Anxiety and depression symptoms among sub-fertile women, women pregnant after infertility treatment, and naturally pregnant women.

BACKGROUND: Infertility has been associated with psychological distress, but whether these symptoms persist after achieving pregnancy via assisted reproductive technology (ART) remains unclear. We compared the prevalence of anxiety and depressive symptoms between women seeking for infertility treatment and women who conceived after ART or naturally. METHODS: Four hundred and sixty-eight sub-fertile non-pregnant women, 2972 naturally pregnant women and 143 women pregnant after ART completed a questionnaire in this cross-sectional study. The Anxiety subscale of the Hospital Anxiety and Depression Scale (HADS-A≥8) and Edinburgh Postnatal Depression Scale (EPDS≥12) were used for assessing anxiety and depressive symptoms, respectively. Multivariate Poisson regression models with robust variance were applied to explore associations with anxiety and depressive symptoms. RESULTS: The prevalence of anxiety and depressive symptoms among sub-fertile, non-pregnant women (57.6% and 15.7%, respectively) were significantly higher compared to women pregnant after ART (21.1% and 8.5%, respectively) and naturally pregnant women (18.8% and 10.3%, respectively). History of psychiatric diagnosis was identified as an independent risk factor for both anxiety and depressive symptoms. The presence of at least one unhealthy lifestyle behavior (daily tobacco smoking, weekly alcohol consumption, BMI≥25, and regular physical exercise<2h/week) was also associated with anxiety (Prevalence Ratio, PR: 1.24; 95%CI: 1.09-1.40) and depressive symptoms (PR: 1.25; 95%CI: 1.04-1.49). CONCLUSIONS: Women pregnant after ART showed no difference in anxiety and depressive symptoms compared to naturally pregnant women. However, early psychological counseling and management of unhealthy lifestyle behaviors for sub-fertile women may be advisable, particularly for women with a previous history of psychiatric diagnosis.

Allogeneic major histocompatibility complex-mismatched equine bone marrow-derived mesenchymal stem cells are targeted for death by cytotoxic anti-major histocompatibility complex antibodies.

BACKGROUND: Allogeneic mesenchymal stem cells (MSCs) are a promising cell source for treating musculoskeletal injuries in horses. Controversy exists, however, over whether major histocompatibility complex (MHC)-mismatched MSCs are recognised by the recipient immune system and targeted for death by a cytotoxic antibody response. OBJECTIVES: To determine if cytotoxic anti-MHC antibodies generated in vivo following MHC-mismatched MSC injections are capable of initiating complement-dependent cytotoxicity of MSCs. STUDY DESIGN: Experimental controlled study. METHODS: Antisera previously collected at Days 0, 7, 14 and 21 post-injection from 4 horses injected with donor MHC-mismatched equine leucocyte antigen (ELA)-A2 haplotype MSCs and one control horse injected with donor MHC-matched ELA-A2 MSCs were utilised in this study. Antisera were incubated with ELA-A2 MSCs before adding complement in microcytotoxicity assays and cell death was analysed via eosin dye exclusion. ELA-A2 peripheral blood leucocytes (PBLs) were used in the assays as a positive control. RESULTS: Antisera from all 4 horses injected with MHC-mismatched MSCs contained antibodies that caused the death of ELA-A2 haplotype MSCs in the microcytotoxicity assays. In 2 of the 4 horses, antibodies were present as early as Day 7 post-injection. MSC death was consistently equivalent to that of ELA-A2 haplotype PBL death at all time points and antisera dilutions. Antisera from the control horse that was injected with MHC-matched MSCs did not contain cytotoxic ELA-A2 antibodies at any of the time points examined. MAIN LIMITATIONS: This study examined MSC death in vitro only and utilized antisera from a small number of horses. CONCLUSIONS: The cytotoxic antibody response induced in recipient horses following injection with donor MHC-mismatched MSCs is capable of killing donor MSCs in vitro. These results suggest that the use of allogeneic MHC-mismatched MSCs must be cautioned against, not only for potential adverse events, but also for reduced therapeutic efficacy due to targeted MSC death.

Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma.

While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.

A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial.

BACKGROUND: Maintenance treatment (mt) with bevacizumab (bev) ± erlotinib (erlo) has modest effect after induction chemotherapy in metastatic colorectal cancer (mCRC). We hypothesized the efficacy of erlo to be dependent on KRAS mutational status and investigated this by exploring mt strategies with bev ± erlo and low-dose capecitabine (cap). PATIENTS AND METHODS: Included patients had mCRC scheduled for first-line therapy, Eastern Cooperative Oncology Group (ECOG) 0-1 and no major comorbidities. Treatment with XELOX/FOLFOX or XELIRI/FOLFIRI + bev was given for 18 weeks. After induction, patients without progression were eligible for randomization to mt; KRAS wild-type (wt) patients were randomized to bev ± erlo (arms wt-BE, N = 36 versus wt-B, N = 35), KRAS mutated (mut) patients were randomized to bev or metronomic cap (arms mut-B, N = 34 versus mut-C, N = 33). Primary end point was progression-free survival (PFS) rate (PFSr) at 3 months after start of mt. A pooled analysis of KRAS wt patients from the previous ACT study was performed. RESULTS: We included 233 patients. Median age was 64 years, 62% male, 68% ECOG 0, 52% with primary tumor in situ. A total of 138 patients started mt after randomization. PFSr was 64.7% versus 63.6% in wt-B versus wt-BE, P = 1.000; and 75% versus 66.7% in mut-B versus mut-C, P = 0.579, with no significant difference in median PFS and overall survival (OS). In the pooled cohort, median PFS was 3.7 months in wt-B (N = 64) and 5.7 months in wt-BE (N = 62) (hazard ratios 1.03, 95% confidence interval 0.70-1.50, P = 0.867). The frequency of any grade 3/4 toxicities during mt was: 28%/58%/18%/15% (wt-B/wt-BE/mut-B/mut-C). CONCLUSIONS: Addition of erlo to bev as mt in KRAS wt mCRC did not significantly improve PFS or OS, but it did increase toxicity. KRAS status does not seem to influence the outcome of treatment with erlotinib. Metronomic cap warrants further investigation in mt strategies, given our explorative results. CLINICALTRIALSGOV: NCT01229813.

Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial.

BACKGROUND: The discussion on the role of adjuvant chemotherapy for rectal cancer patients treated according to current guidelines is still ongoing. A multicentre, randomized phase III trial, PROCTOR-SCRIPT, was conducted to compare adjuvant chemotherapy with observation for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision (TME). PATIENTS AND METHODS: The PROCTOR-SCRIPT trial recruited patients from 52 hospitals. Patients with histologically proven stage II or III rectal adenocarcinoma were randomly assigned (1:1) to observation or adjuvant chemotherapy after preoperative (chemo)radiotherapy and TME. Radiotherapy consisted of 5 × 5 Gy. Chemoradiotherapy consisted of 25 × 1.8-2 Gy combined with 5-FU-based chemotherapy. Adjuvant chemotherapy consisted of 5-FU/LV (PROCTOR) or eight courses capecitabine (SCRIPT). Randomization was based on permuted blocks of six, stratified according to centre, residual tumour, time between last irradiation and surgery, and preoperative treatment. The primary end point was overall survival. RESULTS: Of 470 enrolled patients, 437 were eligible. The trial closed prematurely because of slow patient accrual. Patients were randomly assigned to observation (n = 221) or adjuvant chemotherapy (n = 216). After a median follow-up of 5.0 years, 5-year overall survival was 79.2% in the observation group and 80.4% in the chemotherapy group [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.62-1.39; P = 0.73]. The HR for disease-free survival was 0.80 (95% CI 0.60-1.07; P = 0.13). Five-year cumulative incidence for locoregional recurrences was 7.8% in both groups. Five-year cumulative incidence for distant recurrences was 38.5% and 34.7%, respectively (P = 0.39). CONCLUSION: The PROCTOR-SCRIPT trial could not demonstrate a significant benefit of adjuvant chemotherapy with fluoropyrimidine monotherapy after preoperative (chemo)radiotherapy and TME on overall survival, disease-free survival, and recurrence rate. However, this trial did not complete planned accrual. REGISTRATION NUMBER: Dutch Colorectal Cancer group, CKTO 2003-16, ISRCTN36266738.

A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial.

BACKGROUND: The main objective was to study the effect on progression-free survival (PFS) of adding erlotinib to bevacizumab as maintenance treatment following chemotherapy and bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with untreated mCRC received doublet chemotherapy + bevacizumab during 18 weeks and those without tumor progression were eligible for randomization to bevacizumab + erlotinib (arm A) or bevacizumab alone (arm B), until progression or unacceptable toxic effect. RESULTS: Of the 249 patients enrolled, 80 started maintenance treatment in arm A and 79 in arm B. The rate of any grade 3/4 toxic effect was 53% in arm A and 13% in arm B. Median PFS was 5.7 months in arm A and 4.2 months in arm B (HR = 0.79; 95% confidence interval 0.55-1.12; P = 0.19). Overall survival (OS) from start of induction chemotherapy was 26.7 months in the randomized population, with no difference between the two arms. CONCLUSIONS: The addition of erlotinib to bevacizumab as maintenance treatment after first-line chemotherapy in mCRC did not improve PFS significantly. On-going clinical and translational studies focus on identifying subgroups of patients that may benefit from erlotinib in the maintenance setting. CLINICAL TRIALS NUMBER: NCT00598156.

The initial change in tumor size predicts response and survival in patients with metastatic colorectal cancer treated with combination chemotherapy.

BACKGROUND: To determine whether the change in tumor diameters at the first follow-up computed tomography (CT) examination after baseline examination (first change) correlates with outcome in patients with metastatic colorectal cancer (mCRC) treated with combination chemotherapy. PATIENTS AND METHODS: The first change was analyzed in a multicenter randomized phase III trial (Nordic VI, N = 567) comparing first-line irinotecan with either bolus or infused 5-fluorouracil. Cox proportional hazards multiple regression model and Kaplan-Meier survival analyses after correction for guarantee-time bias were carried out to evaluate correlations between first change, objective response according to RECIST 1.0, progression-free survival (PFS), and overall survival (OS). RESULTS: The hazard ratios for PFS and OS decreased along with first change. A decrease between 10% and <30%, albeit RECIST does not regard this as a partial response, was a positive prognostic factor for PFS and OS. Patients who had new lesions or unequivocal progression of nonmeasurable lesions had a worse prognosis than those with only an increase in size of >20%. CONCLUSIONS: The change in tumor size at the first follow-up CT is strongly prognostic for PFS and OS in mCRC.

Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer.

Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).

Plasma TIMP-1 levels and treatment outcome in patients treated with XELOX for metastatic colorectal cancer.

BACKGROUND: The aim was to evaluate the association between plasma tissue inhibitor of metalloproteinase-1 (TIMP-1) and serum carcinoembryonic antigen (CEA) levels and outcome in patients with metastatic colorectal cancer (mCRC) receiving XELOX (combination chemotherapy with capecitabine and oxaliplatin) as first-line treatment. PATIENTS AND METHODS: One hundred and twenty patients were included. Blood samples were collected before treatment and 3 weeks later before the next treatment cycle. Plasma TIMP-1 and serum CEA levels were correlated to treatment outcome. RESULTS: No significant associations between baseline TIMP-1 or CEA levels and best response to treatment or progression-free survival (PFS) could be demonstrated. In contrast, high baseline plasma TIMP-1 levels were associated with poor overall survival (OS), P = 0.008, hazard ratio (HR) = 1.80 [95% confidence interval (CI): 1.17-2.78]. Furthermore, increase in TIMP-1 levels from baseline to immediately before the second cycle of chemotherapy had a significant negative effect on survival (P = 0.03, HR = 1.30, 95% CI: 1.02-1.65) while a decrease in TIMP-1 was significantly associated with a higher objective response rate (P = 0.03). CONCLUSIONS: Both high baseline and subsequent increase in TIMP-1 levels were associated with shorter OS in patients with mCRC receiving XELOX as first-line treatment, whereas baseline TIMP-1 levels were not associated with response or PFS following XELOX treatment.

An explorative study on the clinical utility of baseline and serial serum tumour marker measurements in advanced upper gastrointestinal cancer.

The value of early tumour marker changes during palliative chemotherapy in patients with upper gastrointestinal adenocarcinoma (UGIA) is unclear. Seventy-three patients with advanced UGIA were randomised to receive 45 mg/m2 docetaxel or 180 mg/m2 irinotecan with 5-FU/leucovorin. After every 2nd course the patients were crossed over to the other regimen. Serum was sampled before start of chemotherapy and every 2nd week during 8 weeks for CEA, TPA, TPS, CA72-4, CA19-9 and CA242 measurements. Eighteen patients (25%) had partial response (PR) and 21 patients had stable disease for at least 4 months (SD4). All baseline marker levels, except CA72-4, correlated with time to progression and survival. Patients with normal levels, except CA72-4, also had more clinical responses (PR+SD4) than patients with elevated values. Tumour marker changes early during treatment provided modest predictive information for tumour response and survival. A model combining baseline level, the change and the interaction between them gave the best prediction of outcome, however, insignificantly better than baseline level for all markers except CA242. Baseline tumour marker levels provide prognostic information for patients with UGIA on palliative chemotherapy. Early changes generally failed to provide accurate information for tumour response and survival.

A window of opportunity phase II study of enzastaurin in chemonaive patients with asymptomatic metastatic colorectal cancer.

BACKGROUND: Preclinically, protein kinase C and AKT activation can be inhibited by enzastaurin and reduce tumor growth of colorectal cancer cells. In asymptomatic patients with metastatic colorectal cancer (mCRC), enzastaurin activity was evaluated by measuring the 6-month progression-free survival (PFS) rate in a window study design. PATIENTS AND METHODS: Chemonaive patients with asymptomatic mCRC who did not require immediate chemotherapy-induced tumor reduction received a 400-mg thrice daily loading dose of enzastaurin on day 1 of cycle 1, followed by 500 mg once daily for the remaining 28-day cycles. Progression was assessed on the basis of radiographic imaging, rise in carcinoembryonic antigen or lactate dehydrogenase (LDH) levels or by appearance of clinical symptoms. RESULTS: Twenty-eight patients received daily enzastaurin. The 6-month PFS rate was 28% [95% confidence interval (CI) 13%-45%] and median PFS was 1.9 months (95% CI 1.8-4.5 months). Twelve (43%) patients had stable disease with a median duration of 6.1 months. The survival rate at 20 months was 77% (95% CI 47%-92%). No grade 4 toxicity was reported and grade 3 toxic effects were observed in three patients with one patient showing probable drug-related elevation of liver transaminases. CONCLUSION: The window design in asymptomatic patients with mCRC can be safely applied to assess the activity and safety of novel cytostatic agents like enzastaurin.

Early prediction of response to first-line chemotherapy by sequential [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with advanced colorectal cancer.

BACKGROUND: To evaluate [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), for early evaluation of response to palliative chemotherapy and for prediction of long-term outcome, in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In a randomized trial, patients with mCRC received irinotecan-based combination chemotherapy. FDG-PET was carried out before treatment and after two cycles in 51 patients at two centers. Visual changes in tumor FDG uptake and changes measured semi-automatically, as standard uptake values (SUVs), were compared with radiological response after four and eight cycles. RESULTS: The mean baseline SUV for all tumor lesions per patient was higher in nonresponders than in responders (mean 7.4 versus 5.6, P = 0.02). There was a strong correlation between metabolic response (changes in SUV) and objective response (r = 0.57, P = 0.00001), with a sensitivity of 77% and a specificity of 76%. There was no significant correlation between metabolic response and time to progression (P = 0.5) or overall survival (P = 0.1). CONCLUSIONS: Although metabolic response assessed by FDG-PET reflects radiological tumor volume changes, the sensitivity and specificity are too low to support the routine use of PET in mCRC. Furthermore, PET failed to reflect long-term outcome and can, thus, not be used as surrogate end point for hard endpoint benefit.

Chronomodulated capecitabine in combination with short-time oxaliplatin: a Nordic phase II study of second-line therapy in patients with metastatic colorectal cancer after failure to irinotecan and 5-flourouracil.

BACKGROUND: Oxaliplatin in combination with capecitabine prolongs survival in patients with metastatic colorectal cancer (mCRC). Chronomodulation might reduce toxicity and improve efficacy. PATIENTS AND METHODS: A phase II study examining chronomodulated XELOX(30) (XELOX(30chron)): oxaliplatin: 130 mg/m(2) on day 1, as a 30-min infusion between 1 and 3 p.m. Capecitabine: total daily dose of 2000 mg/m(2), 20% of the dose between 7 and 9 a.m. and 80% of the dose between 6 and 8 p.m. in patients with mCRC resistant to irinotecan. Seventy-one patients were enrolled. Response rate was 18%; median progression-free survival 5.1 months and median overall survival (OS) 10.2 months. Platelet count and performance status were significantly correlated to OS in multivariate analyses. Neurotoxicity grade 2 and 3 was seen in 25% and 2% of patients, respectively, other grade 3 toxic effects were as follows: nausea 6%, vomiting 3%, diarrhoea 12% (3% experienced grade 4) and palmoplantart erytem 9%. CONCLUSION: XELOX(30chron) is a convenient second-line regimen with efficacy and safety profile similar to other oxaliplatin schedules. To further investigate chronomodulated XELOX, we have started a Nordic randomised phase II study comparing XELOX(30) and XELOX(30chron) as first-line therapy in patients with mCRC.

A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer.

BACKGROUND: To compare irinotecan with the Nordic 5-fluorouracil (5-FU) and folinic acid (FA) bolus schedule [irinotecan 180 mg/m(2) on day 1, 5-FU 500 mg/m(2) and FA 60 mg/m(2) on day 1 and 2 (FLIRI)] or the Lv5FU2 schedule [irinotecan 180 mg/m(2) on day 1, FA 200 mg/m(2), 5-FU bolus 400 mg/m(2) and infused 5-FU 600 mg/m(2) on day 1 and 2 (Lv5FU2-IRI)] due to uncertainties about how to administrate 5-FU with irinotecan. PATIENTS AND METHODS: Patients (n = 567) with metastatic colorectal cancer were randomly assigned to receive FLIRI or Lv5FU2-IRI. Primary end point was progression-free survival (PFS). RESULTS: Patient characteristics were well balanced. PFS did not differ between groups (median 9 months, P = 0.22). Overall survival (OS) was also similar (median 19 months, P = 0.9). Fewer objective responses were seen in the FLIRI group (35% versus 49%, P = 0.001) but the metastatic resection rate did not differ (4% versus 6%, P = 0.3). Grade 3/4 neutropenia (11% versus 5%, P = 0.01) and grade 2 alopecia (18% versus 9%, P = 0.002) were more common in the FLIRI group. The 60-day mortality was 2.4% versus 2.1%. CONCLUSIONS: Irinotecan with the bolus Nordic schedule (FLIRI) is a convenient treatment with PFS and OS comparable to irinotecan with the Lv5FU2 schedule. Neutropenia and alopecia are more prevalent, but both regimens are equally well tolerated.

Phase I study of UFT plus leucovorin with radiotherapy in patients with inextirpable non-rectal gastrointestinal cancer.

BACKGROUND AND PURPOSE: Chemoradiotherapy is increasingly used in the primary management of patients with loco-regionally advanced gastrointestinal (GI) cancer. Oral chemotherapy with uracil and tegafur (UFT) plus leucovorin (LV) may represent a convenient way of delivering protracted infusion of fluorouracil. Our goal was to evaluate the safety of UFT plus LV combined with radiation and determine the maximum-tolerated dose (MTD) and a recommended dose for further testing. PATIENTS AND METHODS: Patients with inextirpable GI cancer received escalating doses of UFT (starting at 300 mg/m(2)/d with 50 mg/m(2)/d increments between consecutive cohorts) and fixed doses of LV (90 mg/d). UFT and LV were given 5 days per week concurrently with radiation to 50 Gy (2 Gy/fraction). RESULTS: Twenty-five patients were treated, and 22 received the planned treatment. Three patients were withdrawn from treatment, two due to disease-progression and one due to toxicity. The MTD of UFT with radiation was 400 mg/m(2)/d with 90 mg/d of LV. Diarrhoea was the main dose limiting toxicity (DLT). Since some toxicity (3/12 DLTs) was seen in the expanded cohort at the level below, but none (0/9 DLT) at the starting level, the recommended dose chosen for further testing is 300-350 mg/m(2)/d depending upon the size of the target volume. CONCLUSION: Concomitant chemoradiation with oral UFT plus LV is feasible and well tolerated and should be further investigated since tumour responses were frequently seen.

Improved survival in patients with peritoneal metastases from colorectal cancer: a preliminary study.

Patients with peritoneal or local metastases from colorectal cancer have a poor prognosis. However, aggressive treatments by debulking surgery and infusional intraperitoneal (i.p.) chemotherapy have been tried and appear to benefit selected patients. We assayed the effects of debulking surgery and i.p. chemotherapy with respect to survival and compared the results with matched control patients treated by intravenous (i.v.) chemotherapy. In all, 18 patients with peritoneal and/or local metastases from colorectal adenocarcinoma underwent debulking surgery followed by 5-fluorouracil (5-FU) 550 mg m(-2) day(-1) i.p. and leucovorin (LV) 60 mg m(-2) day(-1) i.v. The chemotherapy was started the day after surgery and was given daily for 6 days and repeated monthly for totally eight courses. The control patients, matched for age, gender, performance status and metastatic site, were randomly selected from controlled clinical chemotherapy trials and treated with i.v. 5-FU+LV or i.v. methotrexate+5-FU+LV. There was no treatment-related mortality. The median survival among i.p. patients was 32 months compared to 14 months in the control group. In all, 11 patients who underwent macroscopically radical surgery had a longer survival than those who were not radically operated (P=0.02). These results indicate that patients with peritoneal metastases and/or locally advanced cancers but without distant metastases may benefit from cytoreductive surgery combined with i.p. chemotherapy.

Tumour markers as early predictors of response to chemotherapy in advanced colorectal carcinoma.

BACKGROUND: To evaluate the reliability and validity of serum carcinoembryonic antigen (CEA), tissue polypeptide-specific antigen (TPS), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in monitoring palliative chemotherapy in advanced colorectal cancer (ACRC). METHODS: Serum was prospectively collected from 87 patients with ACRC treated with first-line 5-fluorouracil and leucovorin before and 2, 4 and 10 weeks after induction. RESULTS: Eight patients had normal baseline TPS levels, and these patients had a favourable outcome with prolonged survival and a higher rate of objective responses than patients with elevated TPS levels. At 10 weeks, all responders had a decreasing TPS value. The sensitivity for a decrease of >25% using TPS was 83% and 86% for objective and subjective responses, respectively, and the specificity was 65% and 72%, respectively. CEA had, in the same setting, a sensitivity of 45% and 46%, respectively, and the specificity was 88%. VEGF was elevated in 54% of the patients and bFGF in 15% of the patients. The VEGF values decreased during therapy in 94% of the patients, but the changes in serial VEGF values did not correlate with survival or response. Tumour markers used together did not enhance the predictive values of TPS alone. CONCLUSIONS: Repeated measurements of CEA, VEGF and bFGF in serum are of limited value in monitoring chemotherapy in ACRC. TPS seems to be of greater interest, but does not predict exactly which patients are going to have a positive outcome of palliative chemotherapy.

Two postglacial immigration lineages of the polyploid Cerastium alpinum (Caryophyllaceae).

The plant cover of Fennoscandia is young because of the recent glaciation. This study covers the early stages of diversification and the genetic consequences of postglacial migration of a hermaphroditic polyploid plant. Cerastium alpinum. It has a continuous distribution in the alpine region, where it grows on alpine heaths and serpentine soils that are rich in heavy metals. Within the boreal forest C. alpinum has a scattered distribution on serpentine, dolomite and steep slopes. Plants from 31 populations in Norway, Sweden and Finland were subjected to enzyme electrophoresis. Analyses of the enzyme phenotypes suggest that C. alpinum has colonized Fennoscandia through two postglacial immigration events resulting in a southeastern and a southwestern lineage. These two lineages seem to meet in a hybrid zone in northern Sweden. Large genetic differences were found among most populations in both the southeastern and the southwestern lineages. This suggests that the populations are effectively isolated from each other.