) on RFS and CSS rates. Bilobar CRLM are more likely to require extended multimodal efforts to achieve R0 resection.

An appraisal of the current and potential value of web 2.0 contributions to continuing education in oral implantology.

OBJECTIVE: To systematically assess the informational value, quality, intention, source and bias of web 2.0 footage whose aim is peer-to-peer education about oral implantology. METHODS: YouTube (http://www.youtube.com) was scanned on 15 October 2010 for oral implantology-related videos using an adequately pre-defined search query. Search results were filtered with the system-generated category 'education' and the additional criterion 'most viewed'. Only those videos with at least 1000 views were included (total 124, of which 27 were excluded because they were not related to implantology). Filtered videos were discussed and rated with particular regard to the educational needs of potential groups of addressees [(i) undergraduates and laymen, (ii) dentists without or currently undergoing a specialisation in oral implantology and (iii) dentists who have completed a specialisation in the field of oral implantology] by a jury consisting of (i) an accredited post-graduate university instructor with 22 years of professional teaching experience in the field of implantology, (ii) a university lecturer in dentistry/orthodontics with 10 years teaching experience and (iii) a university haematologist/oncologist. They were required to fill out a questionnaire for each video. The data were statistically analysed using non-parametric ANOVA (α = 5%) and a sign test (α = 0.05/3 = 0.017). RESULTS: The YouTube scan produced 1710 results in the category 'EDU'. The analysis revealed that there is a wide range of instructional footage on this topic, but with highly variable range in quality and informational value. Footage intention was to large proportions (47.4%) a mixture of education and advertisement. Its usefulness differed significantly for the three groups of addressees, offering greater novelty to undergraduates and post-graduates. CONCLUSION: YouTube and similar social media websites may have a potential capacity and value in complementing continuing education in the technique of oral implantology. As a means of achieving an acceptable level of knowledge about the topic when used alone, it should not be considered to be suitable at this point in time.

ß-catenin-independent WNT signaling in basal-like breast cancer and brain metastasis.

A role of WNT signaling for primary breast cancers of the basal-like subtype and as a predictor of brain metastasis has been described. However, a responsible WNT ligand has not been identified. To further clarify this question, we comparatively investigated 22 human breast cancer brain metastases as well as the highly invasive human breast cancer cell line MDA-MB-231 and the weakly motile MCF-7 as models for the basal-like and the luminal A subtype. WNT5A and B were found overexpressed in MDA-MB-231 cells as compared with MCF-7. This corresponded to reduction of MDA-MB-231 invasiveness by WNT inhibitors, whereas MCF-7 invasion was enhanced by recombinant WNT5B and abolished by WNT and Jun-N-terminal kinase antagonists. Expression and subcellular distribution of ß-catenin remained uninfluenced. Consistently, ß-catenin was not localized in the nuclei of brain metastases while there was strong nuclear c-Jun staining. Similar to MDA-MB-231, metastases showed expression of WNT5A/B and the alternative WNT receptors ROR1 and 2. These findings were validated using external gene expression datasets (Gene Expression Omnibus) of different breast cancer subtypes and brain metastases. Hierarchical cluster analysis yielded a close relation between basal-like cancers and brain metastases. Gene set enrichment analyses confirmed WNT pathway enrichment not only in basal-like primaries but also in cerebral metastases of all subtypes. In conclusion, WNT signaling seems highly relevant for basal-like and other subtypes of breast cancers metastasizing into the brain. ß-catenin-independent WNT signaling, presumably via ROR1-2, plays a major role in this context.

Tongue position after deglutition in subjects with habitual open-mouth posture under different functional conditions.

OBJECTIVE: To test the null hypothesis of no significant differences in (1) the duration of the post-deglutory, cranial tongue rest position (CTP) between different functional orofacial conditions and (2) the presence or absence of an oral screen (OS) in subjects with a habitual open-mouth posture. SUBJECTS: Twenty-nine subjects (aged 6-16; mean: 9.69 years; 13/16 girls/boys) were selected according to the inclusion criterion of a habitual, daytime open-mouth posture. METHODS: Deglutition was screened at baseline during resting respiration using orofacial polysensography and simultaneous assessment of tongue-to-palate position and nasal airstream, during five functional intervals of 8 min each: F1 without instruction (RR); F2 the same, but including an oral screen (RROS); F3 with OS and the instruction to maintain a tongue-to-palate contact (IROS); F4 with OS and the instruction to perform tongue repositioning manoeuvres at the time of spontaneous swallowing (TRMOS); and F5 corresponds to F3 omitting OS (IR). Duration and frequency of deglutition were analysed descriptively as well as by anova and subsequent multiple comparisons, and the CTP was evaluated with chi-square tests and paired comparisons at a significance level of 5%. RESULTS: Of 542 identified swallowing acts, 75% were accompanied by a post-deglutory CTP. Mean duration of CTP increased for functional conditions RR/1.01s > RROS/2.56s > IR/3.21s > IROS/6.53s > TRMOS/6.58s. The null hypothesis (1) was rejected in comparison of resting respiration (F1, F2) with IROS and TRMOS, whereas the use of an oral screen alone did not significantly prolong the duration of CTP.

Acute and Long-Term Hemodynamic Effects of MitraClip Implantation on a Preexisting Secondary Right Heart Failure.

Positive results of MitraClip in terms of improvement in clinical and left ventricular parameters have been described in detail. However, long-term effects on secondary pulmonary hypertension were not investigated in a larger patient cohort to date. 70 patients with severe mitral regurgitation, additional pulmonary hypertension, and right heart failure as a result of left heart disease were treated in the heart centers Hamburg and Göttingen. Immediately after successful MitraClip implantation, a reduction of the RVOT diameter from 3.52 cm to 3.44 cm was observed reaching a statistically significant value of 3.39 cm after 12 months. In contrast, there was a significant reduction in the velocity of the tricuspid regurgitation (TR) from 4.17 m/s to 3.11 m/s, the gradient of the TR from 48.5 mmHg to 39.3 mmHg, and the systolic pulmonary artery pressure (PAPsyst) from 58.6 mmHg to 50.0 mmHg. This decline continued in the following months (Vmax TR 3.09 m/s, peak TR 38.6 mmHg, and PAPsyst 47.4 mmHg). The tricuspid annular plane systolic excursion (TAPSE) increased from 16.5 mm to 18.9 mm after 12 months. MitraClip implantation improves pulmonary artery pressure, tricuspid regurgitation, and TAPSE after 12 months. At the same time, there is a decrease in the RVOT diameter without significant changes in other right ventricular and right atrial dimensions.

A pro-apoptotic function of iASPP by stabilizing p300 and CBP through inhibition of BRMS1 E3 ubiquitin ligase activity.

The p53 family and its cofactors are potent inducers of apoptosis and form a barrier to cancer. Here, we investigated the impact of the supposedly inhibitory member of the apoptosis-stimulating protein of p53, iASPP, on the activity of the p53 homolog TAp73, and its cofactors p300 and CBP. We found that iASPP interacted with and stabilized the histone acetyltransferase p300 and its homolog CBP upon cisplatin treatment. Vice versa, iASPP depletion by shRNA resulted in decreased amounts of p300 and CBP, impaired binding of p300 and TAp73 to target site promoters, reduced induction of pro-apoptotic TAp73 target genes, and impaired apoptosis. Mechanistically, we observed that the p300-regulatory E3 ubiquitin ligase BRMS1 could rescue the degradation of p300 and CBP in cisplatin-treated, iASPP-depleted cells. This argues that iASPP stabilizes p300 and CBP by interfering with their BRMS1-mediated ubiquitination, thereby contributing to apoptotic susceptibility. In line, iASPP overexpression partially abolished the interaction of BRMS1 and CBP upon DNA damage. Reduced levels of iASPP mRNA and protein as well as CBP protein were observed in human melanoma compared with normal skin tissue and benign melanocytic nevi. In line with our findings, iASPP overexpression or knockdown of BRMS1 each augmented p300/CBP levels in melanoma cell lines, thereby enhancing apoptosis upon DNA damage. Taken together, destabilization of p300/CBP by downregulation of iASPP expression levels appears to represent a molecular mechanism that contributes to chemoresistance in melanoma cells.

[Cardiac effects of a reducing diet]. / Kardiale Auswirkungen einer Reduktionskur.

40 in-patients have been treated by modified fasting during 4 weeks. Routine ECG's and radiological controls of heart size did not show signs of myocardial lesions or of an impairment of the generation, propagation or dissipation of cardiac impulse. Slightly elevated serum levels of CK, CK-MB, alpha-HBDH, SGOT, and SGPT could indicate a reduction of fat-free body-mass including some elements of myocardium. Potassium and magnesium levels should be controlled and sometimes corrected by ingestion of electrolyte preparations. Under the conditions described and with the methods we used, we could not demonstrate an increased cardiac risk during a weight reduction cure by modified fasting of moderate duration. This should also apply to low-calorie diets with a deficit of about 1000 cal./day, whilst total fasting and the substitution with protein preparations of poor nutritional value must be considered as risky procedures.

[Diabetes increases short- and long-term mortality after transcatheter aortic valve implantation (TAVI)]. / Diabetes mellitus erhöht die eingriffsbedingte und die langfristige Mortalität nach kathetergestützter Aortenklappenimplantation.

BACKGROUND AND AIM: Long-term mortality after transcatheter aortic valve implantation (TAVI) in elderly patients with abundant comorbidities is considerable. We aimed to determine the impact of diabetes on short- and long-term mortality after TAVI. METHODS: Our study includes 300 consecutive patients (mean age, 82 ± 5 years) who underwent TAVI (158 transapical, 142 transfemoral procedures). All patients were followed by regular telephone contacts. 36% suffered from diabetes. RESULTS: Diabetes could be identified as significant predictor of short- and long-term mortality after TAVI. In diabetic patients, 30-day-mortality was 2,5 fold elevated (18.3% vs. 7.3%, p = 0.004). Furthermore, they were at significantly higher risk of peri-interventional stroke (p = 0.04), stage 3 acute kidney injury (p = 0.003), and prolonged ventilation (p = 0.01). Even after successful TAVI and discharge from hospital, long-term mortality was significantly elevated in diabetic patients (56% vs. 30%, p < 0.0001). Of note, 25% of diabetic vs. only 8% of non-diabetic patients died from cardiac causes during follow-up, suggesting that TAVI is not able to reduce cardiac-related mortality risk in diabetic patients to the same extent as in non-diabetics. CONCLUSION: Diabetes represents a powerful predictor of adverse early and late outcome after TAVI. These findings should be incorporated into the assessment of the risk-to-benefit ratio of TAVI in diabetic patients.

Nuclear LEF1/TCF4 correlate with poor prognosis but not with nuclear ß-catenin in cerebral metastasis of lung adenocarcinomas.

An essential function of the transcription factors LEF1/TCF4 in cerebral metastases of lung adenocarcinomas has been described in mouse models, suggesting a WNT/ß-catenin effect as potential mechanism. Their role in humans is still unclear, thus we analyzed LEF1, TCF4, ß-catenin, and early stage prognostic markers in 25 adenocarcinoma brain metastases using immunohistochemistry (IHC). IHC revealed nuclear TCF4 in all adenocarcinoma samples, whereas only 36 % depicted nuclear LEF1 and nuclear ß-catenin signals. Samples with nuclear LEF1 as well as high TCF4 (++++) expression were associated with a shorter survival (p = 0.01, HR = 6.68), while nuclear ß-catenin had no significant impact on prognosis and did not significantly correlate with nuclear LEF1. High proliferation index Ki67 was associated with shorter survival in late-stage disease (p = 0.03, HR 3.27). Additionally, we generated a LEF1/TCF4 as well as an AXIN2 signature, the latter as representative of WNT/ß-catenin activity, following a bioinformatics approach with a gene expression dataset of cerebral metastases in lung adenocarcinoma. To analyze the prognostic relevance in primary lung adenocarcinomas, we applied both signatures to a microarray dataset of 58 primary lung adenocarcinomas. Only the LEF1/TCF4 signature was able to separate clusters with impact on survival (p = 0.01, HR = 0.32). These clusters displayed diverging enrichment patterns of the cell cycle pathway. In conclusion, our data show that LEF1/TCF4, but not ß-catenin, have prognostic relevance in primary and cerebrally metastasized human lung adenocarcinomas. In contrast to the previous in vivo findings, these results indicate that LEF1/TCF4 act independently of ß-catenin in this setting.

Percussion pacing--an almost forgotten procedure for haemodynamically unstable bradycardias? A report of three case studies and review of the literature.

More than 80 years after its first description by Eduard Schott, percussion (fist) pacing remains a little known procedure even though it represents an instantly available and easy to perform treatment for temporary emergency cardiac pacing in haemodynamically unstable bradycardias, including bradycardic pulseless electrical activity and complete heart block with ventricular asystole. Based on the Consensus on Science and Treatment Recommendations of the International Liaison Committee on Resuscitation, the European Resuscitation Council recently incorporated percussion pacing in its advanced life support guidelines (Nolan and colleagues, Resuscitation 67 (Suppl 1): S39-S86, 2005). Here, we briefly describe three of our own cases and present a review of the literature on percussion pacing with respect to the available evidence on its efficacy, its practical application, and clinical indications.

Percussion pacing in a three-year-old girl with complete heart block during cardiac catheterization.

Complete heart block frequently requires emergency pacing to restore systemic perfusion. We report the case of a 3-yr-old girl undergoing interventional atrial septal defect closure who suffered from transient complete heart block with circulatory arrest. Transthoracic mechanical pacing for more than 3 min provided temporary support, sustaining an adequate cardiac output until sinus rhythm resumed.

[Thermal side effects after use of the pulsed IR laser on meniscus and bone tissue]. / Thermische Nebeneffekte nach Anwendung gepulster IR-Laser am Meniskus- und Knochengewebe.

Thermal effects on meniscus and bone tissue after application of 314 boreholes using five different infrared (IR) lasers: Nd:YAG, Tm:YAG, Ho:YAG, Er:YAG, Cr,Er:YSGG (application energy 200 mJ, 400 mJ, 600 mJ, 800 mJ, 1000 mJ; repetition rate 2 Hz, 5 Hz; medium air, water rinse) were analyzed. The experimental set-up comprised for the beam guiding a focussing lens (f = 100 mm) or a flexible fiber (Ho:YAG). Damaged tissue was investigated macroscopically, histologically, and by scanning electron microscopy. Application in air caused carbonisation in all cases. Application in water showed thermal brown discoloring using Tm:YAG, Ho:YAG laser on meniscus tissue. The Nd:YAG did not ablate. The Er:YAG laser showed macroscopically precise boreholes without any discoloring of the adjacent tissue as well in meniscus as in bone. Cr:ErYSGG laser results were comparable with the results using an Er:YAG laser although ablation on bone tissue created higher thermal effects. For the aim of developing minimal invasive operating techniques the Er:YAG laser showed best results.