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Supplementary Figures 1-4 from Ckap2 Regulates Aneuploidy, Cell Cycling, and Cell Death in a p53-Dependent Manner

We used DNA microarray screening to identify Ckap2 (cytoskeleton associated protein 2) as a novel p53 target gene in a mouse erythroleukemia cell line. DNA damage induces human and mouse CKAP2 expression in a p53-dependent manner and p53 activates the Ckap2 promoter. Overexpressed Ckap2 colocalizes with and stabilizes microtubules. In p53-null cells, overexpression of Ckap2 induces tetraploidy with aberrant centrosome numbers, suggesting disturbed mitosis and cytokinesis. In p53-competent cells, Ckap2 does not induce tetraploidy but activates p53-mediated cell cycle arrest and apoptosis. Our data suggest the existence of a functional positive feedback loop in which Ckap2 activates the G1 tetraploidy checkpoint and prevents aneuploidy.

Supplementary Methods from Ckap2 Regulates Aneuploidy, Cell Cycling, and Cell Death in a p53-Dependent Manner

Background Salvage radiotherapy (SRT) is utilized for biochemical progression of prostate cancer after radical prostatectomy (RP). Objective To report the outcomes of the SAKK 09/10 trial comparing conventional and dose-intensified SRT. Design, setting, and participants SAKK 09/10 was a randomized, multicenter, phase 3 trial that recruited men with biochemical progression after RP. Intervention Patients were randomly assigned to conventional-dose (64 Gy) or dose-intensified SRT (70 Gy) to the prostate bed without hormonal therapy. Outcome measurements and statistical analysis The primary endpoint was freedom from biochemical progression (FFBP). Secondary endpoints included clinical progression-free survival (PFS), time to hormonal treatment, overall survival (OS), acute and late toxicity (Common Terminology Criteria for Adverse Events v4.0), and quality of life (QoL). Results and limitations Between February 2011 and April 2014, 350 patients were randomly assigned to 64 Gy (n = 175) or 70 Gy (n = 175). Median prostate-specific antigen at randomization was 0.3 ng/ml. After median follow-up of 6.2 yr, the median FFBP was 8.2 yr in the 64 Gy arm and 7.6 in the 70 Gy arm (log-rank p = 0.4), with a hazard ratio of 1.14 (95% confidence interval 0.82–1.60). The 6-year FFBP rates were 62% and 61%, respectively. No significant differences in clinical PFS, time to hormonal treatment, or OS were observed. Late grade 2 and 3 genitourinary toxicity was observed in 35 (21%) and 13 (7.9%) patients in the 64 Gy arm, and 46 (26%) and seven (4%) in the 70 Gy arm, respectively (p = 0.8). Late grade 2 and 3 gastrointestinal toxicity was observed in 12 (7.3%) and seven patients (4.2%) in the 64 Gy arm, and 35 (20%) and four (2.3%) in the 70 Gy arm, respectively (p = 0.009). There were no significant differences in QoL. Conclusions Conventional-dose SRT to the prostate bed is sufficient in patients with early biochemical progression of prostate cancer after RP. Patient summary The optimal radiation therapy dose for patients who have increased tumor markers after surgery for prostate cancer is unclear. We found that administering a higher dose only increased the gastrointestinal side effects without providing any benefits to the patient. This clinical trial is registered on ClinicalTrials.gov as NCT01272050.

We report a case of an uncommon presentation of Epstein-Barr virus (EBV)-associated plasma cell neoplasm in a patient with a history of prostate cancer and hairy cell leukemia (HCL) in remission after chemotherapy. The diagnosis of an EBV-associated plasma cell neoplasm was challenging as initially the findings were also compatible with a recurrence of HCL. We highlight the value of diagnostic vitrectomy to achieve the diagnosis. Our particular case demonstrates the importance of diagnostic pars plana vitrectomy and aqueous analyses in patients with uveitis of an unknown cause to confirm the diagnosis.

To evaluate the results of the radiation therapy (RT) quality assurance (QA) program of the phase 3 randomized SAKK 09/10 trial in patients with biochemically recurrent prostate cancer after prostatectomy.Within the Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) 09/10 trial testing 64-Gy versus 70-Gy salvage RT, a central collection of treatment plans was performed and thoroughly reviewed by a dedicated medical physicist and radiation oncologist. Adherence to the treatment protocol and specifically to the European Organization for the Research and Treatment of Cancer (EORTC) guidelines for target volume definition (classified as deviation observed yes vs no) and its potential correlation with acute and late toxicity (Common Terminology Criteria for Adverse Events version 4.0) and freedom from biochemical progression (FFBP) were investigated.The treatment plans for 344 patients treated between February 2011 and April 2014 depicted important deviations from the EORTC guidelines and the recommendations per trial protocol. For example, in up to half of the cases, the delineated structures deviated from the protocol (eg, prostate bed in 48.8%, rectal wall [RW] in 41%). In addition, variations in clinical target volume (CTV) and planning target volume (PTV) occurred frequently (eg, CTV and PTV deviations in up to 42.4% and 25.9%, respectively). The detected deviations showed a significant association with a lower risk of grade ≥2 gastrointestinal acute toxicity when the CTV did not overlap the RW versus when the CTV overlapped the RW (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.22-0.85; P = .014), and a higher rate of grade ≥2 late genitourinary (GU) toxicity when the CTV overlapped the RW (OR, 2.58; 95% CI, 1.17-5.72; P = .019). A marginally significant lower risk of grade ≥2 late GU toxicity was observed when the prostate bed did not overlap versus did overlap the RW (OR, 0.51; 95% CI, 0.25-1.03; P = .06). In addition, a marginally significant decrease in FFBP was observed in patients with PTV not including surgical clips as potential markers of the limits of the prostate bed (hazard ratio, 1.44; 95% CI, 0.96-2.17; P = .07).Despite a thorough QA program, the central review of a phase 3 trial showed limited adherence to treatment protocol recommendations, which was associated with a higher risk of toxicity by means of acute or late gastrointestinal or GU toxicity and showed a trend toward worse FFBP. Data from this QA review might help to refine future QA programs and prostate bed delineation guidelines.

• We conducted a Swiss survey on patterns of practice during COVID-19 pandemic. • Dedicated IT solutions were implemented in all radiation-oncology departments. • Upfront endocrine treatments for breast and prostate cancer were privileged. • Use of hypofractionation for breast, rectal cancer and palliation was increased.

Background Stage III N2 non-small cell lung cancer (NSCLC) is a very heterogeneous disease associated with a poor prognosis. A number of therapeutic options are available for patients with Stage III N2 NSCLC, including surgery [with neoadjuvant or adjuvant chemotherapy (CTx)/neoadjuvant chemoradiotherapy (CRT)] or CRT potentially followed by adjuvant immunotherapy. We have no clear evidence demonstrating a significant survival benefit for either of these approaches, the selection between treatments is not always straightforward and can come down to physician and patient preference. The very heterogeneous definition of resectability of N2 disease makes the decision-making process even more complex. Methods We evaluated the treatment strategies for preoperatively diagnosed stage III cN2 NSCLC among Swiss thoracic surgeons and radiation oncologists. Treatment strategies were converted into decision trees and analysed for consensus and discrepancies. We analysed factors relevant to decision-making within these recommendations. Results For resectable "non-bulky" mediastinal lymph node involvement, there was a trend towards surgery. Numerous participants recommend a surgical approach outside existing guidelines as long as the disease was resectable, even in multilevel N2. With increasing extent of mediastinal nodal disease, multimodal treatment based on radiotherapy was more common. Conclusions Both, surgery- or radiotherapy-based treatment regimens are feasible options in the management of Stage III N2 NSCLC. The different opinions reflected in the results of this manuscript reinforce the importance of a multidisciplinary setting and the importance of shared decision-making with the patient.

AIM Explore learning processes associated with a psychoeducational pain selfmanagement intervention. BACKGROUND Self-management of cancer pain is challenging for patients and their family caregivers (FCs). While psychoeducational interventions can support them to handle these tasks, it remains unclear how learning processes are hampered or facilitated. METHODS A convergent parallel mixed methods design with qualitative data collection embedded in a randomized controlled trial (RCT) was used. Outpatients with cancer and FCs were recruited from three Swiss university hospitals. The six-week intervention consisted of education, skills building, and nurse coaching. Quantitative data on pain management knowledge and self-efficacy were analyzed using multilevel models. Patients and FCs were interviewed post-RCT regarding their learning experiences. Qualitative data analysis was guided by interpretive description. Finally, quantitative and qualitative data were integrated using case level comparisons and a meta-matrix. RESULTS Twenty-one patients and seven FCs completed this study. The group-by-time effect showed increases in knowledge (p��=��0.035) and self-efficacy (p��=��0.007). Patients' and FCs' learning through experience was supported by an intervention nurse, who was perceived as competent and trustworthy. After the study, most intervention group participants felt more confident to implement pain self-management. Finally, data integration showed that declining health hampered some patients' pain self-management. CONCLUSIONS Competent and trustworthy nurses can support patients' and FCs' pain self-management by providing individualized interventions. Using a diary, jointly reflecting on the documented experiences, and addressing knowledge deficits and misconceptions through the use of academic detailing can facilitate patients' and FCs' learning of critical skills.

Background Current studies about percutaneous endoscopic gastrostomy (PEG) tube placement report equivalent patient outcomes with prophylactic PEG tubes (pPEGs) versus common nutritional support. Unreported was if omitting a pPEG is associated with an increased risk of complications leading to a treatment-related unplanned hospitalization (TRUH). Methods TRUHs were retrospectively analyzed in patients with advanced head and neck squamous cell carcinoma (n = 310) undergoing (chemo)radiotherapy with (pPEG) or without PEG (nPEG). Results In 88 patients (28%), TRUH was reported. One of the leading causes of TRUH in nPEG patients was inadequate oral intake (n = 16, 13%), and in pPEG patients, complications after PEG tube insertion (n = 12, 10%). Risk factors for TRUH were poor performance status, tobacco use, and surgical procedures. Conclusions Omitting pPEG tube placement without increasing the risk of an unplanned hospitalization due to dysphagia, dehydration or malnutrition, is an option in patients being carefully monitored. Patients aged > 60 years with hypopharyngeal carcinoma, tobacco consumption, and poor performance status appear at risk of PEG tube-related complications leading to an unplanned hospitalization.

Background KRAS mutation occurs in ∼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. Methods Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary end-points were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4. Results Fifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m2 twice daily × 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100%, capecitabine 98.6%, and sorafenib 100%. The pCR rate (Dworak 3/4) was 60% (95% CI, 43.3–75.1%) by central independent pathologic review. Sphincter preservation was achieved in 89.5%, R0 resection in 94.7%, and downstaging in 81.6%. The most common grade 3 toxicities during phase II included diarrhoea (15.0%), skin toxicity outside radiotherapy field (12.5%), pain (7.5%), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5%). Conclusions Combining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. www.clinicaltrials.gov : NCT00869570 .

194 Background: Salvage radiotherapy (RT) is often utilized in case of biochemical progression after radical prostatectomy (RP). Here we report the outcomes of the European SAKK 09/10 randomized phase 3 trial with the aim to compare effectiveness and tolerability of conventional vs. dose-intensified salvage RT. Methods: SAKK 09/10 is an open-label, multicenter, randomized phase 3 trial performed in 24 centers in Switzerland, Germany and Belgium. Men with biochemical progression (two consecutive rises with the final PSA > 0.1 ng/mL or three consecutive rises) after RP with a PSA nadir of ≤ 0.4 ng/mL, with a PSA ≤ 2 ng/mL at randomization and without clinical evidence of macroscopic disease were recruited. Patients were randomly assigned to either conventional dose RT (64 Gy in 32 fractions) or dose-intensified RT (70 Gy in 35 fractions) directed to the prostate bed. Three-dimensional conformal RTor intensity-modulated RT/rotational techniques were used. The primary endpoint was freedom from biochemical progression (PSA ≥ 0.4 ng/mL and rising). Secondary endpoints included clinical progression-free survival, time to hormonal treatment, overall survival, acute and late toxicity (according to the NCI CTCAE v4.0) and quality of life (according to the EORTC QLQ-C30 and PR25). The trial was registered under NCT01272050 in clinicaltrials.gov. Results: Between 02/2011 and 04/2014, 350 patients were randomly assigned to 64 Gy (n = 175) or 70 Gy (n = 175), of whom 344 aged between 48 to 75 years were assessable for the intention-to-treat population. The median PSA at randomization was 0.3 ng/mL (range, 0.03-1.61 ng/mL). At the time of data cutoff (July 3, 2020), the median follow-up was 6.2 years (IQR 5.5-7.2) and a total of 138 biochemical progression events occurred. The estimated freedom from biochemical progression rate at 6 years was 62.3% (95% CI 54.2-69.4%) and 61.3% (95% CI 53.4-68.3%) for the 64 Gy and the 70 Gy arm, respectively, and the hazard ratio adjusted by stratification factors was 1.14 (95% CI 0.82-1.60; log-rank p = 0.44). No significant difference was found for clinical progression-free survival, time to hormonal treatment and overall survival between the two arms, respectively. Late grade 2 and 3 genitourinary toxicity was observed in 35 (21.2%) and 13 (7.9%) patients treated with 64 Gy, and in 46 (26.3%) and 7 (4%) patients with 70 Gy (p = 0.81). Lategrade 2 and 3 gastrointestinal toxicity was observed in 12 (7.3%) and 7 (4.2%) patients with 64 Gy, and in 35 (20%) and 4 (2.3%) patients with 70 Gy(p = 0.009). Quality of life data will be presented. Conclusions: Dose-intensified salvage RT to the prostate bed was not superior to conventional dose RT. However, dose-intensified salvage RT was associated with higher frequencies of late grade ≥ 2 gastrointestinal toxicity. Clinical trial information: NCT01272050.

BACKGROUND: A population-based analysis of patients with glioma diagnosed between 1980 and 1994 in the Canton of Zurich in Switzerland confirmed the overall poor prognosis of glioblastoma. To explore changes in outcome, registry data were reevaluated for patients diagnosed between 2005 and 2009. METHODS: Patients with glioblastoma who were diagnosed between 2005 and 2009 were identified by the Zurich and Zug Cancer Registry. The prognostic significance of epidemiological and clinical data, isocitrate dehydrogenase 1 (IDH1)(R132H) mutation status, and O6 methylguanine DNA methyltransferase (MGMT) promoter methylation status was analyzed using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: A total of 264 patients with glioblastoma were identified, for an annual incidence of 3.9 compared with the previous incidence of 3.7. The mean age of the patients at the time of diagnosis was 59.5 years in the current cohort compared with 61.3 years previously. The overall survival (OS) rate was 46.4% at 1 year, 22.5% at 2 years, and 14.4% at 3 years in the current study compared with 17.7% at 1 year, 3.3% at 2 years, and 1.2% at 3 years as reported previously. The median OS for all patients with glioblastoma was 11.5 months compared with 4.9 months in the former patient population. The median OS was 1.9 months for best supportive care, 6.2 months for radiotherapy alone, 6.7 months for temozolomide alone, and 17.0 months for radiotherapy plus temozolomide. Multivariate analysis revealed age, Karnofsky performance score, extent of tumor resection, first-line treatment, year of diagnosis, and MGMT promoter methylation status were associated with survival in patients with IDH1(R132H) -nonmutant glioblastoma. CONCLUSIONS: The OS of patients newly diagnosed with glioblastoma in the Canton of Zurich in Switzerland markedly improved from 1980 through 1994 to 2005 through 2009. Cancer 2016. © 2016 American Cancer Society.

Dose rate is an essential factor in radiobiology. As modern radiotherapy delivery techniques such as volumetric modulated arc therapy (VMAT) introduce dynamic modulation of the dose rate, it is important to assess the changes in dose rate. Both the rate of monitor units per minute (MU rate) and collimation are varied over the course of a fraction, leading to different dose rates in every voxel of the calculation volume at any point in time during dose delivery. Given the radiotherapy plan and machine specific limitations, a VMAT treatment plan can be split into arc sectors between Digital Imaging and Communications in Medicine control points (CPs) of constant and known MU rate. By calculating dose distributions in each of these arc sectors independently and multiplying them with the MU rate, the dose rate in every single voxel at every time point during the fraction can be calculated. Independently calculated and then summed dose distributions per arc sector were compared to the whole arc dose calculation for validation. Dose measurements and video analysis were performed to validate the calculated datasets. A clinical head and neck, cranial and liver case were analyzed using the tool developed. Measurement validation of synthetic test cases showed linac agreement to precalculated arc sector times within ±0.4 s and doses ±0.1 MU (one standard deviation). Two methods for the visualization of dose rate datasets were developed: the first method plots a two-dimensional (2D) histogram of the number of voxels receiving a given dose rate over the course of the arc treatment delivery. In similarity to treatment planning system display of dose, the second method displays the dose rate as color wash on top of the corresponding computed tomography image, allowing the user to scroll through the variation over time. Examining clinical cases showed dose rates spread over a continuous spectrum, with mean dose rates hardly exceeding 100 cGy min(-1) for conventional fractionation. A tool to analyze dose rate distributions in VMAT plans with sub-second accuracy was successfully developed and validated. Dose rates encountered in clinical VMAT test cases show a continuous spectrum with a mean less than or near 100 cGy min(-1) for conventional fractionation.

Background A high neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation and together with the platelet-to-lymphocyte ratio (PLR) is associated with worse outcomes in several solid tumors. We investigated the prognostic value of NLR and PLR in patients with head and neck squamous cell carcinoma (HNSCC) treated with primary or adjuvant (chemo)radiotherapy ((C)RT). Methods A retrospective chart review of consecutive patients with HNSCC was performed. Neutrophil-to-lymphocyte ratio and PLR were computed using complete blood counts (CBCs) performed within 10 days before treatment start. The prognostic role of NLR and PLR was evaluated with univariable and multivariable Cox regression analyses adjusting for disease-specific prognostic factors. NLR and PLR were assessed as log-transformed continuous variables (log NLR and log PLR). Endpoints of interest were overall survival (OS), locoregional recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), and acute toxicity. Results We analyzed 186 patients treated from 2007 to 2010. Primary sites were oropharynx (45%), oral cavity (28%), hypopharynx (14%), and larynx (13%). Median follow-up was 49 months. Higher NLR was associated with OS (adjusted HR per 1 unit higher log NLR = 1.81 (1.16–2.81), p = 0.012), whereas no association could be shown with LRFS (HR = 1.49 (0,83-2,68), p = 0.182), DRFS (HR = 1.38 (0.65–3.22), p = 0.4), or acute toxicity grade ≥ 2. PLR was not associated with outcome, nor with toxicity. Conclusion Our data suggest that in HNSCC patients treated with primary or adjuvant (C)RT, NLR is an independent predictor of mortality, but not disease-specific outcomes or toxicity. Neutrophil-to-lymphocyte ratio is a readily available biomarker that could improve pre-treatment prognostication and may be used for risk-stratification.

Pain is one of cancer patients’ most frequent and distressing symptoms; however, analgesics’ side effects often increase symptom burden. Further, with the home rapidly becoming the primary cancer care setting, family caregivers (FCs) commonly play central roles in patients’ pain self-management, but with little or no preparation. One US-tested intervention, the PRO-SELF© Plus Pain Control Program (PCP), designed to support cancer outpatients and their FCs in pain self-management, is currently being tested in the Swiss multi-centre PEINCA study. The current PEINCA-FAM study is a sub-study of PEINCA. The aims of PEINCA-FAM are: a) to test the efficacy of the adapted German PRO-SELF © Plus PCP to reduce side effects of analgesics; b) to enhance patients’/FCs’ knowledge regarding cancer pain; and c) to explore FCs’ involvement in patients’ pain self-management. This mixed methods project combines a multi-centre randomized controlled clinical trial with qualitative data collection techniques and includes 210 patients recruited from three oncology outpatient clinics. FCs involved in patients’ pain self-management are also invited to participate. After baseline evaluation, eligible participants are randomized to a 6-week intervention group and a control group. Both groups complete a daily pain and symptom diary. Intervention group patients/FCs receive the weekly psychoeducational PRO-SELF© Plus PCP interventions; control group patients receive usual care. After completing the six-week study procedures, a subsample of 7–10 patients/FCs per group and hospital (N = 42–60) will be interviewed regarding their pain management experiences. Data collection will take place from April 2016 until December 2018. An intent-to-treat analysis and generalized linear mixed models will be applied. Qualitative data will be analysed by using interpretive description. Quantitative and qualitative results will be combined within a mixed method matrix. In clinical practice, specially trained oncology nurses in outpatient clinics could apply the intervention to reduce side effects and to enhance patients’/FCs’ self-efficacy and pain management knowledge. The PEINCA study is registered in the Clinical Trials.gov site (code: NCT02713919 , 08 March 2016).

A population-based analysis of patterns of care and outcome in glioma patients diagnosed 1980-1994 in the Canton of Zurich, Switzerland, has confirmed the overall poor prognosis of glioblastoma. To explore changes in outcome over the last decades, the registry data were re-evaluated for patients diagnosed in the time frame 2005-2009. Patients diagnosed with glioblastoma in the Canton of Zurich from 2005-2009 were identified by the Cancer Registry Zurich. Clinical and epidemiological data, as well as molecular markers were assessed, and analyzed using the Kaplan-Meier method and the Cox proportional hazards model. In the current database, there were 264 patients with glioblastoma, including 256 primary glioblastomas with an annual incidence of 3.98 compared to 3.55 in the former patient group. Median age at diagnosis was 60.0 years recently as opposed to 61.3 years previously. Overall survival (OS) for all glioblastoma patients was 41.7% at 1 year, 22.7% at 2 years and 13.1% at 3 years in the present study while previously the OS was significantly lower, namely 17.7% at 1 year, 3.3% at 2 years and 1.2% at 3 years, respectively. Median OS for primary glioblastomas was 11.0 months for the period ending 2009 versus 4.7 months for the patient population of 1980-1994. In the present study, by treatment, the median OS for best supportive care, radiotherapy alone, temozolomide alone or radiotherapy plus temozolomide was 2.0, 6.0, 6.0 or 17.0 months, respectively. Multivariate analysis revealed age, KPS, extent of resection, adjuvant treatment regimens, year of diagnosis, IDH-1 mutation status and MGMT promoter methylation status significantly associated with survival. The OS of patients in the Canton of Zurich with newly diagnosed glioblastoma has markedly improved from the period of 1980-1994 to 2005-2009.

Aims We tested whether delayed pharmacologic preconditioning elicited by isoflurane is protective in infarct-remodelled hearts. Methods and results Male Wistar rats were treated with the preconditioning drug isoflurane 6 weeks after permanent ligation of the left anterior descending coronary artery. Twenty-four and 48 h later, hearts were perfused on the Langendorff system and treated with cyclooxygenase-2 or 12-lipoxygenase inhibitors before exposure to 40 min of ischaemia followed by 90 min of reperfusion. Infarct size was determined by triphenyltetrazolium chloride staining and lactate dehydrogenase release. Cyclooxygenase-2 expression and activity were measured by Western blotting and colorimetric assay. Nuclear translocation of cyclooxygenase-2-inducing transcription factors HIF1α, CREB, STAT3, and NFκB was determined. Post-infarct, remodelled hearts exhibit alterations in cellular signalling, time course and extent of isoflurane-induced late protection. While remodelled, preconditioned hearts exhibited protection exclusively at 24 h, healthy hearts showed sustained protection for up to 48 h, which correlated with cyclooxygenase-2 protein expression and enzymatic activity. The cyclooxygenase-2 inhibitors celecoxib and NS-398, but not the 12-lipoxygenase inhibitor cinnamyl-3,4-dihydroxycyanocinnamate, abolished delayed protection in both healthy and remodelled hearts, identifying cyclooxygenase-2 as a key mediator of late protection in both models. Isoflurane induced nuclear translocation of HIF1α in all hearts, but CREB was exclusively activated in healthy but not remodelled myocardium, which expressed higher levels of the CREB antagonist ICER. Delayed protection by isoflurane in remodelled hearts was more vulnerable to inhibition by celecoxib. Conclusion Isoflurane failed to mobilize cyclooxygenase-2-inducing CREB in ICER-overexpressing, remodelled hearts, which was associated with a shortening of the second window of protection.

Despite current risk stratification systems using traditional clinicopathologic factors, many localized and locally advanced prostate cancers fail radical treatment (ie, radical prostatectomy, radiation therapy with or without androgen deprivation therapy). Therefore, a pressing need exists for enhanced methods of disease stratification through novel prognostic and predictive tools that can reliably be applied in clinical practice. Exosomes are 50- to 150-nm small vesicles released by cancer cells that reflect the genetic and nongenetic materials of parent cancer cells. Cancer cells can contain distinct sets of microRNA profiles, the expression of which can change owing to stress such as radiation therapy. These alterations or distinctions in contents allow exosomes to be used as prognostic and/or predictive biomarkers and to monitor the treatment response. Additionally, microRNAs have been shown to influence multiple processes in prostate tumorigenesis, including cell proliferation, induction of apoptosis, migration, oncogene inhibition, and radioresistance. Thus, comparative exosomal microRNA profiling at different levels could help portray tumor aggressiveness and response to radiation therapy. Although technical challenges persist in exosome isolation and characterization, recent improvements in microRNA profiling have evolved toward in-depth analyses of the exosomal cargo and its functions. We have reviewed the role of exosomes and exosomal microRNAs in biologic processes of prostate cancer progression and radiation therapy response, with a particular focus on the development of clinical assays for treatment personalization.

Despite the prominent pro-apoptotic role of p53, this protein has also been shown to promote cell survival in response to metabolic stress. However, the specific mechanism by which p53 protects cells from metabolic stress-induced death is unknown. Earlier we reported that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific member of a family of mitochondria-associated enzymes that have a central role in fatty acid metabolism promotes cell survival and tumor growth. Unlike other members of the CPT family, the subcellular localization of CPT1C and its cellular function remains elusive. Here, we report that CPT1C is a novel p53-target gene with a bona fide p53-responsive element within the first intron. CPT1C is upregulated in vitro and in vivo in a p53-dependent manner. Interestingly, expression of CPT1C is induced by metabolic stress factors such as hypoxia and glucose deprivation in a p53 and AMP activated kinase-dependent manner. Furthermore, in a murine tumor model, depletion of Cpt1c leads to delayed tumor development and a striking increase in survival. Taken together, our results indicate that p53 protects cells from metabolic stress via induction of CPT1C and that CPT1C may have a crucial role in carcinogenesis. CPT1C may therefore represent an exciting new therapeutic target for the treatment of hypoxic and otherwise treatment-resistant tumors.

Purpose. The goal of the present study was to analyze long-term results of fractionated stereotactic radiotherapy (SRT) in patients with a meningioma. Methods and materials. A total of 72 patients treated between 1996 and 2008 in MAASTRO clinic (n = 45) and University Hospital Zurich (n = 27) were included. SRT was given as primary treatment (n = 46), postoperatively (n = 19) or at recurrence (n = 7); 49 tumours (68%) were located in the skull base. Median total dose was 54 Gy. Results. Median follow-up was 4.13 years (range 0.66-11 years). The 3- and 5-year overall survival were 92 and 79% for grade 0 and I meningioma. Progression-free survival for grade 0 and I was 95% at 3 and 5 years, and 40% for grade II and III at 3 years. In 98.4% of patients, clinical symptoms were stable or improved. The majority of symptoms improved within 24 months after SRT. Local control is significantly better if patients are irradiated immediately after diagnosis compared to a watchful waiting policy (p = 0.017). Grade IV toxicity was low (4.2%, n = 3) Conclusion. SRT is an effective treatment with high local and clinical control. Early SRT resulted in better outcome than late treatment at progression.

Purpose: To investigate the clinical value of 18F-fluorocholine PET/CT (CH-PET/CT) in treatment decisions in patients with recurrent prostate cancer (rPCA). Methods: The study was a retrospective evaluation of 156 patients with rPCA and CH-PET/CT for restaging. Questionnaires for each examination were sent to the referring physicians 14-64months after examination. Questions included information regarding initial extent of disease, curative first-line treatment, and the treatment plan before and after CH-PET/CT. Additionally, PSA values at diagnosis, after initial treatment, before CH-PET/CT and at the end of follow-up were also obtained from the questionnaires. Results: Mean follow-up was 42months. The mean Gleason score was 6.9 at initial diagnosis. Initial treatment was: radical prostatectomy in 110 patients, radiotherapy in 39, and combined prostatectomy and radiotherapy in 7. Median PSA values before CH-PET/CT and at the end of follow-up were 3.40ng/ml and 0.91ng/ml. PSA levels remained stable, decreased or were below measurable levels in 108 patients. PSA levels increased in 48 patients. In 75 of the 156 patients (48%) the treatment plan was changed due to the CH-PET/CT findings. In 33 patients the therapeutic plan was changed from palliative treatment to treatment with curative intent. In 15 patients treatment was changed from curative to palliative. In 8 patients treatment was changed from curative to another strategy and in 2 patients from one palliative strategy to another. In 17 patients the treatment plan was adapted. Conclusion: CH-PET/CT has an important impact on the therapeutic strategy in patients with rPCA and can help to determine an appropriate treatment

Palliative medicine education is an important strategy in ensuring that the needs of terminally ill patients are met. A review was conducted in 2007 of the undergraduate curricula of all five of Switzerland’s medical schools to identify their palliative care-related content and characteristics. The average number of mandatory hours of palliative care education is 10.2 h (median 8 h; range 0–27 h), significantly short of the 40 h recommended by the European Palliative Care Association’s Education Expert Group. The median time allocated to designated palliative care blocks is 3 h (range 0–8 h). Most of the education occurs before the clinical years, and there are no mandatory clinical rotations. Three schools offer optional clinical rotations but these are poorly attended (

Chk1 is a checkpoint kinase and an important regulator of mammalian cell division. Because null mutation of Chk1 in mice is embryonic lethal, we used the Cre-loxP system and the Lck promoter to generate conditional mutant mice in which Chk1 was deleted only in the T lineage. In the absence of Chk1, the transition of CD4 − CD8 − double-negative (DN) thymocytes to CD4 + CD8 + double-positive (DP) cells was blocked due to an increase in apoptosis at the DN2 and DN3 stages. Strikingly, loss of Chk1 activated the checkpoint kinase Chk2 as well as the tumor suppressor p53 in these thymocytes. However, the developmental defects caused by Chk1 deletion were not rescued by p53 inactivation. Significantly, even though Chk1 deletion is highly lethal in proliferating tissues, we succeeded in using in vivo methods to generate Chk1/Chk2 double-knockout T cells. Analysis of these T cells revealed an interesting interaction between Chk1 and Chk2 functions that partially rescued the apoptosis of the double-mutant cells. Thus, Chk1 is both critical for the survival of proliferating cells and engages in cross-talk with the Chk2 checkpoint kinase pathway. These factors have implications for the targeting of Chk1 as an anticancer therapy.

A population-based analysis of patients with glioma diagnosed between 1980 and 1994 in the Canton of Zurich in Switzerland confirmed the overall poor prognosis of glioblastoma. To explore changes in outcome, registry data were reevaluated for patients diagnosed between 2005 and 2009.Patients with glioblastoma who were diagnosed between 2005 and 2009 were identified by the Zurich and Zug Cancer Registry. The prognostic significance of epidemiological and clinical data, isocitrate dehydrogenase 1 (IDH1)(R132H) mutation status, and O6 methylguanine DNA methyltransferase (MGMT) promoter methylation status was analyzed using the Kaplan-Meier method and the Cox proportional hazards model.A total of 264 patients with glioblastoma were identified, for an annual incidence of 3.9 compared with the previous incidence of 3.7. The mean age of the patients at the time of diagnosis was 59.5 years in the current cohort compared with 61.3 years previously. The overall survival (OS) rate was 46.4% at 1 year, 22.5% at 2 years, and 14.4% at 3 years in the current study compared with 17.7% at 1 year, 3.3% at 2 years, and 1.2% at 3 years as reported previously. The median OS for all patients with glioblastoma was 11.5 months compared with 4.9 months in the former patient population. The median OS was 1.9 months for best supportive care, 6.2 months for radiotherapy alone, 6.7 months for temozolomide alone, and 17.0 months for radiotherapy plus temozolomide. Multivariate analysis revealed age, Karnofsky performance score, extent of tumor resection, first-line treatment, year of diagnosis, and MGMT promoter methylation status were associated with survival in patients with IDH1(R132H) -nonmutant glioblastoma.The OS of patients newly diagnosed with glioblastoma in the Canton of Zurich in Switzerland markedly improved from 1980 through 1994 to 2005 through 2009. Cancer 2016;122:2206-15. © 2016 American Cancer Society.

Glioblastoma is the most common primary brain tumor in adults, with an estimated incidence of about 3 per 100 000 inhabitants per year in Europe and North America.1 The standard of care for newly diagnosed glioblastoma, subsequent to surgery, comprises radiotherapy with concomitant temozolomide followed by adjuvant temozolomide. In the study defining this treatment regimen, median survival was limited to 15 months,2 and median survival was reported to be only 12 months in a population-based analysis of more than 10 000 glioblastoma patients.3 Independent of any treatment, fatigue is a common symptom in cancer patients in general as well as in primary brain tumor patients, with an estimated prevalence of 50%–90% and 40%–70%, respectively.4,5 Cancer-related fatigue is defined by the National Comprehensive Cancer Network (NCCN) as a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.6 The patients themselves indicate fatigue as one of the most distressing symptom related to cancer and its treatment.7 It is a strong predictor of decreased patient satisfaction and health-related quality of life (QoL) and may represent one of the key reasons for discontinuing treatment.8–10 Nevertheless, fatigue is believed to be underdiagnosed and underestimated in cancer patients despite its possible impact on treatment compliance.4,11 As a consequence, some groups have questioned whether the standard treatment for glioblastoma is justified in view of the limited benefit on survival and the severity of associated symptoms.12 Compared with other tumor types, namely breast and lung cancer, few studies have addressed the problem of fatigue in glioblastoma patients in depth, and several limitations have to be mentioned. First, many groups have included patients with all sorts of primary brain tumors despite large differences in underlying neurobiology, treatment procedures, and prognosis.5,13 Second, baseline data are often missing, particularly in studies using a cross-sectional design.5 As a consequence, fatigue was mainly assessed as a treatment complication, thereby failing to acknowledge the primary impact of the tumor itself and other treatment-independent factors.14 Third, the results of many older series cannot be directly compared with the current situation because of advances in radiation techniques. Finally, while many validated fatigue questionnaires are available,9,15 the large majority of neuro-oncological studies identified and quantified fatigue in a very rudimental way, using the Visual Analogue Scale (VAS) or one single fatigue item appearing in tools such as the European Organisation for Research and Treatment of Cancer (EORTC) QoL questionnaire, the M D Anderson Symptom Inventory–Brain Tumor Module, or the Symptom Distress Scale.9,12,16–18 Thus, in this prospective study, we aimed at examining frequency and predictors of fatigue severity in a homogeneous cohort of glioblastoma patients at baseline prior to combined radio-chemotherapy. For this goal, we used the Fatigue Severity Scale (FSS), which has been identified as the most widely adopted fatigue questionnaire in clinical practice and has been validated for a variety of neurological diseases.15,19,20 In addition, we explored the evolution of fatigue, sleepiness, and mood disorders during and after combined radio-chemotherapy.

We used DNA microarray screening to identify Ckap2 (cytoskeleton associated protein 2) as a novel p53 target gene in a mouse erythroleukemia cell line. DNA damage induces human and mouse CKAP2 expression in a p53-dependent manner and p53 activates the Ckap2 promoter. Overexpressed Ckap2 colocalizes with and stabilizes microtubules. In p53-null cells, overexpression of Ckap2 induces tetraploidy with aberrant centrosome numbers, suggesting disturbed mitosis and cytokinesis. In p53-competent cells, Ckap2 does not induce tetraploidy but activates p53-mediated cell cycle arrest and apoptosis. Our data suggest the existence of a functional positive feedback loop in which Ckap2 activates the G1 tetraploidy checkpoint and prevents aneuploidy.

Background DNA chips facilitate genomic-wide exploration of gene expression. The authors hypothesized that ischemic (IPC) and anesthetic preconditioning (APC) would differentially modulate gene expression in hearts. Methods Affymetrix rat U34A gene chips were used to explore the transcriptional response to IPC and APC, sustained ischemia (110 min) without reperfusion, and time-matched perfusion in isolated rat hearts. IPC was induced by three cycles of 5 min of ischemia, and APC was induced by 1.5 minimum alveolar concentration isoflurane (110 min). For each heart, a separate chip was used for hybridization. Data were analyzed for significant > or = 2.0-fold changes in gene expression. Microarray results were confirmed by quantitative real-time reverse-transcription polymerase chain reaction. Results Of the 8,799 genes represented on U34A, 217 transcripts in the APC group, 234 in the IPC group, and 29 in the ischemia group displayed significant > or = 2.0-fold up-regulation in messenger RNA levels, and 185 transcripts in the APC group, 55 in the IPC group, and 49 in the ischemia group displayed significant > or = 2.0-fold down-regulation. Many of these transcripts were unknown genes. A high number of commonly regulated genes were found in IPC and APC (39 up-regulated, 17 down-regulated). Genes commonly regulated included those associated with cell defense (heat shock protein 10, aldose reductase, Bcl-xS). Conversely, a pool of protective and antiprotective genes was differentially regulated in APC versus IPC (heat shock protein 27/70, programmed cell death 8), suggesting trigger-dependent transcriptome variability. Conclusions The novel microarray technology provides evidence for distinct cardioprotective phenotypes in IPC and APC. The observed transcriptional changes raise the possibility of a second window of protection by volatile anesthetics. The authors' molecular portraits are the first global genomic comparison between IPC and APC.

In many human hematologic and solid malignancies, intrinsic or acquired treatment resistance remains a major obstacle for successful cancer therapy. The molecular understanding of how tumor cells respond to chemotherapy and ionizing radiation is rapidly evolving. Induction of programmed cell death, apoptosis, is one important strategy for successful cancer therapy. This has been shown convincingly for oncogene-transformed normal cells as well as tumor cells of lymphoid origin. However, the relevance of apoptosis in solid human malignancies is less clear. Loss of apoptosis might be linked to specific mutations in the often tissue-specific apoptotic pathways due to aberrations in the stress-related signal transduction cascades. Restoration of a dysfunctional apoptotic program in cancer tissue where apoptosis has been identified as an important mechanism for tissue homeostasis is one rational approach for innovative cancer therapy. In this review, we focus on the relevance of the tumor suppressor p53 for apoptosis-induction and successful cancer therapy outlining the importance of an intact caspase machinery for apoptosis execution. Strategies are discussed to overcome treatment resistance and a high apoptotic threshold in human malignancies where apoptosis is the dominant mode of cell death and the status of p53 is an important determinant for apoptosis induction.

Introduction : The incidence of ductal carcinoma of the breast (DCIS) increased in Europe and the US up to 10-fold over the last 20 years [8]. This could be linked to more vigorous screening mammography, as well as changes of histopathologic and diagnostic criteria for breast lesions during the last decades [31,26]. Optimal screening for DCIS, the diagnostic procedures and best treatment is still controversial. For many DCIS patients lumpectomy and adjuvant radiotherapy are a valid treatment option. There is need for better prognostic factors in DCIS, which indicate the need for therapy and tailor the intensity of treatment. Recently prognostic factors based on clinical and pathological findings for DCIS were established and are currently validated. Molecular mechanisms involved in DCIS formation, DCIS progression to invasive breast cancer, and predicting DCIS treatment response are rapidly emerging [46]. Results and conclusion : Here we discuss some of the known molecular mechanisms of DCIS and how they could be further exploited as prognostic factors for screening and tailoring DCIS therapy. This review will summarize relevant molecular mechanism of DCIS carcinogenesis including dysregulation of the cell cycle clock and changes of the apoptotic threshold. In particular, recently published molecular and cellular abnormalities in DCIS, potentially relevant for treatment decision, will be discussed.

In order to overcome the limitations of the linear-quadratic model and include synergistic effects of heat and radiation, a novel radiobiological model is proposed. The model is based on a chain of cell populations which are characterized by the number of radiation induced damages (hits). Cells can shift downward along the chain by collecting hits and upward by a repair process. The repair process is governed by a repair probability which depends upon state variables used for a simplistic description of the impact of heat and radiation upon repair proteins. Based on the parameters used, populations up to 4-5 hits are relevant for the calculation of the survival. The model describes intuitively the mathematical behaviour of apoptotic and nonapoptotic cell death. Linear-quadratic-linear behaviour of the logarithmic cell survival, fractionation, and (with one exception) the dose rate dependencies are described correctly. The model covers the time gap dependence of the synergistic cell killing due to combined application of heat and radiation, but further validation of the proposed approach based on experimental data is needed. However, the model offers a work bench for testing different biological concepts of damage induction, repair, and statistical approaches for calculating the variables of state.

PURPOSE To assess dose rates in volumetric modulated arc therapy (VMAT) plans. METHODS For dose rate analysis, using Monte Carlo methods, dose distributions are calculated in sectors of consecutive DICOM control points and each multiplied with the MU-rate obtaining dose rate distributions for every voxel at every time-point during a treatment fraction. Dose rate distributions were calculated for a clinical head and neck, cranial (2 Gy fraction dose) and a SBRT liver treatment case (5 Gy per fraction). To assess optimizer influence on dose rate distributions, five conventionally fractionated head and neck cases were optimized using the progressive resolution optimizer (PRO) versions 2 and 3 (Varian Medical Systems, Palo Alto, CA). RESULTS Firstly, histograms of dose rates over the course of treatment delivery in volumes of interest were generated for the PTV and spine or brainstem of the clinical treatment plans. Secondly, dose rates were assessed as color wash overlay on top of CT slices, allowing the user to explore the dose rate variation over time. For the cases considered, dose rates were spread out over a continuous spectrum with a mean value in the lower half. PRO3 generated plans showed higher maximum dose rates compared to PRO2 (699.80 cGy/min vs. 543.46 cGy/min) and modulation of MU rates in blocks as opposed to gradual modulation. CONCLUSION Calculation and visualization of dose rate distributions in VMAT have been performed. Dose rates in clinical relevant VMAT cases are spread out over a continuous spectrum with a mean in the lower part for both conventional and SBRT test cases. Different optimization algorithms may lead to substantially different dose rate distributions in the same cases. The development of the Swiss Monte Carlo Plan framework has been partially supported by Varian Medical Systems.

There are two movements, each rooted in bioethics and evidence-based medicine, that focus on quite similar aims yet are not fully aligned and integrated in the clinical care of dying patients: The first, “advance care planning” focusses on future decisions when one becomes incapable of decision making, and the second, “shared decision making” has led to decision aids designed on the basis of empirical evidence to solicit and support patients' choices and decisions. The aim of our study, beginning in 2012, is to develop, implement and test a complex intervention (continuous multi-professional development – CPD program) for improving patients' preparation for and participation in end of life decisions including both strategies ACP and SDM/DA on end of life issues in an acute care hospital setting. In order to prepare for our randomised controlled trial, we systematically screened existing ACP and SDM programs for end of life issues and analysed their content, scope, aims, similarities and differences. The SDM philosophy relies more on giving tailored statistical information on distinct measures whereas ACP relies more on defining broader goals of care, which might indicate not only different contents but also differing concepts of autonomy. Outcomes are both similar and different. For example, both investigate impact on satisfaction with care and economy. SDM focuses more on knowledge and decisional conflict whereas ACP focuses on numbers of advance directives (ADs), and decisions made according to wishes. We will discuss philosophical and practical underpinnings of bringing the two movements together.

To evaluate the potential usage of flattening filter-free (FFF) photon beams in the treatment of prostate cancer.Volumetric-modulated arc therapy (VMAT) treatment planning was performed for 7 patients using TrueBeam(®) linear accelerator and photon beams with (X6, X10) and without (X6FFF, X10FFF) flattening filter. Prescribed dose was 19 × 3 Gy = 57 Gy. One or two 360° arcs with dose rate of 600 MU/min for flattened beams, and 1,200 MU/min for FFF beams were used.No difference was detected between the four beams in PTV coverage, conformity, and homogeneity. Mean body dose and body volume receiving 50% of the prescribed dose decreased with increasing mean energy (r(2) = 0.8275, p0.01). X6FFF delivered 3.6% more dose compared with the X6 (p0.01). X10FFF delivered 3.0% (p0.01), and the X10 5.8% (p 0.01) less mean body dose compared with X6. There was a significant increase in the mean dose to the rectum for the X10 compared with X6 (2.6%, p0.01). Mean dose to the bladder increased by 1.3% for X6FFF and decreased by 2.3% for X10FFF. Using a single arc and FFF, treatment time was reduced by 35% (2 SD = 10%).FFF beams resulted in dose distributions similar to flattened beams. X10FFF beam provided the best solution, sparing rectum and bladder and minimizing whole-body dose. FFF beams lead to a time efficient treatment delivery, particularly when combined with hypofractionated VMAT.

Tumor cells gain a survival/growth advantage by adapting their metabolism to respond to environmental stress, a process known as metabolic transformation. The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells up-regulate glycolysis under aerobic conditions. However, other mechanisms mediating metabolic transformation remain undefined. Here we report that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific metabolic enzyme, may participate in metabolic transformation. CPT1C expression correlates inversely with mammalian target of rapamycin (mTOR) pathway activation, contributes to rapamycin resistance in murine primary tumors, and is frequently up-regulated in human lung tumors. Tumor cells constitutively expressing CPT1C show increased fatty acid (FA) oxidation, ATP production, and resistance to glucose deprivation or hypoxia. Conversely, cancer cells lacking CPT1C produce less ATP and are more sensitive to metabolic stress. CPT1C depletion via siRNA suppresses xenograft tumor growth and metformin responsiveness in vivo. CPT1C can be induced by hypoxia or glucose deprivation and is regulated by AMPKα. Cpt1c-deficient murine embryonic stem (ES) cells show sensitivity to hypoxia and glucose deprivation and altered FA homeostasis. Our results indicate that cells can use a novel mechanism involving CPT1C and FA metabolism to protect against metabolic stress. CPT1C may thus be a new therapeutic target for the treatment of hypoxic tumors.

Background Accumulated literature suggests that the acidic nuclear phosphoprotein 32 kilodalton (Anp32) proteins control multiple cellular activities through different molecular mechanisms. Like other Anp32 family members, Anp32e (a.k.a. Cpd1, PhapIII) has been conserved throughout vertebrate evolution, suggesting that it has an important function in organismal survival. Principal Findings Here, we demonstrate that the Anp32e gene can be deleted in mice without any apparent effect on their wellbeing. No defects in thymocyte apoptosis in response to various stresses, fibroblast growth, gross behaviour, physical ability, or pathogenesis were defined. Furthermore, combined deletion of Anp32a and Anp32e also resulted in a viable and apparently healthy mouse. Significance These results provide evidence that significant functional redundancy exists among Anp32 family members.

p53 is a central player in responses to cellular stresses and a major tumor suppressor. The identification of unique molecules within the p53 signaling network can reveal functions of this important transcription factor. Here, we show that brain-expressed RING finger protein ( BERP ) is a gene whose expression is up-regulated in a p53-dependent manner in human cells and in mice. We generated BERP-deficient mice by gene targeting and demonstrated that they exhibit increased resistance to pentylenetetrazol-induced seizures. Electrophysiological and biochemical studies of cultured cortical neurons of BERP-deficient mice showed a decrease in the amplitude of GABA A receptor (GABA A R)-mediated miniature inhibitory postsynaptic currents as well as reduced surface protein expression of GABA A Rs containing the γ2-subunit. However, BERP deficiency did not decrease GABA A Rγ2 mRNA levels, raising the possibility that BERP may act at a posttranscriptional level to regulate the intracellular trafficking of GABA A Rs. Our results indicate that BERP is a unique p53-regulated gene and suggest a role for p53 within the central nervous system.

Detailed recommendations for the treatment of testicular cancer exist and due to the stringent application of the standard therapies, most patients can nowadays be cured. Moreover in the treatment of early stage disease, active surveillance is now a cornerstone of treatment. Hence there is a clear need for recommendations regarding the long term follow-up of these young patients. These have to be safe, feasible and the intensity of procedures have to reflect the known risk of recurrence. Different proposals have been published but they differ widely especially in terms of frequency and modality of imaging. In the last few years, new evidence has become available regarding the relapse pattern of different disease stages of testicular cancer, the use of imaging in follow-up and the risks of excessive radiation due to imaging, in particular with CT scans. In this article, an interdisciplinary, multinational working group has reviewed the evidence and based on this has formulated practical recommendations for the follow-up of patients with testicular cancer.

A 57-year-old man presented with jugular swelling. A leukocytosis of 50,000 WBC/μL (95% neutrophils) was found. PET/CT demonstrated increased fluorine-18-fluorodeoxyglucose uptake in the cervical/retrosternal mass, in the bone marrow, and in the enlarged spleen. Bone marrow biopsy confirmed myeloid hypercellularity with a left shift, but there were no signs of dysplasia and no evidence of tumor infiltration. Pathology of the thyroidectomy specimen confirmed an anaplastic thyroid carcinoma. Serum granulocyte-colony stimulating factor was elevated to 38.8 pg/mL (normal range

Phosphorylation of adenine nucleotide translocator 1 (ANT1) at residue Y194, which is part of the aromatic ladder located within the lumen of the carrier, critically regulates mitochondrial metabolism. Recent data support the concept that members of the Src family of nonreceptor tyrosine kinases are constitutively present in mitochondria and key to regulation of mitochondrial function. Herein, we demonstrate that site mutations of ANT1 (Y190→F190, Y194→F194) mimicking dephosphorylation of the aromatic ladder resulted in loss of oxidative growth and ADP/ATP exchange activity in respiration-incompetent yeast expressing mutant chimeric yN-hANT1. ANT1 is phosphorylated at Y194 by the Src family kinase members Src and Lck, and increased phosphorylation is tightly linked to reduced cell injury in preconditioned protected vs. unprotected cardiac mitochondria. Molecular dynamics simulations find the overall structure of the phosphorylated ANT1 stable, but with an increased steric flexibility in the region of the aromatic ladder, matrix loop m2, and four helix-linking regions. Combined with an analysis of the putative cytosolic salt bridge network, we reason that the effect of phosphorylation on transport is likely due to an accelerated transition between the main two conformational states (c↔m) of the carrier during the transport cycle. Since “aromatic signatures” are typical for other mitochondrial carrier proteins with important biological functions, our results may be more general and applicable to these carriers.

BACKGROUND: Endothelial progenitor cells play a pivotal role in tissue repair, and thus are used for cell replacement therapies in "regenerative medicine." We tested whether the anesthetic sevoflurane would modulate growth or mobilization of these angiogenic cells. METHODS: In an in vitro model, mononuclear cells isolated from peripheral blood of healthy donors were preconditioned with sevoflurane (3 times 30 min at 2 vol% interspersed by 30 min of air). Colony-forming units were determined after 9 days in culture and compared with time-matched untreated control. Using magnetic cell sorting, CD133+/CD34+ endothelial progenitors were enriched from human umbilical cord blood, and vascular endothelial growth factor (VEGF), VEGFR2 (KDR), granulocyte colony-stimulating factor (G-CSF), STAT3, c-kit, and CXCR4 expressions were determined in sevoflurane-treated and untreated cells by real-time reverse transcriptase polymerase chain reaction. In a volunteer study with crossover design, we tested whether sevoflurane inhalation (