A pilot study of a new therapeutic approach in the treatment of locally advanced stages of rectal cancer: neoadjuvant radiation, chemotherapy and regional hyperthermia.

The synergistic effects of hyperthermia (temperatures > or = 41 degrees C) when combined with radiotherapy or cytotoxic drugs, as well as a modulation of tumour-related immunological phenomena have been demonstrated preclinically. Local or regional hyperthermia in combination with radiation or chemotherapy has been studied in patients during recent years, and has convincingly demonstrated that hyperthermia is feasible and tolerated by patients. Furthermore, there is strong evidence that hyperthermia may provide an improvement in local control as compared with radiotherapy or chemotherapy alone. Systems based on radiowave irradiation allow sufficiently tolerable and effective regional hyperthermic therapy in patients with rectal carcinomas. Used as part of curative pre-operative and postoperative multimodal therapeutic strategies in high-risk patients with locally advanced rectal carcinomas, hyperthermia may result in improved local control and a higher rate of sphincter-sparing procedures. 20 patients with non-resectable, locally advanced primary or recurring rectal carcinoma T3/4 entered a phase I/II study of pre-operative radiochemothermotherapy with folinic acid and 5-fluorouracil, radiation (45 Gy HD), as well as regional hyperthermia once a week followed by chemotherapy after surgery. The regimen proved to be sufficiently tolerable. Acute grade III or IV toxicities did not occur after hyperthermia. Tumour resections were performed on 14 of the 20 patients, with 13 being complete. In 9 of the carcinomas, downstaging compared with the pretherapeutic stage was achieved. In 3 of 6 patients with persistent non-resectable tumours, local control has now been maintained for more than 12 months. One patient progressed locally during neoadjuvant combination therapy. These results prompted the initiation of a prospective randomised study to evaluate the relative importance of regional hyperthermia in this setting.

Hyperthermia in the multimodal therapy of advanced rectal carcinomas.

The synergistic effects of hyperthermia (raising temperatures to 40 degrees C and above) when combined with radiotherapy and cytotoxic drugs and a modulation of immunological phenomena have been demonstrated in the laboratory. Pre-clinical data relating to hyperthermia are summed up, along with their implications for clinical application. Controlled studies of local and regional hyperthermia have been performed during recent years, and these show us that the adjunction of hyperthermia provides at least an improvement of local control compared with radiotherapy alone. Current clinical results are summarized. Therapy systems based on radiowave irradiation have been commercially available for regional hyperthermia of the pelvis since the mid 1980s. This technology allows us to perform sufficiently tolerable and effective regional hyperthermia on rectal carcinomas. Used as part of curative preoperative and postoperative multimodal therapeutic strategies, hyperthermia can lead to improvement in local control (resectability, down-staging, progression-free time, recurrence rate), at least for certain risk groups. The preoperative radio-chemo-thermotherapy of advanced primary and recurring rectal carcinoma, uT3/4, was tested in a phase-I/II study of 20 patients. Therapy procedure, acute toxicity, thermal parameters, and response are described and discussed for this patient group. The regimen proved to be sufficiently tolerable, and complications did not occur. Tumor resection was performed on 14 of the 20 patients; 13 of the procedures were R0-resections and one was an R2 resection. In 64% of the resected rectal carcinomas, histopathological down-staging of the pretherapeutic endosonographical stadium was achieved; in three of the patients, despite continued non-resectability, local control has now been maintained for more than 12 months. In two patients with nonresectable rectal carcinomas, local progress was seen during the neoadjuvant combination therapy.

[MR tomography of the liver at 1.5 tesla. The value of T1-weighted imaging with a fast multislice gradient-echo sequence during respiratory standstill]. / MR-Tomographie der Leber bei 1,5 Tesla. Wertigkeit der T1-gewichteten Bildgebung mit schneller Mehrschicht-Gradientenecho-Sequenz während Atemstillstand.

The diagnostic value of a fast multislice gradient-echo sequence was compared with that of conventional spin-echo sequences in a prospective study of 76 patients. With the multislice gradient-echo sequence, the entire liver can be examined in less than 3 minutes since five sections can be imaged during one breath-holding period. The strongly T1-weighted gradient-echo sequence (GRE 100/5/80 degrees) yields a significantly better T1-contrast than the T1-weighted spin-echo sequence (SE 500/15) (p less than 0.01) and thus improves the visualization of liver lesions. Another major advantage of the fast gradient-echo sequence is the pronounced reduction of motion artefacts.

Li-O2 Kinetic Overpotentials: Tafel Plots from Experiment and First-Principles Theory.

We report the current dependence of the fundamental kinetic overpotentials for Li-O2 discharge and charge (Tafel plots) that define the optimal cycle efficiency in a Li-air battery. Comparison of the unusual experimental Tafel plots obtained in a bulk electrolysis cell with those obtained by first-principles theory is semiquantitative. The kinetic overpotentials for any practical current density are very small, considerably less than polarization losses due to iR drops from the cell impedance in Li-O2 batteries. If only the kinetic overpotentials were present, then a discharge-charge voltaic cycle efficiency of ∼85% should be possible at ∼10 mA/cm(2) superficial current density in a battery of ∼0.1 m(2) total cathode area. We therefore suggest that minimizing the cell impedance is a more important problem than minimizing the kinetic overpotentials to develop higher current Li-air batteries.

Twin Problems of Interfacial Carbonate Formation in Nonaqueous Li-O2 Batteries.

We use XPS and isotope labeling coupled with differential electrochemical mass spectrometry (DEMS) to show that small amounts of carbonates formed during discharge and charge of Li-O2 cells in ether electrolytes originate from reaction of Li2O2 (or LiO2) both with the electrolyte and with the C cathode. Reaction with the cathode forms approximately a monolayer of Li2CO3 at the C-Li2O2 interface, while reaction with the electrolyte forms approximately a monolayer of carbonate at the Li2O2-electrolyte interface during charge. A simple electrochemical model suggests that the carbonate at the electrolyte-Li2O2 interface is responsible for the large potential increase during charging (and hence indirectly for the poor rechargeability). A theoretical charge-transport model suggests that the carbonate layer at the C-Li2O2 interface causes a 10-100 fold decrease in the exchange current density. These twin "interfacial carbonate problems" are likely general and will ultimately have to be overcome to produce a highly rechargeable Li-air battery.

Limitations in Rechargeability of Li-O2 Batteries and Possible Origins.

Quantitative differential electrochemical mass spectrometry (DEMS) is used to measure the Coulombic efficiency of discharge and charge [(e(-)/O2)dis and (e(-)/O2)chg] and chemical rechargeability (characterized by the O2 recovery efficiency, OER/ORR) for Li-O2 electrochemistry in a variety of nonaqueous electrolytes. We find that none of the electrolytes studied are truly rechargeable, with OER/ORR <90% for all. Our findings emphasize that neither the overpotential for recharge nor capacity fade during cycling are adequate to assess rechargeability. Coulometry has to be coupled to quantitative measurements of the chemistry to measure the rechargeability truly. We show that rechargeability in the various electrolytes is limited both by chemical reaction of Li2O2 with the solvent and by electrochemical oxidation reactions during charging at potentials below the onset of electrolyte oxidation on an inert electrode. Possible mechanisms are suggested for electrolyte decomposition, which taken together, impose stringent conditions on the liquid electrolyte in Li-O2 batteries.

Multisection FLASH: method for breath-hold MR imaging of the entire liver.

One hundred ten patients with various focal liver lesions were imaged with a multisection fast low-angle shot (FLASH) gradient-echo sequence with an echo time of 4.6 msec. This sequence enabled the acquisition of 19 T1-weighted magnetic resonance (MR) images of the liver within a single 26-second breath hold. Patients were also examined with standard T1- and T2-weighted spin-echo (SE) sequences. The multisection FLASH sequence provided significantly higher (P less than .01) liver-spleen contrast, liver-spleen signal-difference-to-noise ratio (SD/N), liver-tumor contrast, and liver-tumor SD/N than the T1-weighted SE sequence but lower values than the T2-weighted SE sequence. Motion artifacts were reduced with the multisection FLASH sequence compared with both SE sequences (P less than .01). The overall image quality of the multisection FLASH images was similar to that of the T1-weighted SE images and superior to that of T2-weighted SE images. The most important characteristics of the multisection FLASH technique in MR imaging of the liver are the high T1 contrast, the prevention of motion artifacts, and a dramatic reduction in imaging time.

T2-weighted breath-hold MR imaging of the liver at 1.5 T: results with a three-dimensional steady-state free precession sequence in 87 patients.

PURPOSE: To evaluate a fast three-dimensional (3D) sequence that permits the acquisition of 16 T2-weighted images within a 29-second breath hold for magnetic resonance (MR) imaging of the liver. MATERIALS AND METHODS: Eighty-seven patients with focal liver lesions were examined at 1.5 T by using a 3D reversed fast imaging with steady-state precession (PSIF) sequence at flip angles of 15 degrees, 30 degrees, and 70 degrees and a T2-weighted spin-echo (SE) sequence. Quantitative and qualitative image analysis was performed. RESULTS: Contrast and signal difference-to-noise ratios were 56% and 33% (liver-spleen) and 76% and 68% (liver-tumor), respectively, with the 3D-PSIF sequence compared with the T2-weighted SE sequence. With 3D-PSIF, overall image quality was poorer than that of the T2-weighted SE sequence at flip angles of 15 degrees but was similar at 30 degrees and 70 degrees. At low flip angles (15 degrees and 30 degrees) all lesion types were hyperintense. At a flip angle of 70 degrees, it was predominantly cysts and hemangiomas that showed high signal intensity. With the 3D-PSIF sequence, intrahepatic vessels are void of signal and can be better distinguished from small liver lesions compared with the flow-compensated T2-weighted SE sequence. CONCLUSION: The fast 3D-PSIF sequence is a valuable addition to MR imaging of the liver.

Liver metastases: improved detection with dynamic gadolinium-enhanced MR imaging?

PURPOSE: To compare dynamic gadolinium-enhanced with unenhanced magnetic resonance (MR) imaging in detection of liver metastases. MATERIALS AND METHODS: Two groups of patients were prospectively examined with unenhanced and dynamic gadolinium-enhanced MR imaging. The first group (n = 48) had proved liver metastases; the second group (n = 49) did not. One set of unenhanced and one set of gadolinium-enhanced MR images were selected per patient. Three independent, blinded readers assessed the images for presence, number, location, and conspicuity of lesions. Data were analyzed with receiver operating characteristic curves, and contrast-to-noise ratios were calculated for the images. RESULTS: There was no statistically significant difference between the use of unenhanced and gadolinium-enhanced MR images in the differentiation of patients with from patients without metastases. The numbers of false-positive and false-negative diagnoses of individual lesions were higher (not statistically significant) with dynamic MR images than with unenhanced MR images. At dynamic MR imaging, contrast-to-noise ratio was highest in the early phase (30 seconds after injection of the contrast agent) but was not significantly different from the contrast-to noise ratio of the T2-weighted images. CONCLUSION: Dynamic gadolinium-enhanced MR imaging showed no improvement over unenhanced MR imaging in detectability of liver metastases.

Contrast-enhanced MR imaging of liver and spleen: first experience in humans with a new superparamagnetic iron oxide.

The aim of this prospective study was to obtain the first human safety and magnetic resonance (MR) imaging results with a new formulation of superparamagnetic iron oxide (SPIO) (SHU 555 A). The SPIO was tested at four iron doses, from 5 to 40 mumol/kg. Laboratory tests and clinical measurements were done in 32 healthy volunteers for up to 3 weeks after administration. MR imaging at 1.5 T was performed before and 8 hours to 14 days after fast intravenous injection (500 mumol Fe/min) of the SPIO (six subjects per dose). Results of this phase I study demonstrate that SHU 555 A at a concentration of 0.5 mol Fe/L was well tolerated. A dose-dependent minor increase in activated partial thromboplastin time, which remained within the normal range, was seen. All doses of SPIO caused a signal loss in both liver and spleen (P < .05) with a spin-echo sequence (TR = 2,300 msec, TE = 45 msec). The signal losses in the liver 8 hours after contrast agent injection were 58%, 79%, 82%, and 87% for the 5, 10, 20, and 40 mumol Fe/kg doses, respectively. The corresponding signal losses in the spleen were 23%, 45%, 65%, and 78%, respectively. The doses that reduced signal intensity by half were 3.1 mumol Fe/kg for the liver and 12.8 mumol Fe/kg for the spleen. The results suggest that the new SPIO formulation is a safe and efficient MR contrast agent.

Preoperative hyperthermia combined with radiochemotherapy in locally advanced rectal cancer: a phase II clinical trial.

OBJECTIVE: A prospective phase II study was performed to determine the feasibility and efficacy in terms of response rate, resectability, and morbidity in patients with locally advanced rectal cancer who received preoperative regional hyperthermia combined with radiochemotherapy (HRCT). SUMMARY BACKGROUND DATA: Recent studies suggest that preoperative radiochemotherapy in locally advanced rectal cancer can induce downstaging, but after resection the incidence of local recurrences remains high. Hyperthermia (HT) may add tumoricidal effects and improve the efficacy of radiochemotherapy in a trimodal approach. PATIENTS AND METHODS: Thirty-seven patients with histologically proven rectal cancer and T3 or T4 lesions, as determined by endorectal ultrasound and computed tomography, entered the trial. 5-Fluorouracil (300-350 mg/m2) and leucovorin (50 mg) were administered on days 1 to 5 and 22 to 26. Regional HT using the SIGMA 60 applicator (BSD-2000) was given once a week before radiotherapy (45 Gy with 1.8-Gy fractions for 5 weeks). Surgery followed 4 to 6 weeks after completion of HRCT. RESULTS: Preoperative treatment was generally well tolerated, with 16% of patients developing grade III toxicity. No grade IV complications were observed. The overall resectability rate was 32 of 36 patients (89%), and 31 resection specimens had negative margins (R0). One patient refused surgery. In 5 patients (14%), the histopathologic report confirmed no evidence of residual tumor (pCR). A partial remission (PR) was observed in 17 patients (46%). The survival rate after 38 months was 86%. In none of the patients was local recurrence detected after R0(L), but five patients developed distant metastases. CONCLUSION: Preoperative HRCT is feasible and effective and may contribute to locoregional tumor control of advanced rectal cancer, which is to be proven in an ongoing phase III trial.