Changes in hepatic blood flow during whole body hyperthermia.

PURPOSE: Changes in blood flow distribution are important for heat dispersion and for supportive therapeutic strategies such as simultaneous whole body hyperthermia (WBH) and administration of chemotherapy. The aim of this clinical study was to determine changes in hepatic blood flow during WBH for the treatment of metastatic cancer. MATERIALS AND METHODS: This observational clinical study was part of a phase I/II feasibility study of WBH. WBH was induced using a radiant heat device. Hepatic blood flow was estimated using indocyanine green clearance measurements. The plasma disappearance rate of indocyanine green (PDR-ICG) was recorded in percent/min. We used an invasive thermo-dye-dilution technique to estimate hepatic blood flow, cardiac output, and volume status. Mean arterial blood pressure was also measured invasively. To determine the effects of hyperthermia the measurements were performed at defined temperature points. RESULTS: In 10 of 22 treatments the PDR-ICG fell below normal values during hyperthermia, which represented a significant fall in hepatic blood flow. Cardiac output, volume status, and mean arterial blood pressure did not differ between patients whose liver blood flow was reduced and those whose liver blood flow remained unchanged. CONCLUSIONS: We observed distinct reductions in hepatic blood flow during WBH, which suggested a significant redistribution of blood flow away from the core during WBH. This was not mirrored by global circulatory parameters.

The effect of induced hyperthermia on the immune system.

Therapeutical hyperthermia has been considered for cancer therapy since William Coley observed tumour remission after induction of fever by bacterial toxins at the end of the 19th century. Because fever is associated with a variety of immunological reactions, it has been suspected, that therapeutical hyperthermia might also activate the immune system in a reproducible manner and thereby positively influence the course of the disease. During the last decade, new insight has been gained regarding the immunological changes taking place during therapeutic hyperthermia. In this chapter, we review the most relevant data known about the effect of hyperthermia on the immune system with special focus on alterations induced by therapeutical whole-body hyperthermia (WBH) in cancer patients.

Radiochemotherapy combined with regional pelvic hyperthermia induces high response and resectability rates in patients with nonresectable cervical cancer > or =FIGO IIB "bulky".

PURPOSE: To evaluate preoperative radiochemotherapy combined with regional pelvic hyperthermia in patients with nonresectable cervical cancer >/= International Federation of Gynecology and Obstetrics (FIGO) IIB "bulky" in a Phase II study. METHODS AND MATERIALS: Thirty-two patients with nonresectable FIGO IIB-IVA cervical cancer confined to the pelvis were treated with radiochemotherapy (5 x 1.8 Gy/wk, 45-50.4 Gy; cisplatin, 40 mg/m2/wk) and weekly regional pelvic hyperthermia (SIGMA-60 applicator, system BSD-2000; BSD Medical Corp., Salt Lake City, UT). Responders underwent hysterectomy if possible, whereas patients still unresectable received definitive hyperthermic radiochemotherapy. Feasibility, toxicity, as well as response and resectability, local progression free- and overall survival rates, were evaluated. RESULTS: Thirty of 32 patients completed treatment. Grade III/IV toxicities (National Cancer Institute-Common Toxicity Criteria) were diarrhea (n = 5), weight loss >10 kg (n = 4), and nausea (n = 2). Twenty-four of 32 patients (75%) achieved a partial remission after 45-50 Gy, and 20 patients underwent hysterectomy (18 patients, R0; 8 patients pCR). Three-year overall survival was 60%, with moderate (13%) rates of severe late toxicity. R0-resected patients had a favorable chronic toxicity profile and an excellent prognosis (3-year survival rate: 93%). Response depended on thermal parameters (vaginal reference point), whereas response, R0-resection, and FIGO stage are significant prognostic factors for survival. CONCLUSION: Preoperative hyperthermic radiochemotherapy (45-50 Gy) induces high response rates and enables curative surgery in a high proportion of patients with nonresectable cervical cancer. Therefore, the use of hyperthermia in conjunction with standard chemo-/radiotherapy +/- surgery may allow for more effective tumor treatment while decreasing the risk of complications in patients with locally advanced cervical cancer.

Noninvasive magnetic resonance thermography of soft tissue sarcomas during regional hyperthermia: correlation with response and direct thermometry.

BACKGROUND: The objective of this study was to evaluate noninvasive magnetic resonance (MR) thermography for the monitoring of regional hyperthermia (RHT) in patients with soft tissue sarcomas of the lower extremities and pelvis. METHODS: Noninvasive MR monitoring during RHT was performed in 9 patients who had high-risk soft tissue sarcomas of the lower extremities or pelvis during neoadjuvant chemotherapy plus RHT in the scope of the European Organization for Research and Treatment of Cancer 62961/European Society for Hyperthermic Oncology RHT-95 study. Anatomic and temperature-sensitive data sets were acquired every 10 minutes before and during RHT (using gradient-echo-sequences with variable echo times). MR temperature distributions were derived from the phase differences by using the proton-resonance frequency shift method. A phase convolution setting phase shifts to zero in the fat tissue was performed as a drift correction. The mean MR temperatures in the tumor and muscles and the index temperatures (e.g., T90, which covers 90% of the target volume) and thermal doses were determined and compared with pathohistologic responses and direct temperature measurements if available. RESULTS: Thirty of 72 MR-thermography data sets (>40% of heat sessions) were evaluable. A significant correlation was observed between pathohistologic response (defined as a necrosis rate >or=90%) and standardized thermal parameters, such as thermal dose cumulative equivalent minutes at 43 degrees C to 90% of the target volume (T90) (P = .050), mean T90 (P = .048), or T50 (P = .050). The correlation of 13 conventional temperature measurements performed in selected patients and sessions invasively in the tumor or noninvasively in rectum and bladder revealed an excellent correlation with MR temperatures (R2 = .96). CONCLUSIONS: Noninvasive MR thermography of soft tissue sarcoma was feasible and suitable for validating the quality of heating during RHT.

Thermal monitoring: invasive, minimal-invasive and non-invasive approaches.

BACKGROUND: Thermal treatments need verification of effectiveness. Invasive intra-tumoural thermometry was established as a standard method several years ago. However, in deep heating, invasive techniques have disadvantages. Therefore, alternatives have been suggested and are under development. METHODS: In three phase II studies treating rectal cancer, cervical cancer and prostate cancer, this study replaced invasive (intra-tumoural) thermometry by tumour-related reference points or catheter sections in the rectum, vagina or urethra. Index temperatures and thermal dose parameters were determined. Two recent studies treated patients with recurrent rectal cancer and soft tissue sarcoma using non-invasive MR-thermometry employing the SIGMA-Eye applicator. The proton resonance frequency shift (PRFS) method was employed to generate MR-temperature distributions during the entire heat treatment in 10 min intervals (via phase differences). Fat correction (nulling specified regions in the fat tissue) was utilized to calibrate the method, in particular with respect to the B0-drift. RESULTS: Statistically significant correlations were found between response (downstaging, WHO) and thermal parameters in rectal cancer (37 patients, rectum measurement, T90, cum min T90 >or= 40.5 degrees C) and cervical cancer (30 patients, vagina, mean temperature and equ min 43 degrees C in a reference point). In prostate cancer (14 patients), a clear correlation was verified between long-term PSA control (or= 40.5 degrees C). The mean MR-temperature in the tumour at steady-state as well as the mean T90 were significantly correlated with response for recurrent rectal carcinoma regarding palliation and analgesia (15 patients) and with pathohistological regression rate in soft tissue sarcoma (nine patients). CONCLUSIONS: For tumours in the pelvis and in the lower extremities, invasive measurements can be replaced by minimally-invasive or non-invasive techniques, which provide equivalent or even more complete information. Extending the application of these surveillance methods to abdominal tumours or liver metastases is a challenge, but strongly desirable for clinical reasons.

Genetic dissection of apoptosis and cell cycle control in response of colorectal cancer treated with preoperative radiochemotherapy.

BACKGROUND: In previous analyses we identified therapy-induced upregulation of the CDK inhibitor p21CIP/WAF-1 and consequently decreased tumor cell proliferation or loss of Bax as adverse factors for survival in rectal cancer treated with radiochemotherapy. Here, we address the individual role of p53 and its transcriptional targets, p21CIP/WAF-1 and Bax, on apoptosis induced by individual components of multimodal anticancer therapy, i.e. 5-fluorouracil (5-FU), ionising gamma-radiation (IR) and heat shock/hyperthermia. METHODS: We analysed tumor samples 66 patients with rectal carcinoma treated by a neoadjuvant approach with radiochemotherapy +/- heat shock/hyperthermia for the expression and mutation of p53 and the expression of p21CIP/WAF-1 and Bax. These data were correlated with the tumor response. The functional relevance of p53, p21CIP/WAF-1 and Bax was investigated in isogeneic HCT116 cell mutants treated with 5-FU, IR and heat shock. RESULTS: Rectal carcinoma patients who received an optimal heat shock treatment showed a response that correlated well with Bax expression (p = 0.018). Local tumor response in the whole cohort was linked to expression of p21CIP/WAF-1 (p < 0.05), but not p53 expression or mutation. This dichotomy of p53 pathway components regulating response to therapy was confirmed in vitro. In isogeneic HCT116 cell mutants, loss of Bax but not p53 or p21CIP/WAF-1 resulted in resistance against heat shock. In contrast, loss of p21CIP/WAF-1 or, to a lesser extent, p53 sensitized predominantly for 5-FU and IR. CONCLUSION: These data establish a different impact of p53 pathway components on treatment responses. While chemotherapy and IR depend primarily on cell cycle control and p21, heat shock depends primarily on Bax. In contrast, p53 status poorly correlates with response. These analyses therefore provide a rational approach for dissecting the mode of action of single treatment modalities that may be employed to circumvent clinically relevant resistance mechanisms in rectal cancer.

Adjuvant chemotherapy with folinic acid and 5-fluorouracil in patients with locally advanced rectal cancer previously treated by preoperative radiochemotherapy and curative tumor resection.

BACKGROUND AND AIMS: The role of postoperative adjuvant chemotherapy in patients with rectal cancer pretreated by preoperative radiochemotherapy (RCT) and curative surgery is still poorly investigated. PATIENTS AND METHODS: We pooled data from both arms of a phase III trial in which patients with locally advanced (T3/4) rectal cancer were randomized to preoperative RCT alone or combined with pelvic radio-frequency hyperthermia. After surgery, R0-resected patients were scheduled to adjuvant chemotherapy with four monthly courses of 50 mg folinic acid (FA) and gradually escalated 5-fluorouracil (5-FU, 350-500 mg/m2, days 1-5). Reasons preventing initiation of chemotherapy and treatment-related toxicities were evaluated. Patients' characteristics and survival parameters were compared between the treated and untreated patient groups. RESULTS: Out of 93 patients, 73 (79%) started adjuvant chemotherapy, whereas 19 (21%) did not, mostly due to perioperative complications and refusal. Chemotherapy-related toxicities were mild to moderate in most cases, but--together with protracted postoperative complications--prevented the intended dose escalation of 5-FU in 71% of patients. Distant-failure-free (p=0.03) and overall survival (p=0.03) were improved in the chemotherapy group, although there was a negative selection of patients with unfavourable characteristics into the untreated patient group. INTERPRETATION/CONCLUSION: Adjuvant chemotherapy using FA and 5-FU can be safely applied to the majority of patients with rectal cancer pretreated by RCT and surgery. Survival data are not suitable to allow far-reaching conclusions, but are in line with suggestions of a favourable effect of adjuvant chemotherapy in these patients.

Differential gene expression in peripheral blood lymphocytes of cancer patients treated with whole body hyperthermia and chemotherapy: a pilot study.

PURPOSE: The effect of whole body hyperthermia (WBH) at 41.8-42 degrees C on the cellular immune system is still poorly investigated. The aim of this study was to identify genes that become upregulated in peripheral blood lymphocytes (PBLs) of cancer patients during a combined treatment with WBH and chemotherapy by generating complex arrays of cDNA. METHODS: PBLs were obtained from four patients with different malignancies treated with WBH and varying cytostatic schedules before treatment and immediately thereafter. After constructing subtracted cDNA libraries, clones were screened for cDNA induction by dot-blot and semi-quantitative RT-PCR (sq-RT-PCR). RESULTS: Among 192 clones, 39 cDNAs were significantly upregulated. Sequencing revealed three groups of genes for which upregulation of mRNA was confirmed by sq-RT-PCR. The first group consisted of genes encoding for various heat shock proteins (HSP 60, 90a, 90b, 105). Further sq-RT-PCR demonstrated differential expression of HSP27 and HSP70 as well. The second group (calcyclin-binding-protein, haemoglobin-beta-chain) comprised genes without pre-specified association to hyperthermia. The cDNA encoding macrophage-inflammatory-protein-1-beta was also observed and may be associated with the pre-described activation of lymphocyte sub-populations during WBH. CONCLUSION: Treatment with WBH and chemotherapy elicits significant short-term effects on the expression of a variety of genes responsible for cellular integrity, stimulation and migration of immune effector cells. Further investigation is warranted to more clearly define the role of those genes for the clinical effect of WBH.

Stress induced changes in lymphocyte subpopulations and associated cytokines during whole body hyperthermia of 41.8-42.2 degrees C.

Extreme acute physical stress leads to transient impairment of T-lymphocytes, which are essential for tumor defence and prevention of infectious diseases. Radiant whole body hyperthermia (WBH) at 41.8-42.2 degrees C may enhance the efficacy of systemic chemotherapy in patients with advanced malignancies, but is associated with marked physical stress. Aim of this study was to demonstrate stress induced short-time effects on lymphocyte subpopulations and associated cytokines during WBH. Total leukocyte count, white blood cell differential blood count, lymphocyte subpopulations (T-helper-/T4-cells, T-suppressor-/T8-cells, natural-killer-/NK-cells, gammadelta-T-cells) as well as plasma levels of Interleukin(IL)-10, IL-12 and Interferon-gamma (IFN-gamma) were measured in ten patients treated with WBH and additional cytostatic chemotherapy. Blood samples were drawn before treatment, at three temperature points during WBH, and 24 h after start of treatment. Results were compared with those obtained from a control group consisting of six patients receiving chemotherapy alone. Numbers of T4-cells decreased significantly during WBH, while numbers of NK-cells and gammadelta-T-cells increased, resulting in transient impairments of total lymphocyte counts and T4/T8-ratio. IL-12 plasma levels as well as IFN-gamma/IL-10-ratio also decreased during WBH. No significant changes were found in T8-cells of WBH patients. Changes were reversible within 24 h and could not been found in control patients. Our results support the hypothesis that WBH combined with chemo therapy induces a strong but reversible anti-inflammatory stress response in cancer patients during therapy. Further studies are necessary to examine the pathophysiological details and to evaluate the meaning of these transient immunological changes for patient's outcome.

Goal-directed therapy of cardiac preload in induced whole-body hyperthermia.

OBJECTIVES: To optimize volume therapy during induced whole-body hyperthermia (WBH) < or = 42.2 degrees C, pulmonary capillary wedge pressure (PCWP) and intrathoracic blood volume index (ITBVI) were compared as goal parameters. DESIGN: Prospective clinical study. SETTING: ICU at university hospital. PATIENTS: Twenty-three patients with metastatic cancers. INTERVENTIONS: Radiant WBH in combination with induced hyperglycemia, hyperoxemia, and chemotherapy was applied. Volume therapy was directed to the PCWP (group A, 8 to 12 mm Hg [20 treatments]), or to ITBVI (group B, 800 to 1,100 mL/m2 [19 treatments]) following a standardized protocol. Goals other than PCWP and ITBVI were cardiac index of > 3.5 L/min/m2 and mean arterial pressure of > 55 mm Hg. MEASUREMENTS AND RESULTS: In addition to the primary goals PCWP and ITBVI, at defined temperatures, central venous pressure (CVP), extravascular lung water index, the number of infusions, and packed RBCs, as well as serum lactate level, norepinephrine dosage, and levels of liver enzymes, bilirubin, creatinine, and urea were measured. Patients in group A received a significantly greater mean (+/- SD) amount of crystalloids compared to those in group B (6,175 +/- 656 vs 3,947 +/- 375 mL, respectively) and required significantly lower dosages of vasoconstrictors compared with patients in group B. Except for the lower values of CVP in patients in group A during hyperthermia, all of the other hemodynamic and laboratory parameters showed no significant differences between the groups or stayed in a normal range. CONCLUSION: PCWP and ITBVI are useful parameters to assess preload in induced WBH. Differences in crystalloids and vasopressor dosages may suggest an appropriate ITBVI of > 1,100 mL/m2 for patients with good cardiopulmonary health under such extremely hypercirculatory conditions.

Noninvasive magnetic resonance thermography of recurrent rectal carcinoma in a 1.5 Tesla hybrid system.

To implement noninvasive thermometry, we installed a hybrid system consisting of a radiofrequency multiantenna applicator (SIGMA-Eye) for deep hyperthermia (BSD-2000/3D) integrated into the gantry of a 1.5 Tesla magnetic resonance (MR) tomograph Symphony. This system can record MR data during radiofrequency heating and is suitable for application and evaluation of methods for MR thermography. In 15 patients with preirradiated pelvic rectal recurrences, we acquired phase data sets (25 slices) every 10 to 15 minutes over the treatment time (60-90 minutes) using gradient echo sequences (echo time = 20 ms), transformed the phase differences to MR temperatures, and fused the color-coded MR-temperature distributions with anatomic T1-weighted MR data sets. We could generate one complete series of MR data sets per patient with satisfactory quality for further analysis. In fat, muscle, water bolus, prostate, bladder, and tumor, we delineated regions of interest (ROI), used the fat ROI for drift correction by transforming these regions to a phase shift zero, and evaluated the MR-temperature frequency distributions. Mean MR temperatures (T(MR)), maximum T(MR), full width half maximum (FWHM), and other descriptors of tumors and normal tissues were noninvasively derived and their dependencies outlined. In 8 of 15 patients, direct temperature measurements in reference points were available. We correlated the tumor MR temperatures with direct measurements, clinical response, and tumor features (volume and location), and found reasonable trends and correlations. Therefore, the mean T(MR) of the tumor might be useful as a variable to evaluate the quality and effectivity of heat treatments, and consequently as optimization variable. Feasibility of noninvasive MR thermography for regional hyperthermia has been shown and should be further investigated.

Regional hyperthermia in conjunction with definitive radiotherapy against recurrent or locally advanced prostate cancer T3 pN0 M0.

BACKGROUND AND PURPOSE: Since long-term results of the standard treatment of locally advanced or recurrent prostatic carcinoma are unsatisfactory, the role for additional regional hyperthermia was evaluated in a phase I/II study. PATIENTS AND METHODS: From 08/1996 to 03/2000, 22 patients were treated by a standard irradiation regimen (68.4 Gy) in combination with regional hyperthermia (weekly, five to six times), and five of 22 patients received short-term (neoadjuvant) hormonal treatment. Of these, 15 patients had primary prostatic carcinoma T3 pN0 M0 and seven a histologically confirmed local recurrence after radical prostatectomy. Feasibility of hyperthermia, and acute/late toxicity as well as long-term follow-up (prostate- specific antigen [PSA] control, overall survival) were analyzed. Clinical endpoints were correlated with thermal parameters. RESULTS: Mean maximum temperatures along the urethra of 41.4 degrees C (41.0 degrees C for the recurrences), and mean T(90) values of 40.7 degrees C could be achieved. Severe acute toxicity of grade 3 occurred at the rectum in three, at the urethra in four, at the intestine in one, and a burn induced by hyperthermia in one of 22 patients. Late toxicity was only observed rectally in one patient (grade 3) and at the urethra in two patients (grade 2). There was no correlation between thermal parameters and any toxicity. The survival curves showed a PSA control for primary prostatic carcinoma > 50% after 6 years, but no long-term PSA control for the recurrences. Overall survival after 6 years was 95% for primary carcinoma, and 60% for the recurrences. There was a clear correlation between higher temperatures or thermal doses with long-term PSA control. CONCLUSION: Regional hyperthermia might be a low-toxicity approach to increase PSA control of common treatment schedules. Further evaluation, in particular employing improved hyperthermia technology, is worthwhile.

Hepatic arterial port systems for treatment of liver metastases: factors affecting patency and adverse events.

PURPOSE: To assess the outcome of interventional hepatic arterial port placement in a prospective phase II trial. MATERIALS AND METHODS: One-hundred five consecutive patients were included in this study. Primary endpoint was port patency; secondary endpoints were complications, toxicity, response, and progression free and overall survival. Seventy-eight patients presented with liver metastasis only, 6 patients had additional minor extrahepatic disease, and 21 patients had no evidence of disease after liver resection, laser-induced thermotherapy, or computed tomography (CT)-guided interstitial brachytherapy of liver metastasis. Exclusive access route was the femoral artery. Subgroup analysis compared either 4-F catheters (n = 58) to 2.2-F (n = 33) and 2.7-F (n = 20) microcatheters or different strategies in anatomic variants of the celiac branch: neglect (n = 10) or embolization of minor hepatic feeders (n = 11), splenic arterial port (n = 8), double port (n = 7). RESULTS: Technical success was 99%. Assisted port patency after 6 months was 93%. Complications demanding port revisions were significantly lower in patients receiving 4-F versus 2.2-F and 2.7-F systems (P <.001), with disconnection as the major problem with use of microcatheters. Hepatic artery thrombosis occurred in 10 patients (9%), with successful lysis in two patients. With use of 4-F and 2.2-F catheters, there was no difference with respect to catheter occlusion or hepatic thrombosis. No differences were noted in complications or outcome applying four different strategies in celiac branch variants. In a subgroup of patients receiving folinic acid/5-fluorouracil (170 mg/600 mg; 10% dose escalation per cycle) for 5 days every 4 weeks only 15% experienced Grade 3 toxicity. Patients with liver metastasis and salvage therapy demonstrated progression-free survival of 63% after 6 months and a median survival of 16 months. CONCLUSION: Interventional placement of hepatic arterial port systems may overcome frequent hepatic arterial chemotherapy failures as encountered in all published major trials on hepatic arterial infusion.

Description and characterization of the novel hyperthermia- and thermoablation-system MFH 300F for clinical magnetic fluid hyperthermia.

Magnetic fluid hyperthermia (MFH) is a new approach to deposit heat power in deep tissues by overcoming limitations of conventional heat treatments. After infiltration of the target tissue with nanosized magnetic particles, the power of an alternating magnetic field is transformed into heat. The combination of the 100 kHz magnetic field applicator MFH 300F and the magnetofluid (MF), which both are designed for medical use, is investigated with respect to its dosage recommendations and clinical applicability. We found a magnetic field strength of up to 18 kA/m in a cylindrical treatment area of 20 cm diameter and aperture height up to 300 mm. The specific absorption rate (SAR) can be controlled directly by the magnetic field strength during the treatment. The relationship between magnetic field strength and the iron normalized SAR (SAR(Fe)) is only slightly depending on the concentration of the MF and can be used for planning the target SAR. The achievable energy absorption rates of the MF distributed in the tissue is sufficient for either hyperthermia or thermoablation. The fluid has a visible contrast in therapeutic concentrations on a CT scanner and can be detected down to 0.01 g/l Fe in the MRI. The system has proved its capability and practicability for heat treatment in deep regions of the human body.

[Standards and perspectives in locoregional hyperthermia]. / Lokoregionäre Hyperthermie: Standards und neue Entwicklungen.

The term "hyperthermia" summarises different procedures of raising the temperature of a tumour-loaded tissue to a temperature of 40-43 degrees C. In this context, locoregional procedures (radiative/capacitive local, interstitial and regional hyperthermia; endoluminal hyperthermia), hyperthermic perfusion techniques (hyperthermic peritoneal and isolated limb perfusion), and whole-body hyperthermia differ with regard to their indication, expenditure of application, and evidence of efficacy. All hyperthermia techniques have in common that they have no sufficient antineoplastic activity alone in the temperature range below 43-45 degrees C, but act in a synergistic way with radiotherapy and certain cytotoxic drugs. 14 out of 18 published randomised trials on hyperthermia as an adjunct to standard radio- or chemotherapy refer to locoregional approaches. Particular progress has been made in regional radiofrequency hyperthermia, where novel multiantenna-applicators and their integration into MR-applicators ("hybrid-systems") have recently been introduced into clinical practice. In addition, combinations of hyperthermia with novel technologies (magnetic fluid hyperthermia, thermosensitive liposomes, immunotherapy, gene targeting) are imminent. We here give a critical update on the proven indications of the different locoregional hyperthermia approaches and on the current clinical and technological progress in this field.

Repetitive transarterial chemoembolization (rTACE) of hepatocellular carcinoma: comparisons between an arterial port system and conventional angiographic technique.

PURPOSE: To compare the cost and radiation exposure of repetitive transarterial chemoembolization (rTACE) using percutaneously implantable port system with rTACE using conventional catheterization technique. MATERIALS AND METHODS: In five patients with unresectable hepatocellular carcinoma, three cycles of TACE were performed using conventional technique and six cycles using port. The cumulative cost of material and contrast agent and dose area product (DAP) were compared with the cost and DAP that would be expected if the rTACE was performed conventionally. RESULTS: The cost of material and contrast agent was 1002.6 Euro after three cycles of TACE using conventional technique and six cycles using port, but would be 1111.8 Euro if the nine cycles were performed using conventional technique alone. The rTACE with three cycles using conventional technique and six cycles using port led to approximately 63% of the cumulative DAP that would be expected in rTACE using conventional technique alone. CONCLUSION: In rTACE, the use of percutaneously implantable port system might enable a reduction of cost and radiation exposure.

Response prediction by FDG-PET after neoadjuvant radiochemotherapy and combined regional hyperthermia of rectal cancer: correlation with endorectal ultrasound and histopathology.

Accurate response assessment after neoadjuvant therapy is essential in patients with rectal cancer. The aim of this study was to assess the value of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting response of locally advanced rectal cancer to preoperative multimodal treatment. Twenty-two consecutive patients with locally advanced (uT3/4) primary rectal cancer were entered in this prospective pilot study. FDG-PET was performed before and after neoadjuvant radiochemotherapy (RCT) with combined regional hyperthermia (RHT). Treatment consisted of external-beam radiotherapy (45 Gy), chemotherapy (folinic acid and 5-fluorouracil) and regional pelvic hyperthermia followed by curative tumour resection 6-8 weeks later. Semi-quantitative measurements (SUV) of tumour FDG uptake were made before and 2-4 weeks after completion of neoadjuvant treatment. Two patients who did not receive post-therapeutic restaging by FDG-PET were excluded from the analysis. Results were correlated with findings on endorectal ultrasound (EUS, n=17 patients) and histopathology. Histopathological evaluation of the resected tumour revealed complete response in one patient, partial response in 12 and stable disease in seven. SUV reduction in tumours was significantly greater in responders than in non-responders [60% (+/-15%) vs 30% (+/-18%), P=0.003, CI=95%). Using a minimum post-therapeutic SUV reduction of 36% to define response, FDG-PET revealed a sensitivity of 100% (EUS: 33%) and a specificity of 86% (EUS: 80%) in response prediction; the corresponding positive and negative predictive values were 93% (EUS: 80%) and 100% (EUS: 33%), respectively. FDG-PET results were statistically significant (P<0.001, CI=95%). FDG-PET has great potential in the assessment of tumour response to neoadjuvant RCT in combination with RHT and is superior to EUS for this purpose.

Whole body hyperthermia induces apoptosis in subpopulations of blood lymphocytes.

Whole Body Hyperthermia (WBH) has been shown to induce alterations of lymphocyte subpopulations in peripheral blood: T-cells decrease and NK-cells increase in number in the course of this therapy. As elevated temperature induces programmed cell death in healthy lymphocytes in vitro, we intended to determine the role of lymphocyte apoptosis in WBH by measuring the rate of apoptosis in blood lymphocytes in the course of this treatment. Blood was taken from cancer patients, treated with whole body hyperthermia and chemotherapy, before, during and the day after treatment. Apoptosis rates of the whole lymphocyte population, as well as, of B-, T-, CD4 + -T-, CD8 + -T-, and Natural-Killer (NK)-cell-subpopulations were determined by staining with AnnexinV-FITC and FACS flow analysis. A significant rise of apoptosis in the whole lymphocyte population, in CD4 + -T- and in CD8 + -T-cells occurred during treatment. In contrast, an elevated rate of apoptosis in NK-cells was observed 20 hours after termination of WBH. These differences were similar when the cells were incubated at 37 degrees C for 24 hours. Our results suggest, that apoptosis is one reason for the previously described decrease of T-cells during WBH and of NK-cells after WBH, and that the hyperthermia-related apoptosis-inducing mechanism is different in T-cells and NK-cells.

The cellular and molecular basis of hyperthermia.

In oncology, the term 'hyperthermia' refers to the treatment of malignant diseases by administering heat in various ways. Hyperthermia is usually applied as an adjunct to an already established treatment modality (especially radiotherapy and chemotherapy), where tumor temperatures in the range of 40-43 degrees C are aspired. In several clinical phase-III trials, an improvement of both local control and survival rates have been demonstrated by adding local/regional hyperthermia to radiotherapy in patients with locally advanced or recurrent superficial and pelvic tumors. In addition, interstitial hyperthermia, hyperthermic chemoperfusion, and whole-body hyperthermia (WBH) are under clinical investigation, and some positive comparative trials have already been completed. In parallel to clinical research, several aspects of heat action have been examined in numerous pre-clinical studies since the 1970s. However, an unequivocal identification of the mechanisms leading to favorable clinical results of hyperthermia have not yet been identified for various reasons. This manuscript deals with discussions concerning the direct cytotoxic effect of heat, heat-induced alterations of the tumor microenvironment, synergism of heat in conjunction with radiation and drugs, as well as, the presumed cellular effects of hyperthermia including the expression of heat-shock proteins (HSP), induction and regulation of apoptosis, signal transduction, and modulation of drug resistance by hyperthermia.