Efficacy of systemic therapy in advanced pancreatic carcinoma

With a worldwide incidence of more than 200 000 cases and almost as many deaths, pancreatic carcinoma (PC) remains one of the leading causes of cancer deaths, especially in the Western world. Due to the late onset of symptoms, almost all patients suffer from disseminated disease at the time of diagnosis and only a minority will ever be candidates for radical surgery. Only about one tenth of the operated patients remain disease free. For these reasons, development of effective palliative systemic therapy is important. Almost a decade ago, gemcitabine replaced 5-Fu as the gold standard in systemic treatment of advanced PC. Since then, a number of trials have investigated the potential additional effect of several cytotoxic or targeted agents in combination with gemcitabine. As shown in this review, nearly all these trials have proved disappointing. This review provides an overview of the results of current phase III trials of gemcitabine based systemic therapy. Furthermore, we discuss the role of systemic therapy compared to BSC only and the potential future role of targeted therapies.     

Structural and kinetic mapping of side-chain exposure onto the protein energy landscape

Identification and characterization of structural fluctuations that occur under native conditions is crucial for understanding protein folding and function, but such fluctuations are often rare and transient, making them difficult to study. Native-state hydrogen exchange (NSHX) has been a powerful tool for identifying such rarely populated conformations, but it generally reveals no information about the placement of these species along the folding reaction coordinate or the barriers separating them from the folded state and provides little insight into side-chain packing. To complement such studies, we have performed native-state alkyl-proton exchange, a method analogous to NSHX that monitors cysteine modification rather than backbone amide exchange, to examine the folding landscape of Escherichia coli ribonuclease H, a protein well characterized by hydrogen exchange. We have chosen experimental conditions such that the rate-limiting barrier acts as a kinetic partition: residues that become exposed only upon crossing the unfolding barrier are modified in the EX1 regime (alkylation rates report on the rate of unfolding), while those exposed on the native side of the barrier are modified predominantly in the EX2 regime (alkylation rates report on equilibrium populations). This kinetic partitioning allows for identification and placement of partially unfolded forms along the reaction coordinate. Using this approach we detect previously unidentified, rarely populated conformations residing on the native side of the barrier and identify side chains that are modified only upon crossing the unfolding barrier. Thus, in a single experiment under native conditions, both sides of the rate-limiting barrier are investigated.     

Changing clinical presentation of angiosarcomas after breast cancer: from late tumors in edematous arms to earlier tumors on the thoracic wall

Angiosarcoma is a rare complication of breast cancer treatment. In order to define predictors, clinical presentation, and outcome, we characterized a population-based 50-year cohort of angiosarcomas after breast cancer. Clinical data were collected from all females with previous breast cancer who developed angiosarcomas/lymphangiosarcomas on the thoracic wall/upper extremity between 1958 and 2008 in the Southern Swedish health care region. In total, 31 angiosarcomas developed at a median age of 71 years. The patients formed two distinct groups; 14 females treated for breast cancer with radical mastectomy and radiotherapy 1949–1988 developed angiosarcomas in edematous arms (Stewart–Treves syndrome) after median 11 years, and 17 females treated by segmental resection, anti-hormonal treatment and radiotherapy 1980–2005 developed angiosarcomas in the irradiated field on the thoracic wall after median 7.3 years. The clinical presentations were heterogeneous and included hematoma-like lesions, multiple bluish-reddish nodules, and asymptomatic lumps. The overall 5-year survival was 16%. In this population-based cohort, the early angiosarcomas developed in edematous arms after radical mastectomies, whereas more recent cases occurred after a shorter time period in the irradiated fields following breast conserving surgery. We conclude that the clinical presentation of angiosarcomas has changed, parallel with altered treatment principles for breast cancer.     

Whole-exome sequencing of pediatric acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL), the most common malignant disorder in childhood, is typically associated with numerical chromosomal aberrations, fusion genes or small focal deletions, thought to represent important pathogenetic events in the development of the leukemia. Mutations, such as single nucleotide changes, have also been reported in childhood ALL, but these have only been studied by sequencing a small number of candidate genes. Herein, we report the first unbiased sequencing of the whole exome of two cases of pediatric ALL carrying the ETV6/RUNX1 (TEL/AML1) fusion gene (the most common genetic subtype) and corresponding normal samples. A total of 14 somatic mutations were identified, including four and seven protein-altering nucleotide substitutions in each ALL. Twelve mutations (86%) occurred in genes previously described to be mutated in other types of cancer, but none was found to be recurrent in an extended series of 29 ETV6/RUNX1-positive ALLs. The number of single nucleotide mutations was similar to the number of copy number alterations as detected by single nucleotide polymorphism arrays. Although the true pathogenetic significance of the mutations must await future functional evaluations, this study provides a first estimate of the mutational burden at the genetic level of t(12;21)-positive childhood ALL.     

Assessing combined exposures of whole-body vibration and awkward posture--further results from application of a simultaneous field measurement methodology

The drivers of ten vehicles (tram, helicopter, saloon car, van, forklift, two mobile excavators, wheel loader, tractor, elevating platform truck) were studied with regard to the combined exposures of whole-body vibration and awkward posture during occupational tasks. Seven degrees of freedom (DOFs), or body angles, were recorded as a function of time by means of the CUELA measuring system (Computer-assisted registration and long-term analysis of musculoskeletal workloads) for the purpose of posture assessment. The vibrational exposure is expressed as the vector sum of the frequency-weighted accelerations in the three Cartesian coordinates; these were recorded simultaneously with the posture measurement. Based upon the percentage of working time spent under different workloads, a scheme is proposed for classification of the two exposures into three categories. In addition, a risk of adverse health effects classified as low, possible or high can be assigned to the combination of the two exposures. With regard to posture, the most severe exposure was measured for the drivers of the wheel loader and for the tractor driver, whereas the lowest exposure was measured for the helicopter pilots and van drivers. With regard to the combination of whole-body and posture exposures, the tractor driver and the elevating platform truck driver exhibited the highest workloads.     

Reduction of radiation pneumonitis by V20-constraints in breast cancer

Background

To assess the accuracy of fractionated stereotactic radiotherapy (FSRT) using a stereotactic mask fixation system.

Patients and Methods

Sixteen patients treated with FSRT were involved in the study. A commercial stereotactic mask fixation system (BrainLAB AG) was used for patient immobilization. Serial CT scans obtained before and during FSRT were used to assess the accuracy of patient immobilization by comparing the isocenter position. Daily portal imaging were acquired to establish day to day patient position variation. Displacement errors along the different directions were calculated as combination of systematic and random errors.

Results

The mean isocenter displacements based on localization and verification CT imaging were 0.1 mm (SD 0.3 mm) in the lateral direction, 0.1 mm (SD 0.4 mm) in the anteroposterior, and 0.3 mm (SD 0.4 mm) in craniocaudal direction. The mean 3D displacement was 0.5 mm (SD 0.4 mm), being maximum 1.4 mm. No significant differences were found during the treatment (P = 0.4). The overall isocenter displacement as calculated by 456 anterior and lateral portal images were 0.3 mm (SD 0.9 mm) in the mediolateral direction, -0.2 mm (SD 1 mm) in the anteroposterior direction, and 0.2 mm (SD 1.1 mm) in the craniocaudal direction. The largest displacement of 2.7 mm was seen in the cranio-caudal direction, with 95% of displacements < 2 mm in any direction.

Conclusions

The results indicate that the setup error of the presented mask system evaluated by CT verification scans and portal imaging are minimal. Reproducibility of the isocenter position is in the best range of positioning reproducibility reported for other stereotactic systems.