Continuation of fluoropyrimidine treatment with S-1 after cardiotoxicity on capecitabine- or 5-fluorouracil-based therapy in patients with solid tumours: a multicentre retrospective observational cohort study.

BACKGROUND: Capecitabine- or 5-fluorouracil (5-FU)-based chemotherapy is widely used in many solid tumours, but is associated with cardiotoxicity. S-1 is a fluoropyrimidine with low rates of cardiotoxicity, but evidence regarding the safety of switching to S-1 after 5-FU- or capecitabine-associated cardiotoxicity is scarce. PATIENTS AND METHODS: This retrospective study (NCT04260269) was conducted at 13 centres in 6 countries. The primary endpoint was recurrence of cardiotoxicity after switch to S-1-based treatment due to 5-FU- or capecitabine-related cardiotoxicity: clinically meaningful if the upper boundary of the 95% confidence interval (CI; by competing risk) is not including 15%. Secondary endpoints included cardiac risk factors, diagnostic work-up, treatments, outcomes, and timelines of cardiotoxicity. RESULTS: Per protocol, 200 patients, treated between 2011 and 2020 [median age 66 years (range 19-86); 118 (59%) males], were included. Treatment intent was curative in 145 (73%). Initial cardiotoxicity was due to capecitabine (n = 170), continuous infusion 5-FU (n = 22), or bolus 5-FU (n = 8), which was administered in combination with other chemotherapy, targeted agents, or radiotherapy in 133 patients. Previous cardiovascular comorbidities were present in 99 (50%) patients. Cardiotoxic events (n = 228/200) included chest pain (n = 125), coronary syndrome/infarction (n = 69), arrhythmia (n = 22), heart failure/cardiomyopathy (n = 7), cardiac arrest (n = 4), and malignant hypertension (n = 1). Cardiotoxicity was severe or life-threatening in 112 (56%) patients and led to permanent capecitabine/5-FU discontinuation in 192 (96%). After switch to S-1, recurrent cardiotoxicity was observed in eight (4%) patients (95% CI 2.02-7.89, primary endpoint met). Events were limited to grade 1-2 and occurred at a median of 16 days (interquartile range 7-67) from therapy switch. Baseline ischemic heart disease was a risk factor for recurrent cardiotoxicity (odds ratio 6.18, 95% CI 1.36-28.11). CONCLUSION: Switching to S-1-based therapy is safe and feasible after development of cardiotoxicity on 5-FU- or capecitabine-based therapy and allows patients to continue their pivotal fluoropyrimidine-based treatment.

Treatment response of colorectal cancer liver metastases to neoadjuvant or conversion therapy: a prospective multicentre follow-up study using MRI, diffusion-weighted imaging and 1H-MR spectroscopy compared with histology (subgroup in the RAXO trial).

BACKGROUND: Colorectal cancer liver metastases respond to chemotherapy and targeted agents not only by shrinking, but also by morphologic and metabolic changes. The aim of this study was to evaluate the value of advanced magnetic resonance imaging (MRI) methods in predicting treatment response and survival. PATIENTS AND METHODS: We investigated contrast-enhanced MRI, apparent diffusion coefficient (ADC) in diffusion-weighted imaging and 1H-magnetic resonance spectroscopy (1H-MRS) in detecting early morphologic and metabolic changes in borderline or resectable liver metastases, as a response to first-line neoadjuvant or conversion therapy in a prospective substudy of the RAXO trial (NCT01531621, EudraCT2011-003158-24). MRI findings were compared with histology of resected liver metastases and Kaplan-Meier estimates of overall survival (OS). RESULTS: In 2012-2018, 52 patients at four Finnish university hospitals were recruited. Forty-seven patients received neoadjuvant or conversion chemotherapy and 40 liver resections were carried out. Low ADC values (below median) of the representative liver metastases, at baseline and after systemic therapy, were associated with partial response according to RECIST criteria, but not with morphologic MRI changes or histology. Decreasing ADC values following systemic therapy were associated with improved OS compared to unchanged or increasing ADC, both in the liver resected subgroup (5-year OS rate 100% and 34%, respectively, P = 0.022) and systemic therapy subgroup (5-year OS rate 62% and 23%, P = 0.049). 1H-MRS revealed steatohepatosis induced by systemic therapy. CONCLUSIONS: Low ADC values at baseline or during systemic therapy were associated with treatment response by RECIST but not with histology, morphologic or detectable metabolic changes. A decreasing ADC during systemic therapy is associated with improved OS both in all patients receiving systemic therapy and in the resected subgroup.

Centralized repeated resectability assessment of patients with colorectal liver metastases during first-line treatment: prospective study.

BACKGROUND: Metastasectomy is probably underused in metastatic colorectal cancer. The aim of this study was to investigate the effect of centralized repeated assessment on resectability rate of liver metastases. METHODS: The prospective RAXO study was a nationwide study in Finland. Patients with treatable metastatic colorectal cancer at any site were eligible. This planned substudy included patients with baseline liver metastases between 2012 and 2018. Resectability was reassessed by the multidisciplinary team at Helsinki tertiary referral centre upfront and twice during first-line systemic therapy. Outcomes were resectability rates, management changes, and survival. RESULTS: Of 812 patients included, 301 (37.1 per cent) had liver-only metastases. Of these, tumours were categorized as upfront resectable in 161 (53.5 per cent), and became amenable to surgery during systemic treatment in 63 (20.9 per cent). Some 207 patients (68.7 per cent) eventually underwent liver resection or ablation. At baseline, a discrepancy in resectability between central and local judgement was noted for 102 patients (33.9 per cent). Median disease-free survival (DFS) after first resection was 20 months and overall survival (OS) 79 months. Median OS after diagnosis of metastatic colorectal cancer was 80, 32, and 21 months in R0-1 resection, R2/ablation, and non-resected groups, and 5-year OS rates were 68, 37, and 9 per cent, respectively. Liver and extrahepatic metastases were present in 511 patients. Of these, tumours in 72 patients (14.1 per cent) were categorized as upfront resectable, and 53 patients (10.4 per cent) became eligible for surgery. Eventually 110 patients (21.5 per cent) underwent liver resection or ablation. At baseline, a discrepancy between local and central resectability was noted for 116 patients (22.7 per cent). Median DFS from first resection was 7 months and median OS 55 months. Median OS after diagnosis of metastatic colorectal cancer was 79, 42, and 17 months in R0-1 resection, R2/ablation, and non-resected groups, with 5-year OS rates of 65, 39, and 2 per cent, respectively. CONCLUSION: Repeated centralized resectability assessment in patients with colorectal liver metastases improved resection and survival rates.

Quality of life with biweekly docetaxel and capecitabine in advanced gastro-oesophageal cancer.

PURPOSE: This study aimed to evaluate the feasibility and tolerability of biweekly docetaxel with capecitabine as first-line treatment in advanced gastro-oesophageal cancer. METHODS: Fifty-three patients at median age of 61 years with advanced gastric cancer were included in this prospective, non-randomized, multicentre phase II trial to receive intravenous docetaxel 50 mg/m2 on days 1 and 15, and oral capecitabine 1250 mg/m2 every 12 h, on days 1-7 and 15-21 of each 28-day cycle. QOL was assessed using EORTC QLQ-C30, together with the gastric module (QLQ-STO 22). RESULTS: Forty-six patients were evaluable for QOL analyses. No deterioration in global health status was found. Social functioning scores improved, and eating difficulties and pain were alleviated during treatment. The most common grade 3 or 4 toxicity was neutropenia (47%), whereas neutropenic fever was uncommon (6%). The clinical benefit rate was 60%, including complete and partial responses as well as stabilized disease. Median overall survival was 8.8 months (95% CI 5.8-11.9 months), and median time to progression was 6.2 months (95% CI 4.9-7.5 months). CONCLUSIONS: Biweekly docetaxel with capecitabine is a feasible treatment in AGC, delivered on an outpatient basis, with no need for central venous access device. No deterioration of global health status was reported. In addition, pain and eating difficulties were alleviated during study treatment. This trial is registered at ClinicalTrials.gov , number NCT00669370.

Expression of CD11b/CD18 adhesion molecules on circulating phagocytes-a novel aid to diagnose infection in patients with cancer.

GOALS OF WORK: No blood marker available to date is useful for distinguishing infection-related from neoplasm-related fever. We evaluated the expression of the peripheral blood phagocyte CD11b/CD18 adhesion molecule complex for this purpose. MATERIALS AND METHODS: Neutrophil and monocyte CD11b/CD18 expression was assessed in two cohorts of patients with advanced solid cancer (n = 120) and in healthy controls (n = 63). The cancer series included 89 patients with verified infection, 23 without infection, and eight with neoplastic fever. CD11b/CD18 expression was measured using flow cytometry, and serum C-reactive protein (CRP) concentration was determined with immunoturbidimetric assay. RESULTS: Cancer patients with infection had higher blood neutrophil and monocyte CD11b/CD18 expression levels than patients with neoplastic fever, those with advanced cancer without infection, or healthy controls (p < 0.01 for all analyses). High CD11b/CD18 values were measured exclusively in individuals diagnosed with infection. Receiver-operating characteristic area under the curve (AUC) for neutrophil and monocyte CD11b/CD18 expression for the discrimination of infection from neoplastic fever was 0.80 (95% CI, 0.70 to 0.88), which was superior (p = 0.039 and p = 0.049, respectively) to serum CRP on admission (AUC 0.51, 0.40 to 0.62). CONCLUSIONS: Peripheral blood phagocytic cell CD11b/CD18 expression is useful for making a differential diagnosis between infection and neoplasm-related fever in cancer patients.

Serological evidence for Borna disease virus infection in humans, wild rodents and other vertebrates in Finland.

BACKGROUND: Borna disease virus (BDV) can infect many vertebrate species, including humans. BDV infection may lead to meningoencephalomyelitis in animals. An association with human neuropsychiatric diseases has been reported, but the causal relationship between BDV and human disease remains unclear. OBJECTIVES AND STUDY DESIGN: To find out whether BDV is present in Finland and to look for a potential reservoir, we examined a large panel of blood samples from different vertebrate species with immunofluorescence assay. Samples from horses, cats, dogs, sheep, cattle, large predators, grouse, wild rodents and humans were included. Most positive results were confirmed by other specific methods and in other laboratories. RESULTS AND CONCLUSIONS: BDV-specific antibodies were detected in 10 horses, 2 cats, as well as 2 horses and 1 dog from farms housing a previously detected seropositive horse. Interestingly, BDV-specific antibodies were further detected in three wild rodents. In humans, BDV-specific antibodies were detected in a veterinarian and in two patients suspected to have a Puumala hantavirus infection. Our serological analysis suggests that BDV infects various vertebrates in Finland, including humans. Furthermore, our data indicate for the first time that BDV infects also wild rodents.

Admission neopterin and interleukin 12 concentrations in identifying infections in adult cancer patients.

Differential diagnosis between infections and neoplastic fever is a common diagnostic problem. The utility of admission serum concentrations of neopterin and interleukin 12 (IL-12) was prospectively evaluated in this respect. The infection group (n=56) had a higher median neopterin value (12.8 nmol/l vs 4.0 nmol/l, P<0.001) and neopterin-to-IL-12 ratio (1.74 vs 0.11, P<0.001) than the non-infection group (n=36); the median IL-12 values were higher in the latter group (10.6 pg/ml vs 71.6 pg/ml, P=0.007). According to the area under the operating characteristics curves (AUC), especially neopterin (0.90), but also the neopterin-to-IL-12 ratio (0.79), was good at identifying bacteremia. However, in differentiating infections in general from neoplastic fever (n=10), the neopterin-to-IL-12 ratio was less powerful (0.64), though still better than neopterin (0.58) and clearly better than IL-12 (0.42). The present results show that the neopterin-to-IL-12 ratio, which reflects simultaneously both the ongoing infection and the tumour load, may have promising clinical implications for differential diagnosis between infections and neoplastic fever.

Balance between interleukin-10 and interleukin-12 in adult cancer patients with or without infections.

Reliable markers for identifying infections in cancer patients on admission are lacking. The utility of the balance between interleukin (IL)-10 and IL-12 was analysed in this respect. The infection group (n=56) had higher median serum levels of IL-10 (3.8 pg/ml; interquartile range (IQR) 1.7-11.4 pg/ml versus 1.8 pg/ml; IQR 0.6-4.6 pg/ml; P=0.005) and IL-10 to IL-12 ratio (0.4; IQR 0.06-4.23pg/ml versus 0.05; IQR 0.02-0.31pg/ml; P<0.001) than the non-infection group (n=36). IL-10 and the ratio had the following figures of sensitivity (79%; 95% confidence interval (CI) 66-88 versus 39%; 95% CI 27-53), specificity (40%; 95% CI 12-74 versus 90%; 95% CI 56-100) and positive predictive value (88%; 95% CI 76-96 versus 96%; 95% CI 78-100) for identifying infections (56 cases with infection and 10 with neoplastic fever), and the corresponding area under curve (AUC) values for IL-10 and the ratio in identifying infections in general were 0.58; 95% CI 0.39-0.78 versus 0.64; 95% CI 0.46-0.82 and in bacteraemia 0.71; 95% CI 0.50-0.92 versus 0.75; 95% CI 0.58-0.93, respectively. Thus, IL-10 can be used as a screening method for identifying infections in cancer patients and the ratio of IL-10 to IL-12 for confirming the diagnosis.

C-reactive protein and erythrocyte sedimentation rate in differential diagnosis between infections and neoplastic fever in patients with solid tumours and lymphomas.

The goals of our work were to study prospectively the possibility of differentiating between infections and neoplastic fever in adult cancer patients on admission, by means of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) or of follow-up CRP values. Patients and methods were as follows: the final infection group consisted of 56 patients and the noninfection group of 10 patients with neoplastic fever; CRP was measured on days 0, 3 and 5 and ESR at entry. The main results showed that the median CRP did not differ between the groups (91 mg/l vs 102 mg/l) on entry, while the ESR level was higher in the neoplastic fever group (50 mm/H vs 89 mm/H, P = 0.023). On admission, both markers had low area under receiver operating characteristic curves for the demonstration of infection (CRP 0.42; ESR 0.27). The CRP level dropped significantly in the infection group within 5 days (P = 0.009). We conclude that neither of the markers was useful in differentiating between infections and neoplastic fever on admission, but that the follow-up CRP values were advantageous in this respect.

C-reactive protein, procalcitonin and interleukin-8 in the primary diagnosis of infections in cancer patients.

The diagnostic utility of C-reactive protein (CRP), procalcitonin (PCT) and interleukin-8 (IL-8) were studied in 66 cancer patients with suspected infection (39 with definite foci of infection, 17 with antibiotic responses without foci and 10 with neoplastic fever without infection) and 26 patients scheduled for chemotherapy. The infection group (n=56) had higher median CRP (91 versus 19 mg/l, P<0. 001), PCT (0.28 versus 0.12 ng/ml, P<0.001) and IL-8 values (27.7 versus 16.9 pg/ml, P=0.032) than the non-infection group (n=36). In patients with suspected infection, only PCT was a good marker to discriminate bacteraemia with an area under the receiver operating characteristics curve of 0.92 (95% confidence interval (CI), 0.77-1. 0), but even PCT was less well able to differentiate between non-bacteraemic infections and neoplastic fever (0.56; 95% CI, 0. 35-0.77). In conclusion, PCT was a good indicator for bacteraemia, but none of the three markers were reliable indicators for minor infections in non-neutropenic cancer patients.

Microbial metabolism of the isoprenoid alkane pristane.

The "inert" hydrocarbon pristane (2,6,10,14-tetramethylpentadecane) can be utilized as the sole source of carbon and energy for growth of a coryneform soil isolate. Identification of the metabolites 4,8,12-trimethyltridecanoic acid and alpha-methylglutaric acid indicates that two pathways of fatty acid metabolism operate in this bacterial strain. The widespread use of pristane as a biological marker appears to be predicated on its structural similarity to phytol and its apparent stability, which may be only a reflection of the inability of microorganisms to carry out its anaerobic destruction.

Bacterial oxidation of 2-tridecanone to 1-undecanol.

A study of the microbial utilization of long-chain methyl ketones was under-taken. In general, enrichment culture experiments revealed that soil microorganisms capable of utilizing these compounds as growth substrates are ubiquitous. Gram-negative, rod-shaped bacteria were the prominent organisms exhibiting this capability. In particular, a strain of Pseudomonas isolated from soil degraded 2-tridecanone into several products that were recovered from cell-free culture fluid. These products were identified by gas-liquid chromatography as 2-tridecanol, 1-undecanol, 1-decanol, and undecanoic acid. A large amount of the substrate was converted to 1-undecanol. This compound was characterized further by classical methods of organic analysis. Unequivocal identification of 1-undecanol has established that some unique mechanism that involves subterminal oxidation must exist to degrade 2-tridecanone. No such mechanism has been reported for the biological degradation of long-chain, aliphatic, methyl ketones. A pathway for utilization of 2-tridecanone was proposed that is consistent with, but not confirmed by, the data presented.