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Background: In phase II studies, irinotecan is active in metastatic colorectal cancer, but the overall benefit has not been assessed in a randomised clinical trial.Methods: Patients with proven metastatic colorectal cancer, which had progressed within 6 months of treatment with fluorouracil, were randomly assigned either 300-350 mg/m2 irinotecan every 3 weeks with supportive care or supportive care alone, in a 2:1 ratio.Findings: 189 patients were allocated irinotecan and supportive care and 90 supportive care alone. The mean age of the participants was 58.8 years; 181 (65%) were men and 98 (35%) were women. WHO performance status was 0 in 79 (42%) patients, 1 in 77 (41%) patients, and 2 in 32 (17%) patients. Tumour-related symptoms were present in 134 (71%) patients and weight loss of more than 5% was seen in 15 (8%) patients. With a median follow-up of 13 months, the overall survival was significantly better in the irinotecan group (p=0.0001), with 36.2% 1-year survival in the irinotecan group versus 13.8% in the supportive-care group. The survival benefit, adjusted for prognostic factors in a multivariate analysis, remained significant (p=0.001). Survival without performance-status deterioration (p=0.0001), without weight loss of more than 5% (p=0.018), and pain-free survival (p=0.003) were significantly better in the patients given irinotecan. In a quality-of-life analysis, all significant differences, except on diarrhoea score, were in favour of the irinotecan group.Interpretation: Our study shows that despite the side-effects of treatment, patients who have metastatic colorectal cancer, and for whom fluorouracil has failed, have a longer survival, fewer tumour-related symptoms, and a better quality of life when treated with irinotecan than with supportive care alone. [ABSTRACT FROM AUTHOR]

Human cryo-IgM rheumatoid factor (RF) preparations blocked the tumor-specific in vitro cytotoxicity of ovarian or bladder carcinoma patients' lymphoid cells in microcytotoxicity assays. The effect was mediated by pretreatment of the effector cells. Cryo-IgM RF free of detectable IgG blocked in a dilution-dependent manner, and immunosorbent purification of contaminating IgG from another preparation did not abrogate the blocking effect. Control IgM preparations lacking RF activity did not block the cytotoxicity, and normal human serum preincubation of the RF preparations rendered them inactive, indicating that the blocking effect was due to the anti-IgG activity of the RF. [ABSTRACT FROM AUTHOR]

Background/aim: Interferon-alpha (IFN-alpha) has shown survival benefits in metastatic renal cell carcinoma (mRCC), but the knowledge about long-term outcome is sparse. Additional knowledge is beneficial because IFN-alpha usage in combination therapy such as immune checkpoint inhibitor for mRCC is an area of interest. This is the longest follow-up concerning IFN-alpha treatment., Patients and Methods: A total of 117 metastatic renal cell cancer (mRCC) patients without prior chemotherapy were enrolled between 1994-2002 and followed-up until January 2022. The median follow-up was 18 months. After progression to IFN-alpha, the patients were not treated with tyrosine kinase, mTOR inhibitors or bevacizumab as these were not standard therapies at that time or the patients' performance status was too poor. Mean treatment duration was 11 months., Results: Median overall survival was 19.0 months, 5-year survival rate 16.2%, and 10-year survival rate 9.0%. There were statistically significant differences in survival in response to treatment (log-rank test, p<0.001): median overall survival was 52.0 months for objective responses, 25.0 months for stable disease and 5.0 months for progressive disease. Proportion of 5-year survivors was 29% in low, 20% in intermediate, and 7% in high-risk groups, respectively (p=0.001)., Conclusion: With prolonged INF-alpha treatment stable and responding patients can obtain late objective responses, long-lasting complete responses, and long-term outcome with acceptable toxicity. IFN-alpha is an alternative therapy when multiple treatment lines are used for mRCC and an interesting option to study for combined therapies such as immune checkpoint inhibitor-based therapies., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Regorafenib inhibits VEGF receptors 1, 2, and 3 and PDGF receptors like other anti-angiogenic tyrosine-kinase inhibitors approved for treatment of advanced renal-cell cancer. Regorafenib also inhibits other potentially important angiogenic kinases like TIE2, activation of which is thought to be important in tumour escape mechanisms. This phase 2, open-label, non-randomised study assessed the safety and efficacy of the multikinase inhibitor regorafenib for treatment of renal-cell carcinoma., Methods: Patients were recruited from 18 academic oncology centres across Europe and USA. Patients with previously untreated metastatic or unresectable clear-cell renal-cell carcinoma received oral regorafenib (160 mg per day) in repeating cycles of 3 weeks on, 1 week off until disease progression or until patients met the criteria for removal from study. The primary efficacy endpoint was the proportion of patients who achieved an objective overall response, assessed in all patients who were evaluable for response. The trial has finished. This trial is registered with ClinicalTrials.gov, number NCT00664326., Findings: The study was done between April 30, 2008, and June 1, 2011. We screened 64 patients, of whom 49 received regorafenib. Median duration of treatment was 7·1 months (range 0·7-34·4, IQR 2·5-18·0) and at the time of data cutoff, six patients (12%) were still receiving treatment. 48 patients were assessable for tumour response. 19 patients (39·6%, 90% CI 27·7-52·5) had an objective response, all of which were partial responses. Drug-related adverse events occurred in 48 patients (98%) and drug-related serious adverse events in 17 (35%). Grade 3 drug-related adverse events were common, most frequently hand and foot skin reaction (16 patients, 33%), diarrhoea (five patients, 10%), renal failure (five patients, 10%), fatigue (four patients, 8%), and hypertension (three patients, 6%). Two patients had grade 4 treatment-related adverse events: two cardiac ischaemia or infarction, one hypomagnesaemia, and one pain in the chest or thorax. Four patients died during study treatment or within 30 days of last dose, of which two were deemed likely to be related to the study drug., Interpretation: Regorafenib has antitumour activity as first-line treatment for metastatic or unresectable renal-cell carcinoma. The drug's safety profile requires close monitoring., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: The NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on treatment outcome was also investigated., Patients and Methods: Patients were randomly assigned to receive either standard Nordic FLOX (arm A), cetuximab and FLOX (arm B), or cetuximab combined with intermittent FLOX (arm C). Primary end point was progression-free survival (PFS). Overall survival (OS), response rate, R0 resection rate, and safety were secondary end points., Results: Of the 571 patients randomly assigned, 566 were evaluable in intention-to-treat (ITT) analyses. KRAS and BRAF mutation analyses were obtained in 498 (88%) and 457 patients (81%), respectively. KRAS mutations were present in 39% of the tumors; 12% of tumors had BRAF mutations. The presence of BRAF mutations was a strong negative prognostic factor. In the ITT population, median PFS was 7.9, 8.3, and 7.3 months for the three arms, respectively (not significantly different). OS was almost identical for the three groups (20.4, 19.7, 20.3 months, respectively), and confirmed response rates were 41%, 49%, and 47%, respectively. In patients with KRAS wild-type tumors, cetuximab did not provide any additional benefit compared with FLOX alone. In patients with KRAS mutations, no significant difference was detected, although a trend toward improved PFS was observed in arm B. The regimens were well tolerated., Conclusion: Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.

Aim: To examine the expression of thymidylate synthase (TS) and oncoprotein Bcl-2 in advanced colorectal cancer (CRC) patients, and to determine their mutual relationship, association to therapeutic response and impact on disease outcome., Methods: Tumor samples from 67 patients with CRC, who were treated at advanced stage with either irinotecan alone or in combination with 5-fluorouracil/leucovorin, were analyzed for expression of TS and Bcl-2 using immunohistochemistry., Results: A significant linear correlation between lower expression levels of Bcl-2 and lower levels of TS expression was found (P = 0.033). Patients with high levels of both TS and Bcl-2 expression had a significantly longer disease-free survival (DFS) (42.6 mo vs 5.4 mo, n = 25) than those with low TS/Bcl-2 index (P = 0.001). Tumors with low levels of both TS and Bcl-2 were associated with a longer survival with metastasis (WMS) interval in the whole patients group (n = 67, P = 0.035). TS/Bcl-2 index was not significantly related to disease-specific survival., Conclusion: The present data suggest that CRC patients with low TS/Bcl-2 demonstrate a significantly shorter DFS and longer WMS.

Aim: To investigate the changing pattern of beta-catenin expression and its prognostic value in advanced colorectal cancer (CRC)., Methods: Archival tumor samples were analyzed for beta-catenin using immunohistochemistry (IHC) in 95 patients with advanced CRC., Results: Membranous beta-catenin expression was found in the normal colorectal epithelium. Almost 100% of CRC cases showed membranous and cytoplasmic expression, and 55 (58%) cases showed nuclear expression. In univariate (Kaplan-Meier) survival analysis, only the nuclear index (NI) was a significant predictor of disease free survival (DFS) (P = 0.023; n = 35), with a NI above the median associated with longer DFS (34.2 mo) than those with a NI below the median (15.5 mo) (P = 0.045, ANOVA). The other indices were not significant predictors of DFS, and none of the three tested indices (for membranous, cytoplasmic, or nuclear expression) predicted disease-specific survival (DSS). However, when dichotomized as positive or negative nuclear expression, the former was a significant predictor of more favorable DFS (P = 0.041) and DSS (P = 0.046)., Conclusion: Nuclear beta-catenin expression provides additional information in predicting patient outcome in advanced CRC.

Aim: To investigate the changes that occur in E-cadherin expression during the process of metastasis in colorectal cancer., Methods: E-cadherin expression was detected by immunohistochemistry and two indices of expression were calculated which reflected the level of expression and the locations (membrane and cytoplasm). Univariate and multivariate survival analyses were used to assess the value of these two E-cadherin indices as predictors of both disease-free (DFS) and disease-specific (DSS) survival., Results: E-cadherin membrane index (MI), but not cytoplasmic index (CI), was significantly higher in primary tumors than their metastases (P = 0.0001). Furthermore, both primary tumor MI and CI were higher among the patients who developed subsequent metastasis (P = 0.022 and P = 0.007, respectively). Interestingly, both indices were higher in liver metastase compared to other anatomic sites (MI, P = 0.034 and CI, P = 0.022). The CI of the primary tumors was a significant predictor of DFS (P = 0.042, univariate analysis), with a strong inverse correlation between CI and DFS (P = 0.006, multivariate analysis). Finally, the MI of primary tumor proved to be a significant independent predictor of DSS, with higher indices being associated with a more favorable outcome (P = 0.016)., Conclusion: Examination of E-cadherin expression and distribution in colorectal tumors can be extremely valuable in predicting disease recurrence. The observation that aberrant cytoplasmic expression of E-cadherin can predict disease recurrence is obviously of great importance for both patients and clinicians, and significantly affects decisions concerning the therapy and management of the patients.

We reported earlier that despite the well-known cytolytic effect of anticancer drugs, mean stimulated salivary flow rates were not significantly affected during a 12-month follow-up of patients undergoing treatment for lymphomas (Laine et al. Oral Oncol, Eur J Cancer 1992, 28B, 125-128). Therefore, we set out to investigate in more detail the flow rates and composition of salivas in these patients, but now grouped according to their initial flow rate values, which had been assessed before the start of treatment. 49 patients of the original material (30 men and 19 women, mean age 49.9 years) were divided into hyposalivation and normal flow rate groups, according to their baseline values. Stimulated saliva flow > or = 0.8 ml/min was regarded as the limit for a normal flow rate. 11 patients were found to have reduced flow at baseline (hyposalivation group), while 38 patients had normal flow rate. Analysis of repeated saliva samples taken during the 12-month follow-up showed that flow rates remained significantly lower in the hyposalivation group compared with those of the other group (P < 0.001). Further, the concentrations of total protein, albumin, lysozyme, amylase, IgG, IgA and IgM were, and remained, all significantly higher in patients of the hyposalivation group. Counts for salivary mutans streptococci and yeasts were higher and remained significantly so among patients with hyposalivation than among those with normal flow rate while lactobacilli counts were higher in patients with normal initial flow rate.(ABSTRACT TRUNCATED AT 250 WORDS)