Efficacy and quality of life for FOLFOX/bevacizumab +/- irinotecan in first-line metastatic colorectal cancer-final results of the AIO CHARTA trial.

BACKGROUND: FOLFOXIRI plus bevacizumab has demonstrated benefits for metastatic colorectal cancer (mCRC) patients. However, challenges arise in its clinical implementation due to expected side effects and a lack of stratification criteria. METHODS: The AIO "CHARTA" trial randomised mCRC patients into clinical Group 1 (potentially resectable), 2 (unresectable/risk of rapid progression), or 3 (asymptomatic). They received FOLFOX/bevacizumab +/- irinotecan. The primary endpoint was the 9-month progression-free survival rate (PFSR@9). Secondary endpoints included efficacy in stratified groups, QoL, PFS, OS, ORR, secondary resection rate, and toxicity. RESULTS: The addition of irinotecan to FOLFOX/bevacizumab increased PFSR@9 from 56 to 67%, meeting the primary endpoint. The objective response rate was 61% vs. 69% (P = 0.21) and median PFS was 10.3 vs. 12 months (HR 0.83; P = 0.17). The PFS was (11.4 vs. 12.9 months; HR 0.83; P = 0.46) in potentially resectable patients, with a secondary resection rate of 37% vs. 51%. Moreover, Group 3 (asymptomatic) patients had a PFS of 11.1 vs. 16.1 months (HR 0.6; P = 0.14). The addition of irinotecan did not diminish QoL. CONCLUSION: The CHARTA trial, along with other studies, confirms the efficacy and tolerability of FOLFOXIRI/bevacizumab as a first-line treatment for mCRC. Importantly, clinical stratification may lead to its implementation. TRIAL REGISTRATION: The trial was registered as NCT01321957.

Lymph node count and prognosis in colorectal cancer: the influence of examination quality.

Colorectal cancer guidelines recommend adjuvant chemotherapy in stage II disease when less than 12 lymph nodes are assessed. The recommendation bases on previous studies showing an association of a low lymph node count and adverse outcome. Compared to current standards, however, the quality of lymph node examination in the studies was low. We, therefore, investigated the prognostic role of <12 lymph nodes in cancers diagnosed adherent to current quality measures. Stage I-IV colorectal cancers from 1,899 patients enrolled into a population-based cohort study were investigated for the prognostic impact of a lymph node count <12. The stage specific share of patients diagnosed with ≥12 nodes (stage I-IV: 62, 85, 85, 78%, respectively) was used to compare lymph node examination quality to other studies. We found no impact of a lymph node count <12 on overall, cancer-specific or recurrence-free survival for any tumour stage. Compared to studies reporting an adverse prognostic impact of a low lymph node count in stages II and III the stage-specific shares of patients with ≥12 nodes were markedly higher in this study (85% vs. 24-58% in previous analyses) and this correlated with increased rates of stage III compared to stage II cancers. In conclusion our data indicate, that the previously reported effect of a low lymph node count on the patients' outcomes is eliminated by improved lymph node examination quality and thus question the general applicability of a 12 lymph node cut off for adjuvant chemotherapy decision making in stage II disease.

Upfront FOLFOXIRI+bevacizumab followed by fluoropyrimidin and bevacizumab maintenance in patients with molecularly unselected metastatic colorectal cancer.

BACKGROUND: The addition of bevacizumab (BEV) to standard doublet chemotherapy improves outcomes compared with chemotherapy alone in patients with metastatic colorectal cancer (mCRC). The OPAL study examined the effect of BEV+FOLFOXIRI followed by 5FU/LV and BEV maintenance on progression-free survival (PFS) in patients with previously untreated unresectable mCRC. METHODS: Eligible patients had histologically confirmed mCRC, ECOG performance status ⩽1 and were 18-70 years old. Patients received up to 12 cycles of FOLFOXIRI+BEV q2w (induction phase) followed by up to ⩽40 cycles of 5FU/LV+BEV q2w (maintenance phase). Median PFS was the primary end point; secondary end points included response, OS, secondary resection rate, safety and prognostic value of pharmacogenetic profiling. RESULTS: Ninety-seven patients were enrolled. Of these, 90 received study medication and formed the safety population: 64 males; median age 58 (range 28-71) years; ECOG performance status 0/1 in 54%/46% patients; and liver only disease in 35 patients. Relative dose intensities were 79-85% for all four drugs. The incidence of adverse events (AEs) was as previously reported and there were no new safety signals. In total, 87 serious AEs occurred in 39 patients (43%). Median PFS was 11.1 months (95% CI 9.4-12.0) and did thus not meet the primary objective of 12 months. Median OS was 32.2 months (95% CI 22.6-36.9). Fifty-two patients were pharmacogenetically profiled. CONCLUSIONS: FOLFOXIRI+BEV was feasible in this molecularly unselected mCRC patient population, showing a high efficacy in terms of survival, overall response and secondary resection rate. Pharmacogenomic profiling revealed no clinically relevant marker.

Interventionally implanted port catheter systems for hepatic arterial infusion of chemotherapy in patients with primary liver cancer: a phase II-study (NCT00356161).

BACKGROUND: Hepatic arterial infusion (HAI) of chemotherapy requires the implantation of a transcatheter application system which is traditionally performed by surgery. This procedure, but particularly the adjacent drug application via pump or port is often hampered by specific complications and device failure. Interventionally implanted port catheter systems (IIPCS) facilitate the commencement of HAI without need for laparatomy, and are associated with favorable complication rates. We here present an evaluation of the most important technical endpoints associated with the use of IIPCS for HAI in patients with primary liver cancers. METHODS: 70 patients (pts) with hepatocellular (HCC, n=33) and biliary tract cancer (BTC, n=37) were enrolled into a phase II -study. Of those, n=43 had recurrent disease and n=31 suffered from liver-predominant UICC-stage IVb. All pts were provided with IIPCSs before being treated with biweekly, intraarterial chemotherapy (oxaliplatin, 5-Flourouracil, folinic acid). The primary objective of the trial was defined as evaluation of device-related complications and port duration. RESULTS: Implantation of port catheters was successful in all patients. Mean treatment duration was 5.8 months, and median duration of port patency was not reached. Disease-progression was the most common reason for treatment discontinuation (44 pts., 63%), followed by chemotherapy-related toxicity (12 pts., 17%), and irreversible device failure (5 pts., 7%). A total of 28 port complications occurred in 21 pts (30%). No unexpected complications were observed. CONCLUSIONS: HAI via interventionally implanted port catheters can be safely applied to patients with primary liver tumors far advanced or/and pretreated.

Treatment with bevacizumab and FOLFOXIRI in patients with advanced colorectal cancer: presentation of two novel trials (CHARTA and PERIMAX) and review of the literature.

BACKGROUND: More than half of patients with colorectal cancer will develop metastatic disease either evident at the time of initial diagnosis or during their course of disease. Besides multidisciplinary management further treatment intensification is warranted to improve the still limited prognosis. METHODS/DESIGN: In these two multi-centre, randomized phase II trials, conducted in Germany, 380 patients with R0-resectable colorectal liver metastases (PERIMAX) and with unresectable, metastatic colorectal cancer (CHARTA) will be recruited. Patients previously untreated for metastatic disease with either synchronous or metachronous metastases are randomly assigned in a 1:1 ratio to resection of colorectal liver metastases followed by postoperative FOLFOX for 6 months or perioperative FOLFOXIRI and bevacizumab for 3 months pre- and postoperative and resection (PERIMAX), or to induction chemotherapy with FOLFOX and bevacizumab +/- irinotecan for a maximum of 6 months followed by maintenance treatment with fluoropyrimidine and bevacizumab. The primary objective of these trials is to evaluate the feasibility and efficacy of FOLFOXIRI and bevacizumab in metastatic colorectal cancer. Primary endpoint is failure free survival rate at 18 months in the PERIMAX trial and progression free survival rate at 9 months in CHARTA. Secondary objectives include efficacy, safety and tolerability. DISCUSSION: The CHARTA and PERIMAX trials are designed to evaluate the benefits and limitations of a highly active four-drug regimen in distinct treatment situations of metastatic CRC. Eligible patients are classified into resectable liver metastases to be randomized to perioperative treatment with FOLFOXIRI and bevacizumab or postoperative FOLFOX in the PERIMAX, or unresectable metastatic CRC to be randomized between FOLFOX and bevacizumab with or without irinotecan, stratified for clinical groups according to disease and patients' characteristics in the CHARTA trial. TRIAL REGISTRATION: Clinical trial identifier CHARTA: NCT01321957, PERIMAX: NCT01540435.

Long-term observation of the frequency of secondary colorectal cancer and other malignancies in tyrosine kinase inhibitor treated chronic myeloid leukemia patients and controls.

In this analysis, we examined the risk of secondary malignancies for tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) patients. We also collected data on specific risk factors for colorectal cancer. Ninety-one patients with CML and 76 controls were included and in total 4 (4.4%) secondary malignancies were found in patients and 8 (10.5%) in controls. The risk for secondary malignancies was not significantly elevated for CML patients (p = 0.141). Two (2.2%) CML patients developed colorectal cancer compared to 4 (5.3%) in the reference group. A higher risk for CML patients for colorectal cancer could not be found (p = 0.414).

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.

Adult jejunojejunal intussusception caused by metastasized pleomorphic carcinoma of the lung: report of a case.

Adult small-intestinal intussusception is rare and very different from childhood intussusception. Both benign and malignant pathologies can underlie small intestinal intussusception in adults, but malignancy is much less frequent. We report a case of jejunojejunal intussusception caused by an intestinal metastasis of the sarcomatoid component of pleomorphic carcinoma of the right lung. The patient, a 61-year-old man, underwent successful segmental jejunal resection. Adult small bowel intussusception, though an unusual cause of acute abdomen, requires early diagnosis and timely management. To our knowledge, this is the first report of adult jejunojejunal double intussusception caused by metastatic sarcomatoid carcinoma of the lung.

Intraoperative fresh-frozen plasma versus human albumin in craniofacial surgery--a pilot study comparing coagulation profiles in infants younger than 12 months.

The transfusion of fresh-frozen plasma (FFP) is suggested to minimize dilution coagulopathy when applied instead of colloids during paediatric craniofacial surgery (pCFS). We prospectively compared plasmatic haemostaseologic function between volume replacement with FFPs versus human albumin (HA) in a pilot study. Thirty infants with primary craniosynostosis were scheduled for pCFS. In 15 of those, FFPs were available from the identical donor as for packed red blood cells (pRBC), and were thus employed for intraoperative volume replacement. The remaining 15 infants were infused with HA-5% instead. Haemoglobin(Hb)-values, global coagulation parameters (activated partial thromboplastin time-aPTT; prothrombin time-PT), selected clotting factors (F) (VIII, XI, XIII), antithrombin-AT, fibrinolytic factors (fibrinogen; plasminogen; alpha2-antiplasmin-alpha2A), and activation parameters (thrombin-antithrombin-complex-TAT; plasmin-antiplasmin-complex-PAP; D-dimers) were assessed and compared between both groups after induction of anaesthesia, before transfusion of pRBC, and at the end of surgery. Patients and treatment characteristics were balanced between both groups. Prolongation of aPTT and decreases of PT, FXI, FXIII, AT3, and fibrinolytic factors were more pronounced in the HA-group. Increases in F VIII activity, activation parameters, and the course of Hb-values were similar among both groups. There was no difference regarding clinical endpoints (peri-/postoperative pRBC-transfusions, postoperative blood loss). In conclusion, the application of HA was associated with a more distinct dilution of procoagulant factors, AT3, and fibrinolytic factors than the use of FFPs. However, the course of activation markers suggested a similar extent of clotting and fibrinolytic activation with the use of both transfusion regimens, and there were no differences with regard to clinical endpoints.

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.

Interventionally implanted port catheter systems for hepatic arterial infusion of chemotherapy in patients with colorectal liver metastases: a Phase II-study and historical comparison with the surgical approach.

BACKGROUND: The high complication rates of surgically implanted port catheter systems (SIPCS) represents a major drawback in the treatment of isolated liver neoplasms by hepatic arterial infusion (HAI) of chemotherapy. Interventionally implanted port catheter systems (IIPCS) have evolved into a promising alternative that enable initiation of HAI without laparatomy, but prospective data on this approach are still sparse. Aim of this study was to evaluate the most important technical endpoints associated with the use of IIPCS for the delivery of 5-fluorouracil-based HAI in patients with colorectal liver metastases in a phase 2-study, and to perform a non-randomised comparison with a historical group of patients in which HAI was administered via SIPCS. METHODS: 41 patients with isolated liver metastases of colorectal cancer were enrolled into a phase II-study and provided with IIPCS between 2001 and 2004 (group A). The primary objective of the trial was defined as evaluation of device-related complications and port duration. Results were compared with those observed in a pre-defined historical collective of 40 patients treated with HAI via SIPCS at our institution between 1996 and 2000 (group B). RESULTS: Baseline characteristics were balanced between both groups, except for higher proportions of previous palliative pre-treatment and elevated serum alkaline phosphatase in patients of group A. Implantation of port catheters was successful in all patients of group A, whereas two primary failures were observed in group B. The frequency of device-related complications was similar between both groups, but the secondary failure rate was significantly higher with the use of surgical approach (17% vs. 50%, p < 0.01). Mean port duration was significantly longer in the interventional group (19 vs. 14 months, p = 0.01), with 77 vs. 50% of devices functioning at 12 months (p < 0.01). No unexpected complications were observed in both groups. CONCLUSION: HAI via interventionally implanted port catheters can be safely provided to a collective of patients with colorectal liver metastases, including a relevant proportion of preatreated individuals. It appears to offer technical advantages over the surgical approach.

Cetuximab: appraisal of a novel drug against colorectal cancer.

Cetuximab (C225, Erbitux, Merck, Darmstadt, Germany) is a human-mouse chimeric therapeutic monoclonal antibody (mAb) that competitively binds to the extracellular domain of the human epidermal growth-factor receptor (EGFR). It has been developed out of the murine antibody M225 "from bench to bedside" in less than two decades, and is the anti-EGFR mAb furthest ahead in clinical evaluation. In Europe, cetuximab is approved for the treatment of patients with EGFR-expressing, metastatic colorectal cancer after failure of treatment with irinotecan since 2004, and for the treatment of patients with locally advanced squamous cell cancer of the head and neck concomitant to radiotherapy since 2006. We here summarize the current role of cetuximab in the treatment of colorectal cancer, give an overview on the ongoing studies, address the most important controversies, and point out the chances and challenges for the future use of cetuximab in colorectal cancer and other human malignancies.

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.

A non-randomised, single-centre comparison of induction chemotherapy followed by radiochemotherapy versus concomitant chemotherapy with hyperfractionated radiotherapy in inoperable head and neck carcinomas.

BACKGROUND: The application of induction chemotherapy failed to provide a consistent benefit for local control in primary treatment of advanced head and neck (H&N) cancers. The aim of this study was to compare the results of concomitant application of radiochemotherapy for treating locally advanced head-and-neck carcinoma in comparison with the former standard of sequential radiochemotherapy. METHODS: Between 1987 and 1995 we treated 122 patients with unresectable (stage IV head and neck) cancer by two different protocols. The sequential protocol (SEQ; 1987-1992) started with two courses of neoadjuvant chemotherapy (cisplatin [CDDP] + 120-h continuous infusions (c.i.) of folinic acid [FA] and 5-fluorouracil [5-FU]), followed by a course of radiochemotherapy using conventional fractionation up to 70 Gy. The concomitant protocol (CON; since 1993) combined two courses of FA/5-FU c.i. plus mitomycin (MMC) concomitantly with a course of radiotherapy up to 30 Gy in conventional fractionation, followed by a hyperfractionated course up to 72 Gy. Results from the two groups were compared. RESULTS: Patient and tumor characteristics were balanced (SEQ = 70, CON = 52 pts.). Mean radiation dose achieved (65.3 Gy vs. 71.6 Gy, p = 0.00), response rates (67 vs. 90 % for primary, p = 0.02), and local control (LC; 17.6% vs. 41%, p = 0.03), were significantly lower in the SEQ group, revealing a trend towards lower disease-specific (DSS; 19.8% vs. 31.4%, p = 0.08) and overall (14.7% vs. 23.7%, p = 0.11) survival rates after 5 years. Mucositis grades III and IV prevailed in the CON group (54% versus 44%). Late toxicity was similar in both groups. CONCLUSION: Concurrent chemotherapy seemed more effective in treating head and neck tumors than induction chemotherapy followed by chemoradiation, resulting in better local control and a trend towards improved survival.

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.

Resting heart rate is an independent predictor of death in patients with colorectal, pancreatic, and non-small cell lung cancer: results of a prospective cardiovascular long-term study.

AIMS: Patients with advanced cancer have been shown to suffer from abnormal cardiac function and impaired exercise capacity that may contribute to their impaired quality of life. As tachycardia is considered as a sign of potential early cardiac damage, we sought to determine whether resting heart rate and other ECG-derived variables have prognostic value. METHODS AND RESULTS: From 2005 to 2010, we enrolled 145 patients with histologically confirmed cancer (36 colorectal, 72 pancreatic, and 37 non-small cell lung cancer patients) and 59 healthy controls. During a mean follow-up of 27 months, 82 patients (57%) died from any cause. The mean resting heart rate of healthy subjects was 70 ± 13 b.p.m., and that of cancer patients was 79 ± 14 b.p.m. (P< 0.0001). As a sensitivity analysis, we excluded control subjects taking a beta-blocker, but resting heart rate remained increased in cancer patients vs. controls (P < 0.0001). Resting heart rate ≥75 b.p.m. [hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.16-2.94; P = 0.01] significantly predicted survival in univariable analyses and remained an independent predictor of survival in a multivariate model (HR 1.67, 95% CI 1.01-2.78; P = 0.04). Furthermore, the heart rate stayed significant in a second model that included age and sex as well. CONCLUSION: The present study is the first to show that resting heart rate independently of haemoglobin and tumour stage predicts survival in patients with advanced colorectal, pancreatic, and non-small cell lung cancer, and may therefore represent a therapeutic target.

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.

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.

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.