Marine resource abundance drove pre-agricultural population increase in Stone Age Scandinavia.

How climate and ecology affect key cultural transformations remains debated in the context of long-term socio-cultural development because of spatially and temporally disjunct climate and archaeological records. The introduction of agriculture triggered a major population increase across Europe. However, in Southern Scandinavia it was preceded by ~500 years of sustained population growth. Here we show that this growth was driven by long-term enhanced marine production conditioned by the Holocene Thermal Maximum, a time of elevated temperature, sea level and salinity across coastal waters. We identify two periods of increased marine production across trophic levels (P1 7600-7100 and P2 6400-5900 cal. yr BP) that coincide with markedly increased mollusc collection and accumulation of shell middens, indicating greater marine resource availability. Between ~7600-5900 BP, intense exploitation of a warmer, more productive marine environment by Mesolithic hunter-gatherers drove cultural development, including maritime technological innovation, and from ca. 6400-5900 BP, underpinned a ~four-fold human population growth.

Recurrent pleural effusion: who benefits from a tunneled pleural catheter?

Recurrent malignant pleural effusion (MPE) is a common concomitant phenomenon of malignant disease, which can worsen the patient's quality of life and lead to significant morbidity. Tunneled indwelling pleural catheters (TIPC) offer new modalities in patients with recurrent MPE and impaired dilatability of the lung. We report on our experience with 100 consecutive patients suffering from recurrent benign (n = 12) and malignant pleural effusion (n = 88) who were treated with TIPC. The catheter was placed during a VATS procedure or under local anesthesia in an open technique. The median residence time of the TIPC was 70 days; spontaneous pleurodesis was achieved in 29 patients. The rate of complications was low: pleura empyema (n = 4), accidental dislodgement (n = 2), malfunction of the drainage (n = 3). In conclusion, TIPC is a useful method for the palliative treatment of patients with recurrent malignant or nonmalignant pleural effusions and 3 groups of patients seem to benefit most: a) patients with the intraoperative finding of a trapped lung in diagnostic VATS procedure; b) patients after a history of repeated pleuracenteses or previously failed attempts at pleurodesis; c) patients in a reduced condition with a limited lifespan due to underlying disease.

[New therapeutic options in chemotherapy of advanced colorectal cancer]. / Neue Therapieoptionen in der Chemotherapie des fortgeschrittenen kolorektalen Karzinoms.

BACKGROUND: Chemotherapeutic options in the treatment of advanced colorectal cancer have markedly improved during the last years. This is partly due to the high-dose 5-FU regimen, but also to the development of new cytotoxic agents and drug combinations. RESULTS: High-dose 5-FU, irinotecan, and oxaliplatin seem to be superior to low-dose 5-FU in terms of response rate and disease control. Combination of irinotecan with 5-FU/FA showed significant longer overall survival rates compared to 5-FU/FA alone in both published phase III trials. Today most patients are treated by a sequential therapeutic concept using the newer drugs mainly for second or third line therapy. However, there are reasons for the use of more intensive chemotherapy combinations in first line treatment. Combination of oxaliplatin with 5-FU/FA, that failed improvement of overall survival compared to 5-FU/FA alone, could downstage previously unresectable liver metastases for potentially curative surgery in some patients. Oral fluoropyrimidines mark another progress in the treatment of advanced colorectal cancer. They seem to be comparable to low-dose 5-FU/FA and could ease chemotherapy. PERSPECTIVE: Prospective randomized phase III trials must confirm the best chemotherapy and the best strategy for the different subgroup of patients.

Ex vivo evaluation of novel miniaturized laser-induced interstitial thermotherapy applicators for effective small-volume tissue ablation.

RATIONALE AND OBJECTIVES: For effective small-volume tissue ablation in clinical and experimental settings, smaller laser-induced interstitial thermotherapy (LITT) applicator designs are required. The aim of this study was to compare the ablation properties of recently developed ultrasmall and small to standard LITT applicators. METHODS: Laser-induced interstitial thermotherapy was performed on liver samples using ultrasmall, small, and standard LITT applicators. Thermotherapy was monitored by magnetic resonance imaging, and lesion sizes were measured for each image. True lesion sizes were then determined macroscopically and by histology. RESULTS: For continuous laser application over 5 minutes, maximum power settings were 5 W for the ultrasmall and small applicators and 10 W for the standard applicator. Given identical LITT settings, lesion volume measured by magnetic resonance imaging was significantly larger and histological tissue damage was more severe with the ultrasmall and small applicators than with the standard applicator. CONCLUSIONS: Small and ultrasmall LITT applicators can be used for effective tissue ablation of small target volumes in experimental and clinical applications.

[Pathomorphology of laser-induced interstitial tumor thermotherapy of the liver]. / Pathomorphologie der Laser-induzierten interstitiellen Tumor-Thermotherapie an der Leber.

The aim of this study was to analyse pathomorphological findings after treatment with laser induced tumor thermotherapy (LITT) on liver tissue and to correlate the results with magnetic resonance imaging. LITT was performed ex vivo and in vivo using a Neodym-YAG-Laser. Lesions were monitored by MR-thermometry ex vivo and by contrast-enhanced MRI in vivo. After LITT the lesions were examined macroscopically, histologically, and electronmicroscopically. LITT-induced tissue damage was qualitatively evaluated, classified, and quantified by means of digital image analysis. Four different zones of tissue damage were identified within the lesions. Adjacent to the applicator the tissue was completely ablated while more peripheral lesions exhibited only sublethal cell damages seen by EM. In vivo the pattern of tissue injury followed the lobular architecture of the liver tissue. Ultrastructural examination revealed only in areas of minor tissue injury intact sinusoidal patterns. MRI overestimated the diameter of the core zone of complete tissue ablation both ex vivo and to a lesser extent in vivo.

Preclinical assessment of hepatocyte-targeted MR contrast agents in stable human liver cell cultures.

Much effort has been expended in the search for hepatocyte-specific MR contrast agents to improve the detection and characterization of liver tumors. The purpose of this study was to establish human hepatocyte cell cultures to preclinically assess hepatocyte-targeted magnetopharmaceuticals. Cultured human hepatocytes were sandwiched between two layers of collagen preserving both hepatocyte function and morphology over prolonged period of time. Cultures (n = 37) were subsequently used to test different fluorescinated MR contrast agents. Plain and rhodaminated monocrystalline iron oxide particles (MION and MION-rh) and asialoglycoprotein-receptor-specific rhodaminated asialofetuin coupled to MION (MION-ASF-rh) were prepared. Competition experiments of these agents were performed with D(+)-galactose to study the specificity of galactose-mediated cell uptake. To assess the impact of cell integrity on cell uptake, functional experiments with CCl4 were performed. Normal cell cultures showed significantly higher fluorescence light emission after incubation with hepatocyte-directed ASF-MION-rh than after incubation with MION-rh. Competition experiments of ASF-MION-rh with galactose showed a dose-dependent decrease of calibrated fluorescence light emission. Cell cultures treated with CCl4 demonstrated a dose-dependent significant reduction of calibrated fluorescence light emission, indicating reduced uptake of ASF-MION-rh. Our data demonstrate that stable human hepatocyte cell cultures can be used to preclinically assess novel magnetopharmaceuticals. Different contrast agents may be directly compared to each other and may accelerate their preclinical design. Because the assay can be applied to cells from any species, it may represent an ideal test system before clinical trials of new cell-directed MR contrast agents.

MR-monitored LITT as a palliative concept in patients with high grade gliomas: preliminary clinical experience.

The purpose of this study was to evaluate the clinical utility of laser-induced thermotherapy (LITT) as a palliative treatment for patients with high-grade gliomas. Four consenting patients with recurrent high grade III/IV gliomas near the primary language or motor areas were palliatively treated with LITT (2-5 W, 3-13 minutes; Neodym YAG Laser, Dornier, Friedrichshafen, Germany). Temperature monitoring was performed by T1-weighted turbo-fast low-angle shot (FLASH) imaging at 1.5 T (Siemens Magnetom SP 4000, Siemens, Erlangen, Germany). MRI studies before LITT included contrast-enhanced conventional scans and functional activation studies to localize the primary motor cortex or language areas using an echo-planar imaging (EPI) spin-echo (SE) sequence. Follow-up studies consisted of contrast-enhanced conventional scans as well as diffusion studies (contrast-enhanced Fourier-acquired steady-state technique and EPI-SE) and perfusion studies (EPI-SE with .2 mmol of gadolinium (Gd)/kg body weight) to differentiate post-therapeutic effects from residual or recurrent tumor growth. Local tumor control was achieved in areas with laser energy deposition with clinically stable conditions > or = 6 months. Conventional contrast-enhanced scans demonstrated strong enhancement surrounding ablated tumor components, which showed a reduction in CBV/CBF. Perfusion studies were useful to discriminate granulomatous tissue enhancement from residual or recurrent tumor growth. Careful application of LITT may evolve as an alternative palliative concept for patients with end-stage high-grade cerebral gliomas reducing clinical symptoms from circumscribed areas of pathology.

Preliminary clinical experience with laser-induced interstitial thermotherapy in patients with hepatocellular carcinoma.

The purpose of this preliminary study was to evaluate whether laser-induced interstitial thermotherapy (LITT) may be used for palliative treatment of localized hepatocellular carcinomas (HCC). We applied LITT to two patients suffering from unresectable localized hepatocellular carcinomas of different sizes (2.5 and 4 cm). LITT was performed with an Nd:YAG laser (1,064 nm) at 5 W laser power (15-20 minutes). Thermometry during LITT was performed by MRI using a temperature-sensitive T1-weighted fast low-angle shot (FLASH) sequence. Follow-up for local tumor control was performed by MRI and ultrasound. LITT was well tolerated and no adverse events occurred during or after LITT; no secondary liver lesions were seen in the follow-up (11 or 12 months, respectively). Only minimal tumor growth was observed in the larger HCC (from 4 to 5 cm), whereas the smaller HCC remained unchanged in size during 11 months of follow-up. We conclude that LITT might be an effective minimally invasive palliative treatment option for patients with small unresectable HCC.

[High dosage Gd-DPTA-BMA (Gadodiamid) administration in diagnosis and therapeutic monitoring of malignant bone tumors]. / Hochdosierte Anwendung von Gd-DTPA-BMA (Gadodiamid) in der Diagnostik und Therapiebeurteilung maligner Knochentumoren.

PURPOSE: To evaluate the efficacy of high-dose Gd-DTPA-BMA (gadodiamide, Omniscan) as a contrast for magnetic resonance imaging of malignant bone tumors and the use of high-dose dynamic studies for predicting the response to pre-operative chemotherapy. MATERIALS AND METHODS: Examinations were performed in 22 patients with suspected malignant bone tumor on a 1.5 T system. In 8 cases a follow-up examination was done after preoperative chemotherapy. Static studies included Pd- and T2-weighted spin-echo sequences as well as T1-weighted spin-echo sequences, obtained pre- and post-contrast. Dynamic studies were performed using a FLASH 2D-gradient-echo sequence (TR 40 ms/TE 10 ms, 90 degrees flip angle) every 20 s after intravenous bolus injection of Gd-DTPA-BMA (0.3 mmol/kg body weight). MR images were evaluated qualitatively by visual assessment of conspicuity size, extraosseous delineation and structure of the lesion and quantitatively by measurement of the signal intensities and calculation of the relative increase in signal intensity. RESULTS: Qualitative image analysis showed best demonstration of the lesions on contrast-enhanced T1-weighted images. Comparison of T1-weighted pre- and postcontrast spin-echo sequences revealed significantly better assessment of tumor structure after administration of contrast media. After preoperative chemotherapy, all responders showed a markedly stronger reduction in relative increase in signal intensity in dynamic studies compared to nonresponders. CONCLUSION: Gd-DTPA-BMA is effective for magnetic resonance imaging of musculoskeletal lesions and improves assessment of the tumor structure. Dynamic studies may help to predict the response to preoperative chemotherapy.