Biochemical differentiation between cancerous and normal human colorectal tissues by micro-Raman spectroscopy.

Human colorectal tissues obtained by ten cancer patients have been examined by multiple micro-Raman spectroscopic measurements in the 500-3200 cm-1 range under 785 nm excitation. Distinct spectral profiles are recorded from different spots on the samples: a predominant 'typical' profile of colorectal tissue, as well as those from tissue topologies with high lipid, blood or collagen content. Principal component analysis identified several Raman bands of amino acids, proteins and lipids which allow the efficient discrimination of normal from cancer tissues, the first presenting plurality of Raman spectral profiles while the last showing off quite uniform spectroscopic characteristics. Tree-based machine learning experiment was further applied on all data as well as on filtered data keeping only those spectra which characterize the largely inseparable data clusters of 'typical' and 'collagen-rich' spectra. This purposive sampling evidences statistically the most significant spectroscopic features regarding the correct identification of cancer tissues and allows matching spectroscopic results with the biochemical changes induced in the malignant tissues.

Boron detection from blood samples by ICP-AES and ICP-MS during boron neutron capture therapy.

OBJECTIVE: The concept of boron neutron capture therapy (BNCT) involves infusion of a (10)B containing tracer into the patient's bloodstream followed by local neutron irradiation(s). Accurate estimation of the blood boron level for the treatment field before irradiation is required. Boron concentration can be quantified by inductively coupled plasma atomic emission spectrometry (ICP-AES), mass spectrometry (ICP-MS), spectrofluorometric and direct current atomic emission spectrometry (DCP-AES) or by prompt gamma photon detection methods. MATERIAL AND METHODS: The blood boron concentrations were analysed and compared using ICP-AES and ICP-MS to ensure congruency of the results if the analysis had to be changed during the treatment, e.g. for technical reasons. The effect of wet-ashing on the results was studied in addition. RESULTS: The mean of all samples analysed with ICP-MS was 5.8 % lower than with ICP-AES coupled to wet-ashing (R (2) = 0.88). Without wet-ashing, the mean of all samples analysed with ICP-MS was 9.1 % higher than with ICP-AES (R (2) = 0.99). CONCLUSIONS: Boron concentration analysed from whole blood samples with ICP-AES correlated well with the values of ICP-MS with wet-ashing of the sample matrix, which is generally considered the reference method. When using these methods in parallel at certain intervals during the treatments, reliability of the blood boron concentration values remains satisfactory, taking into account the required accuracy of dose determination in the irradiation of cancer patients.

SPCG-15: a prospective randomized study comparing primary radical prostatectomy and primary radiotherapy plus androgen deprivation therapy for locally advanced prostate cancer.

OBJECTIVE: To describe study design and procedures for a prospective randomized trial investigating whether radical prostatectomy (RP) ± radiation improves cause-specific survival in comparison with primary radiation treatment (RT) and androgen deprivation treatment (ADT) in patients with locally advanced prostate cancer (LAPC). MATERIALS AND METHODS: SPCG-15 is a prospective, multi-centre, open randomized phase III trial. Patients are randomized to either standard (RT + ADT) or experimental (RP with extended pelvic lymph-node dissection and with addition of adjuvant or salvage RT and/or ADT if deemed necessary) treatment. Each centre follows guidelines regarding the timing and dosing of postoperative RT and adjuvant treatment such as ADT The primary endpoint is cause-specific survival. Secondary endpoints include metastasis-free and overall survival, quality-of-life, functional outcomes and health-services requirements. Each subject will be followed up for a minimum of 10 years. RESULTS: Twenty-three centres in Denmark, Finland, Norway and Sweden, well established in performing RP and RT for prostate cancer participated. Each country's sites were coordinated by national coordinating investigators and sub-investigators for urology and oncology. Almost 400 men have been randomized of the stipulated 1200, with an increasing rate of accrual. CONCLUSIONS: The SPCG-15 trial aims to compare the two curatively intended techniques supplying new knowledge to support future decisions in treatment strategies for patients with LAPC The Scandinavian healthcare context is well suited for performing multi-centre long-term prospective randomized clinical trials. Similar care protocols and a history of entirely tax-funded healthcare facilitate joint trials.

The immune response of women with prolonged exposure to electromagnetic fields produced by radiotelevision broadcasting stations.

Twelve women, five of them housewives, exposed in their residences to electromagnetic fields (EMFs)emitted by radio-television broadcasting stations for a mean period of 13 years, were investigated. The EMFs in the balconies of the homes were (mean + S.D.) 4.3 + 1.4 V/m in the year 2000 and 3.7 + 1.3 V/m in 2005, while the exposure in the nearby area was <2.0 V/m. The EMF exposed women showed in 2000 reduced blood NK lymphocytes as well as PHA stimulated PBMC proliferation and IL-2 and IFN-gamma release. In the year 2005, the EMF exposed women and 48 control women with similar ages(mean 43 years), smoking habits, atopy and social level were investigated. State (temporary) and trait(tendency of the personality) anxiety were determined by STAI I and II, respectively. Blood cytotoxic activity and lymphocyte subsets were also determined. The ratio STAI I/STAI II of the EMF exposed group was lower than that of the control group. The blood cytotoxic activity of the exposed women was lower (p<0.01), percent of B CD45+-CD19+ lymphocytes higher and percent of CD45+-CD3+-CD8+ cells lower (p<0.05). Moreover, cytotoxic activity/CD45+-CD16+-56+ NK lymphocytes of the controls was negatively correlated with STAI I and STAI II (p<0.001). In conclusion, this study demonstrates reduced blood cytotoxic activity and increased trait anxiety in relation to state anxiety in EMF exposed women. An effect of EMFs on immune functions, in part mediated by nervous mechanisms, may be hypothesized. However, the influence of lifestyle may not be excluded.

Adjuvant chemotherapy after radical surgery for non-small-cell lung cancer: a randomized study.

PURPOSE: The aims of this study were to assess the effect of adjuvant chemotherapy on overall survival, disease-free survival, and relapse pattern, as well as its toxicity in patients who underwent radical surgery for non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: One hundred ten patients with T1-3N0 (World Health Organization [WHO] 1981) NSCLC underwent radical surgery during the period of 1982 through 1987. After surgery, the patients were randomized to receive adjuvant chemotherapy (n = 54) (cyclophosphamide 400 mg/m2, doxorubicin 40 mg/m2, and cisplatin 40 mg/m2 [CAP] for six cycles) or no active treatment (n = 56). RESULTS: After 10 years from the start of the study, 61% of patients were alive in the chemotherapy group and 48% were alive in the control group (P = .050). Seventeen patients (31%) in the CAP group and 27 patients (48%) in the control group had a recurrence during the follow-up period (P = .01). The 5-year survival rate was 67% in the chemotherapy group and was 56% in the control group (P = .050). The patients in the chemotherapy group who completed the planned treatment had a slightly better 5-year survival than those whose chemotherapy was discontinued (72.5% v 50.3%; P = .15). Chemotherapy-related gastrointestinal toxicity grade 3 to 4 (WHO) occurred in 63% and was the main reason why patients refused further planned therapy. CONCLUSION: Our results suggest that patients with NSCLC at pathologic stage I who have undergone radical surgery benefit from adjuvant chemotherapy.

1H MRS studies in the Finnish boron neutron capture therapy project: detection of 10B-carrier, L-p-boronophenylalanine-fructose.

This article summarizes the current status of 1H MRS in detecting and quantifying a boron neutron capture therapy (BNCT) boron carrier, L-p-boronophenylalanine-fructose (BPA-F) in vivo in the Finnish BNCT project. The applicability of 1H MRS to detect BPA-F is evaluated and discussed in a typical situation with a blood containing resection cavity within the gross tumour volume (GTV). 1H MRS is not an ideal method to study BPA concentration in GTV with blood in recent resection cavity. For an optimal identification of BPA signals in the in vivo 1H MR spectrum, both pre- and post-infusion 1H MRS should be performed. The post-infusion spectroscopy studies should be scheduled either prior to or, less optimally, immediately after the BNCT. The pre-BNCT MRS is necessary in order to utilise the MRS results in the actual dose planning.

Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients.

OBJECTIVE: To study the long-term effects of radiotherapy on cognitive function in adult patients operated on for low-grade glioma. METHODS: A cohort of 160 patients who underwent surgery for low-grade gliomas of cerebral hemisphere between 1980 and 1992 in a single institution serving a defined population was studied. At a mean follow-up time of 7 years, 28 of the 101 patients who had postoperative irradiation (and no second surgery or chemotherapy) were still alive and eligible for MRI and neuropsychological study. Twenty-three of 59 patients who did not have radiotherapy, second surgery, or chemotherapy were alive and eligible at a mean of 10 years. RESULTS: The group that had postoperative irradiation performed significantly worse than the group that did not in cognitive tests. This difference was not accounted for by histologic diagnosis; location, extent of removal, or progression of the tumor; or any patient factor. Leukoencephalopathy was more severe in the group that had postoperative irradiation than in the group without radiotherapy, and correlated to poor memory performances only in the postoperative radiotherapy group. Average Karnofsky performance scale score was significantly lower in the group that had postoperative irradiation than in the group that did not. CONCLUSION: In adults with low-grade glioma, postoperative radiotherapy poses a significant risk of long-term leukoencephalopathy and cognitive impairment.

Phase II study of epirubicin sequential methotrexate and 5-fluorouracil for advanced colorectal cancer.

91 patients with measurable metastatic colorectal carcinoma entered a phase II study. A three-drug schedule; epirubicin (20 mg/m2), sequential methotrexate (150 mg/m2), 5-fluorouracil (600 mg/m2) with 1-h interval (EMF) with folinic acid rescue was given weekly three times followed by 2-3 weeks rest. 85 patients were evaluable for response. 5 patients (6%) experienced a complete response (CR), 20 (23%) a partial response (PR), 31 (37%) had disease stabilisation (SD) and 29 (34%) progressive disease (PD). The median survival time was 13.7 months in all patients (n = 91) and 14.0 months in those evaluable for response (n = 85). In patients with CR, PR, SD and PD the median survival time was 46.7, 19.8, 14.7 and 8.7 months, respectively. The response rate was significantly (P < 0.05) higher in tumours originating from the colon (41%) than in those originating from the rectum (18%) and also significantly (P < 0.001) higher in non-symptomatic than in symptomatic patients, 40 vs. 4%, respectively. The treatment was fairly well tolerated as an outpatient regimen, the main dose-limiting side-effect being diarrhoea. Deaths for septic fever, which may be attributable to the treatment were encountered in 3 patients, all with progressive cancer. Further studies to disclose differences in response rate in subsets of patients are warranted.

Poor prognosis associated with elevated serum CA 19-9 level in advanced colorectal carcinoma, independent of DNA ploidy or SPF.

DNA ploidy, S-phase fraction (SPF) for the tumours, serum tumour markers such as carcinoembryonic antigen (CEA) and serum CA 19-9 and major clinical parameters were analysed as prognostic factors in 105 patients with advanced colorectal carcinoma. All 105 were treated with a three-drug schedule including low dose epirubicin and sequential methotrexate, 5-fluorouracil, followed by leucovorin rescue. In univariate analysis, gender, Karnofsky index, extent of metastases, presence of abdominal metastases, CEA and CA 19-9 correlated with survival. Age, presence of liver or of lung metastases, DNA ploidy or SPF were not significantly associated with survival. In stepwise multivariate analysis an elevated serum CA 19-9 level, a poor Karnofsky index and multiple sites of metastases were independent adverse prognostic factors. Based on the multivariate analysis, patients were grouped in three categories. Group 1 consisted of 32 patients with Karnofsky > or = 80, with a normal serum CA 19-9 level and a single site of metastases. Group 2 consisted of 48 patients with Karnofsky > or = 80 and with an elevated serum CA 19-9 level or multiple sites of metastases. Group 3 consisted of 14 patients with Karnofsky < or = 70. This classification gave a highly significant correlation with survival (chi 2 = 45.52, P < 0.001, log rank test). The median survival in group 1, group 2 and group 3 was 30.1 months, 13.5 months and 3.9 months, respectively. Based on these results we suggest that trials involving advanced colorectal cancer should include the measurement of serum CA 19-9 levels as one of the most important prognostic factors, but also include documentation of other independent prognostic factors.

Biweekly dose escalation in curative accelerated hyperfractionation for advanced head and neck cancer: a feasibility study.

PURPOSE: To study the feasibility of a dose-escalated accelerated hyperfractionation schedule for patients with advanced head and neck cancer. MATERIALS AND METHODS: Twenty-nine previously untreated patients with advanced squamous cell carcinoma were treated with the following biweekly dose-escalated accelerated hyperfraction schedule: during the first 2 weeks 1.2 Gy twice a daily (bid) up to 24 Gy, thereafter during the next following 2 weeks 1.4 Gy bid to 28 Gy in 20 fractions, and thereafter 22.4 Gy in 1.6 Gy bid fractions during 1 1/2 weeks. Thus, the the total dose was 74.4 Gy in 54 fractions given in 5 1/2 weeks. RESULTS: The planned total dose was given within the planned time to 19 (66%) patients. For seven patients the treatment time was prolonged with 1 to 6 days because of department closure for holidays or machine-down days, and in three cases the treatment time was prolonged more than 8 weeks. When the tumor responses were evaluated at 3 months after given radiotherapy, 27 (93%) patients showed complete tumor clearance, 1 patient had a recidual focus, and 1 patient showed progressive disease. The ultimate 1-, 2-, and 3-year local control rates were: 87, 71, and 60%. Four patients had a salvage laryngectomy. The 1-, 2-, and 3-year survival rates for all patients were as follows: 96, 81, and 73%. All patients developed confluent mucositis, 15 patients were hospitalized for nutritional support, and 11 patients had moist desquamation. However, all acute reactions healed completely, and no serious late complications were observed. CONCLUSIONS: This is a safe and effective treatment schedule for patients with advanced head and neck cancer.

Design and construction of shoulder recesses into the beam aperture shields for improved patient positioning at the FiR 1 BNCT facility.

Improvements have been made at the FiR 1 BNCT facility to ease the positioning of the patient with a tumor in the head and neck region into a lateral neutron beam. Shoulder recesses were constructed horizontally on both sides of the beam aperture. When shoulder recesses are not needed, they are filled with neutron attenuating filling blocks. MCNP simulations using an anthropomorphic human model BOMAB phantom showed that the main contribution to the increase in the effective dose to the patient's body due to the shoulder recesses was from the neutron dose of the arm. In a position when one arm is inside the shoulder recess, the maximal effective dose of the patient was estimated to be 0.7Sv/h. Dose measurements using the twin ionization chamber technique showed that the neutron dose increased on the sides as predicted by the MCNP model but there was no noticeable change in the gamma doses. When making the recesses into the lithium containing neutron shield material tritium contamination was confined using an underpressurized glove box and machine tools with local exhaust. The shoulder recesses give space for more flexible patient positioning and can be considered as a significant improvement of the Finnish BNCT facility.

"In vitro" effects of different arsenic compounds on PBMC (preliminary study).

Aim of this investigation was to compare the effects of 10(-4) M and 10(-7) M As compounds on spontaneous and PHA stimulated PBMC proliferation and IFN-gamma and TNF-alpha release. The inhibitory effect of the 10(-4) M As salts was in the following order: momo-methyl-arsinous acic (MMAs(III)) > sodium arsenite (As(III)) > tetraphenyl arsonium chloride (As(V)) > sodium arsenate (As(V)) > potassium- and sodium-esa-fluorum arsenate (As(V)) > dimethyl arsinic acid (DMAs(V)), while monomethyl-arsonic-acid (MMAs(V)) and arsenobetaine did not exert immune effects. 10(-7) M MMAs(III) stimulated the spontaneous PBMC proliferation, while As(III) and DMAs(V) enhanced the PHA stimulated PBMC proliferation. This study shows that the immune effects of As salts depends on speciation; moreover, the immunotoxicity of inorganic arsenic in part depends on the intracellular bio-synthesis of MMAs(III) from MMAs(V).

Does preoperative radiotherapy with postoperative chemotherapy increase acute side-effects and postoperative complications of total mesorectal excision? Report of the randomized Finnish rectal cancer trial.

BACKGROUND AND AIMS: In a randomized trial the effect of short-term preoperative radiotherapy and postoperative chemotherapy was studied in patients undergoing total mesorectal excision (TME) for clinically resectable rectal cancer. The primary endpoint was overall survival. The secondary endpoints published herein were the incidence of postoperative complications and adverse events with perioperative adjuvant therapy. MATERIAL AND METHODS: In 1995-2002, 278 eligible patients with stage II and stage III rectal cancer were randomly assigned to TME alone (surgery group) or to preoperative 25 Gy radio-therapy in 5 fractions and postoperative 5-fluorouracil and leucovorin chemotherapy in addition (RT+CT group). RESULTS: Anastomotic leakage rate did not significantly differ between the surgery and the RT + CT group, 20.6% vs. 27.4%. Postoperative infections (15.5 vs. 26.2%, p = 0.037) and perineal wound dehiscence (15.9 vs. 38.5%, p = 0.045) were more common after radiotherapy. Grade 3-5 adverse events were uncommon with preoperative radiotherapy (one, 0.7% with reversible lumbar plexopathy) and postoperative chemotherapy (hematologic in 10.8%, with one septic death, and gastrointestinal in 4.8%). CONCLUSIONS: Perioperative adjuvant therapy was generally well tolerated and did not lead to an increase in serious surgical complications. Wound infections and perineal wound dehiscence were more common in irradiated patients.

Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study.

5-Fluorouracil (5-FU)-based chemotherapy is frequently associated with diarrhoea. We compared two 5-FU-based regimens and the effect of Lactobacillus and fibre supplementation on treatment tolerability. Patients diagnosed with colorectal cancer (n=150) were randomly allocated to receive monthly 5-FU and leucovorin bolus injections (the Mayo regimen) or a bimonthly 5-FU bolus plus continuous infusion (the simplified de Gramont regimen) for 24 weeks as postoperative adjuvant therapy. On the basis of random allocation, the study participants did or did not receive Lactobacillus rhamnosus GG supplementation (1-2 x 10(10) per day) and fibre (11 g guar gum per day) during chemotherapy. Patients who received Lactobacillus had less grade 3 or 4 diarrhoea (22 vs 37%, P=0.027), reported less abdominal discomfort, needed less hospital care and had fewer chemotherapy dose reductions due to bowel toxicity. No Lactobacillus-related toxicity was detected. Guar gum supplementation had no influence on chemotherapy tolerability. The simplified de Gramont regimen was associated with fewer grade 3 or 4 adverse effects than the Mayo regimen (45 vs 89%), and with less diarrhoea. We conclude that Lactobacillus GG supplementation is well tolerated and may reduce the frequency of severe diarrhoea and abdominal discomfort related to 5-FU-based chemotherapy.

DNA ploidy of colorectal carcinoma by tumour site, gender and history of noncolorectal malignancies.

DNA ploidy was analysed by flow cytometer from frozen samples of 205 colorectal carcinomas. Sixty-two percent of the tumours had an abnormal DNA stemline. Forty-eight percent of carcinomas in the right colon, 62% of carcinomas in the left colon and 74% of carcinomas in the rectum were aneuploid (p = 0.007). Sixty-nine percent of tumours in males and 55% of tumours in females were aneuploid (p = 0.029). The difference in frequency of aneuploidy between females and males was greatest in tumours of the right colon, where 37% of the tumours in females and 62% of the tumours in males were aneuploid (p = 0.047). The percentage of diploid colorectal carcinomas was higher (55%) in patients with a history of noncolorectal malignancy than in others (34%, p = 0.031). These results suggest that flow cytometry may be helpful in understanding the development of colorectal carcinomas.

Elevated CA19-9 as the most significant prognostic factor in advanced colorectal carcinoma.

Tumor markers such as carcinoembryonic antigen (CEA) and CA19-9 were analyzed as response indicators and prognostic factors in advanced colorectal carcinoma. Eighty-five patients participated in a phase II chemotherapy study from October 1984 to July 1990. A three-drug schedule was administered including low dose epirubicin and sequential methotrexate 5-fluorouracil, followed by leucovorin rescue. Serum specimens for CEA and CA19-9 were obtained prior to the initiation of chemotherapy, and subsequently at 4-6 weeks' intervals. In univariate analysis Karnofsky, the site of the primary tumor, the extent of metastases, the presence of abdominal or liver metastases, serum CEA (cut-off of 20 micrograms/l), and CA19-9 levels correlated with survival. In stepwise multivariate analysis an elevated CA19-9 level, a poor Karnofsky, and the presence of liver metastases were independent adverse prognostic factors. Tumors originating from the left colon had a better prognosis than the others. This was related to a higher response rate in this patient group. Serum CA19-9 level was the most significant prognostic factor whether it was entered as a continuous or as a dichotomized variable into the model. The median survival of patients with a normal CA19-9 level was 30.0 months (lower 95% confidence interval: 16.4 months; upper limit was not calculable), and with an elevated CA19-9 value 10.3 months (8.0-12.6 months, 95% confidence interval). Five of 85 patients had a complete response and 20 a partial response, the overall response rate being 29%. When compared with tumor shrinkage, "CEA response" and "CA19-9 response" had a sensitivity of 84% and 88% and specificity of 77% and 67%, respectively. In conclusion, serum CEA value seems to be the best tumor marker for response prediction, while CA19-9 level is one of the best available prognostic indicators in advanced colorectal carcinoma.