Early MRI response monitoring of patients with advanced hepatocellular carcinoma under treatment with the multikinase inhibitor sorafenib

<p>Abstract</p> <p>Background</p> <p>New therapeutic principles in clinical oncology require the adjustment of response criteria to govern therapy decisions. For advanced hepatocellular carcinoma (HCC) a new era has recently begun by the approval of the multikinase inhibitor sorafenib. As a unique feature, HCC usually develops in a diseased liver and current imaging technologies employing classical response criteria have not been prospectively evaluated for this new treatment.</p> <p>Methods</p> <p>MRI signal patterns were assessed in 21 advanced HCC patients receiving sorafenib. MRI was performed at baseline and in short-term intervals thereafter. Signal changes under therapy on T1WI, T2WI and post-gadolinium images including necrosis volume and its ratio to the entire tumor volume were compared to baseline imaging. To assess the association between the categorical variables, Fisher's exact tests were applied for a statistical analysis. Survey time ranged from 2–65 weeks, and a total of 39 target lesions were evaluated.</p> <p>Results</p> <p>Signal abnormalities during sorafenib therapy were disclosed by T1WI and T2WI in 15/21 patients. The predominant tumor signal change was hyperintensity on both T1WI and T2WI. Interestingly, most patients developed MRI signal changes within 4 weeks of therapy; in contrast, two non-responders did not show any signal alteration at follow-up. Under therapy, 16/21 patients presented with new or progressive necrosis, whereas 7 patients achieved temporarily >75% tumor necrosis under sorafenib. Significantly associated MRI variables were increase in T1WI signal and tumor necrosis (p = 0.017) as well as increase of tumor necrosis with an elevated ratio of necrotic to vital tumor areas (p = 0.002). Remarkably, some (3/13) of the patients developing necrotic tumor areas showed a relevant (>20%) increase in tumor volume, which should be considered in the assessment of imaging studies.</p> <p>Conclusion</p> <p>As sorafenib induces early intralesional necrosis with profound changes in T1WI/T2WI MRI signal intensities and measurable necrotic tumor areas in most HCC patients, early MRI-based evaluation could pave the way for its rationale and cost-effective application.</p

Early prediction of treatment response to high-dose salvage chemotherapy in patients with relapsed germ cell cancer using [18F]FDG PET

To assess the ability of [18F]fluorodeoxyglucose positron emission tomography for the early prediction of response in patients with relapsed metastatic germ cell tumours undergoing salvage high-dose chemotherapy. The role of positron emission tomography was compared with established means of tumour response assessment such as CT scans/MRI and serum tumour marker changes. In addition, positron emission tomography was compared with a current prognostic score which differentiates three prognostic groups with failure-free survival rates ranging from 5–50%. [18F]fluorodeoxyglucose uptake of metastases from germ cell tumours as well as CT scans and serum tumour marker were acquired after 2–3 cycles of induction chemotherapy but before the start of high-dose chemotherapy and CT scans/serum tumour marker were compared with the baseline examinations in 23 patients with relapsed germ cell tumours. To evaluate the validity of early response prediction by positron emission tomography, radiological monitoring and serum tumour marker decline, histopathologic response after resection of residual masses and/or the clinical course over 6 months after the end of treatment (relapse vs freedom of progression) were used. Overall, 10 patients (43%) achieved a marker-negative partial remission, three (13%) a marker-positive partial remission, five (22%) a disease stabilization and five (22%) progressed during treatment. Nine patients (39%) remained progression-free over 6 months following treatment, whereas 14 (61%) progressed. The outcome of high-dose chemotherapy was correctly predicted by positron emission tomography/CT scan/serum tumour marker in 91/59/48%. Eight patients with a favourably predicted outcome by CT scans plus serum tumour marker but a positive positron emission tomography prior to high-dose chemotherapy, failed treatment. This results in the following sensitivities/specificities for the prediction of failure of high-dose chemotherapy: positron emission tomography 100/78%; radiological monitoring 43/78%; serum tumour marker 15/100%. The positive and negative predictive values of positron emission tomography were 88 and 100%, respectively. As compared with the prognostic score, positron emission tomography was correctly positive in all patients of the three risk groups who failed treatment. In addition, a negative positron emission tomography correctly predicted a favourable outcome in the good and intermediate group. [18F]fluorodeoxyglucose positron emission tomography imaging can be used to assess response to chemotherapy in patients with relapsed germ cell tumours early in the course of treatment and may help to identify patients most likely to achieve a favourable response to subsequent high-dose chemotherapy. In patients with response to induction chemotherapy according to CT scans or serum tumour marker evaluation, positron emission tomography seems to add information to detect patients with an overall unfavourable outcome. It may also be a valuable addition to the prognostic model particularly in the good and intermediate group for further selection of patients who will profit from high-dose chemotherapy

Transient simulation of the last glacial inception. Part II: Sensitivity and feedback analysis

The sensitivity of the last glacial-inception (around 115 kyr BP, 115,000 years before present) to different feedback mechanisms has been analysed by using the Earth system model of intermediate complexity CLIMBER-2. CLIMBER-2 includes dynamic modules of the atmosphere, ocean, terrestrial biosphere and inland ice, the last of which was added recently by utilising the three-dimensonal polythermal ice-sheet model SICOPOLIS. We performed a set of transient experiments starting at the middle of the Eemiam interglacial and ran the model for 26,000 years with time-dependent orbital forcing and observed changes in atmospheric CO2 concentration (CO2 forcing). The role of vegetation and ocean feedback, CO2 forcing, mineral dust, thermohaline circulation and orbital insolation were closely investigated. In our model, glacial inception, as a bifurcation in the climate system, appears in nearly all sensitivity runs including a run with constant atmospheric CO2 concentration of 280 ppmv, a typical interglacial value, and simulations with prescribed present-day sea-surface temperatures or vegetation cover—although the rate of the growth of ice-sheets growth is smaller than in the case of the fully interactive model. Only if we run the fully interactive model with constant present-day insolation and apply present-day CO2 forcing does no glacial inception appear at all. This implies that, within our model, the orbital forcing alone is sufficient to trigger the interglacial–glacial transition, while vegetation, ocean and atmospheric CO2 concentration only provide additional, although important, positive feedbacks. In addition, we found that possible reorganisations of the thermohaline circulation influence the distribution of inland ic

Evaluation of CMIP5 palaeo-simulations to improve climate projections

Structural differences among models account for much of the uncertainty in projected climate changes, at least until the mid-twenty-first century. Recent observations encompass too limited a range of climate variability to provide a robust test of the ability to simulate climate changes. Past climate changes provide a unique opportunity for out-of-sample evaluation of model performance. Palaeo-evaluation has shown that the large-scale changes seen in twenty-first-century projections, including enhanced land–sea temperature contrast, latitudinal amplification, changes in temperature seasonality and scaling of precipitation with temperature, are likely to be realistic. Although models generally simulate changes in large-scale circulation sufficiently well to shift regional climates in the right direction, they often do not predict the correct magnitude of these changes. Differences in performance are only weakly related to modern-day biases or climate sensitivity, and more sophisticated models are not better at simulating climate changes. Although models correctly capture the broad patterns of climate change, improvements are required to produce reliable regional projections

The Time-Transgressive Termination of the African Humid Period

During the African Humid Period about 14,800 to 5,500 years ago, changes in incoming solar radiation during Northern Hemisphere summers led to the large-scale expansion and subsequent collapse of the African monsoon. Hydrologic reconstructions from arid North Africa show an abrupt onset and termination of the African Humid Period. These abrupt transitions have been invoked in arguments that the African monsoon responds rapidly to gradual forcing as a result of nonlinear land surface feedbacks. Here we present a reconstruction of precipitation in humid tropical West Africa for the past 20,000 years using the hydrogen isotope composition of leaf waxes preserved in sediments from Lake Bosumtwi, Ghana. We show that over much of tropical and subtropical Africa the monsoon responded synchronously and predictably to glacial reorganizations of overturning circulation in the Atlantic Ocean, but the response to the relatively weaker radiative forcing during the African Humid Period was more spatially and temporally complex. A synthesis of hydrologic reconstructions from across Africa shows that the termination of the African Humid Period was locally abrupt, but occurred progressively later at lower latitudes. We propose that this time-transgressive termination of the African Humid Period reflects declining rainfall intensity induced directly by decreasing summer insolation as well as the gradual southward migration of the tropical rainbelt that occurred during this interval