Cytokine Profile in Patients with Postacute Sequelae of COVID-19.

The enduring impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its disease manifestation, COVID-19, on public health remains significant. Postacute sequelae of SARS-CoV-2 infection (PASC) affect a considerable number of patients, impairing their quality of life. While the role of the cytokine storm in acute COVID-19 is well established, its contribution to the pathophysiology of PASC is not fully understood. This study aimed to analyze the cytokine profile of patients with PASC following in vitro stimulation of Toll-like receptor (TLR) pathways, comparing them with a healthy control group. From October 2020 till March 2021, Brugmann University Hospital's clinical research unit included patients with PASC in the study. Whole blood samples were collected from 50 patients and 25 healthy volunteers. After in vitro stimulation under five different conditions, cytokine levels were measured using a multiplex method. Significantly decreased cytokine levels were observed in patients with PASC compared with healthy volunteers, particularly after TLR4 (interleukin [IL]-1α, IL-1ß, IL-2, IL-10, interferon (IFN)α, IFNγ, IFNω, and tumor necrosis factor (TNF)α) and TLR7/8 (IL-1α, IL-1ß, IFNα, IFNω, IFNγ, and TNFα) pathway stimulation. Principal component analysis identified two distinct clusters, suggesting a likely dysregulation of immunity involving TLR4 and TLR7/8 pathways in patients with PASC. Our study suggests that TLR4 and TLR7/8 pathways play a role in the pathophysiology of PASC. Continuous basal activation of immunity could explain the high basal concentrations of cytokines described in these patients and the decreased amplitude of response of these signaling pathways following specific stimulation.

Towards a better detection of patients at-risk of linezolid toxicity in clinical practice: a prospective study in three Belgian hospital centers.

Introduction: Linezolid is a last-resort antibiotic for infections caused by multidrug-resistant microorganisms. It is widely used for off-label indications and for longer than recommended treatment durations, exposing patients at higher risk of adverse drug reactions (ADRs), notably thrombocytopenia. This study aimed to investigate ADR incidence and risk factors, identify thrombocytopenia-related trough levels based on treatment duration, and evaluate the performance of predictive scores for ADR development. Methods: Adult in- and outpatients undergoing linezolid therapy were enrolled in three hospitals and ADRs and linezolid trough levels prospectively monitored over time. A population pharmacokinetic (pop-PK model) was used to estimate trough levels for blood samples collected at varying times. Results: A multivariate analysis based on 63 treatments identified treatment duration ≥10 days and trough levels >8 mg/L as independent risk factors of developing thrombocytopenia, with high trough values correlated with impaired renal function. Five patients treated for >28 days did not develop thrombocytopenia but maintained trough values in the target range (<8 mg/L). The Buzelé predictive score, which combines an age-adjusted Charlson comorbidity index with treatment duration, demonstrated 77% specificity and 67% sensitivity to predict the risk of ADR. Conclusion: Our work supports the necessity of establishing guidelines for dose adjustment in patients with renal insufficiency and the systematic use of TDM in patients at-risk in order to keep trough values ≤8 mg/L. The Buzelé predictive score (if ≥7) may help to detect these at-risk patients, and pop-PK models can estimate trough levels based on plasma samples collected at varying times, reducing the logistical burden of TDM in clinical practice.

Assessment of whole-body MRI including diffusion-weighted sequences in the initial staging of breast cancer patients at high risk of metastases in comparison with PET-CT: a prospective cohort study.

OBJECTIVE: The aim of this study was to assess the diffusion-weighted whole-body-MRI (WBMRI) in the initial staging of breast cancer at high risk of metastases in comparison with positron emission tomography (PET)-CT. METHODS: Forty-five women were prospectively enrolled. The inclusion criteria were female gender, age >18, invasive breast cancer, an initial PET-CT, and a performance status of 0-2. The exclusion criteria were contraindication to WB-MRI and breast cancer recurrence. The primary outcome was the concordance of WB-MRI and PET-CT in the diagnosis of distant metastases, whereas secondary outcomes included their concordance for the primary tumor and regional lymph nodes (LN), as well as the agreement of WB-MRI interpretation between two radiologists. RESULTS: The mean age was 51.2 years with a median size of the primary tumor of 30 mm. Concordance between the two modalities was almost perfect for metastases staging, all sites included (k = 0.862), with excellent interobserver agreement. The accuracy of WB-MRI for detecting regional LN, distant LN, lung, liver, or bone metastases ranged from 91 to 96%. In 2 patients, WB-MRI detected bone metastases that were overlooked by PET-CT. WB-MRI showed a substantial agreement with PET-CT for staging the primary tumor, regional LN status, and stage (k = 0.766, k = 0.756, and k = 0.785, respectively) with a high interobserver agreement. CONCLUSION: WB-MRI including DWI could be a reliable and reproducible examination in the initial staging of breast cancer patients at high risk of metastases, especially for bone metastases and therefore could be used as a surrogate to PET-CT. CLINICAL RELEVANCE STATEMENT: Whole-body-MRI including DWI is a promising technique for detecting metastases in the initial staging of breast cancer at high risk of metastases. KEY POINTS: Whole-body-MRI (WB-MRI) was effective for detecting metastases in the initial staging of 45 breast cancer patients at high risk of metastases in comparison with PET-CT. Concordance between WB-MRI and PET-CT was almost perfect for metastases staging, all sites included, with excellent interobserver agreement. The accuracy of WB-MRI for detecting bone metastases was 92%.

Assessment of diffusion-weighted MRI in predicting response to neoadjuvant chemotherapy in breast cancer patients.

To compare region of interest (ROI)-apparent diffusion coefficient (ADC) on diffusion-weighted imaging (DWI) measurements and Ki-67 proliferation index before and after neoadjuvant chemotherapy (NACT) for breast cancer. 55 women were enrolled in this prospective single-center study, with a final population of 47 women (49 cases of invasive breast cancer). ROI-ADC measurements were obtained on MRI before and after NACT and were compared to histological findings, including the Ki-67 index in the whole study population and in subgroups of "pathologic complete response" (pCR) and non-pCR. Nineteen percent of women experienced pCR. There was a significant inverse correlation between Ki-67 index and ROI-ADC before NACT (r = - 0.443, p = 0.001) and after NACT (r = - 0.614, p < 0.001). The mean Ki-67 index decreased from 45.8% before NACT to 18.0% after NACT (p < 0.001), whereas the mean ROI-ADC increased from 0.883 × 10-3 mm2/s before NACT to 1.533 × 10-3 mm2/s after NACT (p < 0.001). The model for the prediction of Ki67 index variations included patient age, hormonal receptor status, human epidermal growth factor receptor 2 status, Scarff-Bloom-Richardson grade 2, and ROI-ADC variations (p = 0.006). After NACT, a significant increase in breast cancer ROI-ADC on diffusion-weighted imaging was observed and a significant decrease in the Ki-67 index was predicted. Clinical trial registration number: clinicaltrial.gov NCT02798484, date: 14/06/2016.

Circulating DNA in the neoadjuvant setting of early stage colon cancer.

BACKGROUND: While circulating tumour (ct)DNA is an indicator of minimal residual disease and negative prognostic factor in stage II-III colon cancer, no study has ever analysed the value of this biomarker in colon cancer patients treated with neoadjuvant chemotherapy. We sought to fill this gap by using prospectively collected plasma samples from 80 stage III colon cancer patients, receiving one cycle of neoadjuvant FOLFOX followed by surgery +/- adjuvant FOLFOX in the PePiTA trial. MATERIAL AND METHODS: Samples were collected at baseline, 2 weeks and surgery. NPY and WIF1 were selected as universal methylation markers for ctDNA, and analysed with ddPCR technology. ROC curves were applied for cut-off points, and outcome measures included 5-year disease-free survival (DFS) and 6-year overall survival (OS). RESULTS: After a median follow-up of 52.5 months, baseline circulating-free (cf) DNA was an independent prognostic factor for DFS (HR 3.35, 95% CI: 1.15-9.77, p = .03), and a trend towards a similar association was observed for relative cfDNA changes between baseline and surgery (HR 2.57, 95% CI: 0.94-7.05, p = .07). Among 60 ctDNA assessable patients, 25 (42%) had detectable ctDNA at baseline. While detection of ctDNA at any pre-operative timepoint was not associated with outcome, patients with ctDNA increase (change of the worst trending methylation marker ≥11%, or mean ctDNA change of NPY and WIF1 ≥ 0%) between baseline and surgery showed a trend towards worse 5-year DFS (HR 3.66, 95% CI: 0.81-16.44, p = .09). CONCLUSION: This is the first study of ctDNA in the neoadjuvant setting of early-stage colon cancer. Results are hypothesis-generating and should be confirmed in larger series.

Pre-OPerative accelerated radiotherapy for early stage breast cancer patients (POPART): A feasibility study.

Pre-operative 5-fraction breast radiotherapy followed by immediate breast-sparing surgery and sentinel node procedure was feasible in 14 patients with 15 clinical early-stage breast cancers. However wound problems occurred frequently and was documented in 5 of the 14 patients: 2 patients with a mastitis needing antibiotics, 2 patients developed a fistula with exudate needing antibiotics and local disinfection and 1 patient developed a fistula needing surgical reintervention. Other acute and late iatrogenic events were rather limited. Two patients had a pathological lymph node involvement, which underlines the importance to perform the sentinel node procedure before pre-operative radiotherapy.

Value of diffusion-weighted MRI in predicting early response to neoadjuvant chemotherapy of breast cancer: comparison between ROI-ADC and whole-lesion-ADC measurements.

OBJECTIVE: The aim of the study was to assess DWI with ROI-ADC and WL-ADC measurements in early response after NAC in breast cancer. METHODS: Between January 2016 and December 2019, 55 women were enrolled in this prospective single-center study. MRI was performed at three time points for each patient: before treatment (MRI 1: DW and DCE MRI), after one cycle of NAC (MRI 2: noncontrast DW MRI), and after completion of NAC before surgery (MRI 3: DW and DCE MRI). ROI-ADC and WL-ADC measurements were obtained on MRI and were compared to histology findings and to the RCB class. Patients were categorized as having pCR or non-pCR. RESULTS: Among 48 patients, 9 experienced pCR. An increase of ROI-ADC between MRI 1 and 2 of more than 47.5% had a sensitivity of 88.9% and a specificity of 63.4% in predicting pCR, whereas WL-ADC did not predict pCR. An increase of ROI-ADC between MRI 1 and 2 of more than 47.5% had a sensitivity of 83.3% and a specificity of 64.9% in predicting radiologic complete response. An increase of WL-ADC between MRI 1 and 2 of more than 25.5% had a sensitivity of 83.3% and a specificity of 75.5% in predicting radiologic complete response. CONCLUSION: After one cycle of NAC, a significant increase in breast tumor ROI-ADC at DWI predicted complete pathologic and radiologic responses. KEY POINTS: • An increase of WL-ADC between MRI 1 and 2 of more than 25.5% had a sensitivity of 83.3% and a specificity of 75.5% in predicting radiologic complete response. • An increase of ROI-ADC between MRI 1 and 2 of more than 47.5% had a sensitivity of 88.9% and a specificity of 63.4% in predicting pCR, and a sensitivity of 83.3% and a specificity of 64.9% in predicting radiologic complete response. • A significant increase in breast tumor ROI-ADC at DWI predicted complete pathologic and radiologic responses.

Tocilizumab-Induced Unexpected Increase of Several Inflammatory Cytokines in Critically Ill COVID-19 Patients: The Anti-Inflammatory Side of IL-6.

Early evidence during the coronavirus disease 2019 (COVID-19) pandemic indicated high levels of interleukin (IL)-6 in patients with severe COVID-19. This led to the off-label use of tocilizumab (TCZ) during the first wave of the pandemic. While the monoclonal antibody blocks IL-6 pathway, its effect on other inflammatory cytokines remains poorly described. To better understand the effect of TCZ on the biological inflammatory profile, we monitored a large panel of inflammatory cytokines in critically ill COVID-19 patients receiving off-label TCZ. Twenty-three patients with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were included in the study, among which 15 patients received TCZ and 8 patients did not. Serum samples were collected for 8 days, before and following TCZ administration or hospital admission for the control group. Serum profile of 12 cytokines (IL-1ß, -2, -4, -6, -8, -10, -12, -13, -17, -18, tumor necrosis factor α (TNF-α), interferon-gamma (IFN-γ), and sIL-6R were assessed in these two groups. Although the increased IL-6 concentrations after TCZ infusion were expected, we observed an unexpected increase in IL-1ß, -2, -4, -10, -12p70, -18, and sIL-6R levels in the treated patients with maximal values reaching 2 to 4 days after TCZ. In contrast, no change in cytokine levels was observed in the control group. Our results suggested that some inflammatory pathways escape IL-6R blockade and even appeared amplified. This finding highlights an old observation of the anti-inflammatory effects of IL-6 as already suggested over 20 years ago. Clinical Trial Registration number: NCT04346017.

Safety and efficacy of a single intra-articular injection of a novel enhanced protein solution (JTA-004) compared to hylan G-F 20 in symptomatic knee osteoarthritis: a randomized, double-blind, controlled phase II/III study.

BACKGROUND: New minimally invasive treatments are vital to delay joint replacement surgery in patients with knee osteoarthritis. This study was designed to select the most effective among three formulations of an enhanced protein solution containing clonidine, hyaluronic acid, and human plasma (JTA-004), and compare the safety and efficacy of intra-articular administration of the selected formulation with a reference treatment (hyaluronic acid) in symptomatic knee osteoarthritis patients. METHODS: In this two-stage, double-blind, phase II/III study conducted in 12 Belgian centers, 50-79-year-old patients with primary knee osteoarthritis were randomized (1:1:1:1) to receive one dose of one of three JTA-004 formulations (differing in clonidine concentration [50 or 100 µg/ml] and volume [2 or 4 ml]) or the reference treatment (hylan G-F 20). Patients were evaluated using Western Ontario McMaster Universities (WOMAC®) Scores and the Short-Form health survey up to 6 months post-injection (Month 6). Drug consumption and safety were evaluated. RESULTS: Among 164 treated patients, 147 completed the study. The JTA-004 formulation containing 200 µg clonidine and 20 mg hyaluronic acid in 2 ml (JTA-200/2) was selected based on interim results at Month 6. The difference in adjusted mean change in WOMAC Pain Subscale Score from baseline (JTA-200/2 minus reference group) at Month 6 was - 9.49 mm; statistical superiority of JTA-200/2 over the reference was not demonstrated. No statistically significant differences in adjusted mean changes from baseline between JTA-200/2 and reference groups were observed for Pain, Physical Function and Stiffness Subscales WOMAC Scores, Total WOMAC Score, and Well-being Score at any timepoint, although JTA-200/2 induced larger improvements in WOMAC Scores than the reference. Statistically significantly larger improvements in WOMAC Pain Subscale Scores for JTA-004 versus the reference were observed in post-hoc analyses on pooled data from all JTA-004 formulations at Month 6 (p = 0.030) and Month 3 (p = 0.014). All JTA-004 formulations had clinically acceptable safety profiles. CONCLUSIONS: This study provided preliminary evidence of the safety of intra-articular injection of JTA-004 in knee osteoarthritis patients. Phase III randomized controlled trials with larger sample sizes are needed to evaluate the efficacy of JTA-004 in knee osteoarthritis. TRIAL REGISTRATION: Clinicaltrials.gov/identifier NCT02740231; clinicaltrialsregister.eu/identifier 2015-002117-30. Retrospectively registered 13/4/2016.

A score combining early detection of cytokines accurately predicts COVID-19 severity and intensive care unit transfer.

OBJECTIVES: We aimed to explore cytokine profile in patients as it relates to Coronavirus Disease 2019 (COVID-19) severity, and to establish a predictive cytokine score to discriminate severe from non-severe cases and provide a prognosis parameter for patients that will require intensive care unit (ICU) transfer. METHODS: Serum samples of 63 patients diagnosed with SARS-CoV-2 infection were collected early after hospital admission (day 0-3). Patients were categorized in five groups based on the clinical presentation, the PaO2/FiO2 ratio and the requirement of mechanical ventilation. RESULTS: Three cytokines, IL-6, IL-8 and IL-10, were markedly higher in severe forms (n = 44) than in non-severe forms (n = 19) (p < 0.005). A score combining levels of these three cytokines (IL-6*IL-8*IL-10) had the highest performance to predict severity: sensitivity of 86.4% (95% CI, 72.4-94.8) and specificity of 94.7% (95% CI, 74.0-99.9) for a cutoff value of 2068 pg/mL. Elevated levels of IL-6, IL-8 and IL-10 were also found in critically ill patients. The combination of IL-6*IL-10 serum levels allowed the highest predictability for ICU transfer: AUC of 0.898 (p < 0.0001). CONCLUSION: The combinatorial IL-6*IL-8*IL-10 score at presentation was highly predictive of the progression to a severe form of the disease, and could contribute to improve patient triage and to adapt therapeutic strategy within clinical trials more accurately and efficiently.

Evaluation of Cardiac Function in Patients with Sickle Cell Disease with Left Ventricular Global Longitudinal Strain.

BACKGROUND AND OBJECTIVES: The importance of myocardial dysfunction in sickle cell disease (SCD) is currently debated. It is difficult to find a reliable index of function in patients with chronic overload as in SCD. Speckle tracking echocardiography, a new mean of evaluating cardiac function, might be a useful tool in SCD. It has been applied in many fields to detect early cardiac function deterioration, and it is less load dependent compared with other function parameters. Studies in patients with SCD are rare, and the results are conflicting. The present study aimed to determine whether left ventricular global longitudinal strain (LV-GLS) was abnormal in a population of adults with SCD and whether it was correlated with clinical or biological parameters. METHODS: We prospectively enrolled 37 patients and 34 age- and sex-matched healthy controls. Echocardiography was performed in patients and controls. RESULTS: We found that the left ventricular diameter and mass were higher and the ejection fraction and longitudinal strain were lower in patients compared with controls. Diastolic dysfunction was uncommon. LV-GLS was abnormal in 21% of the patients. No correlation was observed between strain and clinical or biological parameters. CONCLUSIONS: We concluded that LV-GLS could be a useful tool for evaluating these patients. However, the clinical impact of reduced LV-GLS remains to be determined.

Neurophysiological markers of cue reactivity and inhibition subtend a three-month period of complete alcohol abstinence.

OBJECTIVE: Finding new tools for conventional management of alcohol disorders is a challenge for psychiatrists. Brain indications related to cognitive functioning could represent such an add-on tool. METHODS: Forty alcohol-dependent inpatients undertook two cognitive event-related potential (ERP) tasks at the beginning and at the end of a 4-week detoxification program. These comprised a visual oddball task investigating cue reactivity and a Go/No-go task tagging inhibition using oddball P3d and No-go P3d ERP components. Three months after discharge, the patient group (N = 40) was split into two subgroups: patients who remained abstinent during this post-treatment period (90 days; n = 15), and patients who relapsed (mean time: 28.5 ± 26.2 days; n = 25). Pattern changes of both ERP markers (oddball P3d and No-go P3d) during the detoxification were compared to differentiate these populations. RESULTS: Abstinent patients exhibited similar P3d responses devoted to alcohol cues in Sessions 1 and 2, but an increased No-go P3d devoted to No-go trials in alcohol-related contexts in Session 2 compared to Session 1. CONCLUSIONS: Specific cue-reactivity and inhibitory neurophysiological markers subtend a further three-months of complete abstinence. SIGNIFICANCE: Monitoring these ERP changes during detoxification may provide important clues regarding patients' future abstinence vs. relapse.

Alteration of humoral, cellular and cytokine immune response to inactivated influenza vaccine in patients with Sickle Cell Disease.

INTRODUCTION: Patients suffering from Sickle Cell Disease (SCD) are at increased risk for complications due to influenza virus. Annual influenza vaccination is strongly recommended but few clinical studies have assessed its immunogenicity in individuals with SCD. The aim of this study was to explore the biological efficacy of annual influenza vaccination in SCD patients by characterizing both their humoral and cell-mediated immunity against influenza antigen. We also aimed to investigate these immunological responses among SCD individuals according to their treatment (hydroxyurea (HU), chronic blood transfusions (CT), both HU and CT or none of them). METHODS: Seventy-two SCD patients (49 receiving HU, 9 on CT, 7 with both and 7 without treatment) and 30 healthy controls were included in the study. All subjects received the tetravalent influenza α-RIX-Tetra® vaccine from the 2016-2017 or 2017-2018 season. RESULTS: Protective anti-influenza HAI titers were obtained for the majority of SCD patients one month after vaccination but seroconversion rates in patient groups were strongly decreased compared to controls. Immune cell counts, particularly cellular memory including memory T and memory B cells, were greatly reduced in SCD individuals. Functional activation assays confirmed a poorer CD8+ T cell memory. We also document an imbalance of cytokines after influenza vaccination in SCD individuals with an INFγ/IL-10 ratio (Th1-type/Treg-type response) significantly lower in the SCD cohort. CONCLUSION: SCD patients undergoing CT showed altered immune regulation as compared to other treatment subgroups. Altogether, the cytokine imbalance, the high regulatory T cell levels and the low memory lymphocyte subset levels observed in the SCD cohort, namely for those on CT, suggest a poor ability of SCD patients to fight against influenza infection. Nevertheless, our serological data support current clinical practice for annual influenza vaccination, though immunogenicity to other vaccines involving immunological memory might be hampered in SCD patients and should be further investigated.

A phase II trial to assess efficacy and safety of afatinib in extensively pretreated patients with HER2-negative metastatic breast cancer.

Afatinib (BIBW 2992) is an ErbB-family blocker that irreversibly inhibits signaling from all relevant ErbB-family dimers. Afatinib has demonstrated preclinical activity in human epidermal growth factor receptor HER2 (ErbB2)-positive and triple-negative xenograft models of breast cancer, and clinical activity in phase I studies. This was a multicenter phase II study enrolling patients with HER2-negative metastatic breast cancer progressing following no more than three lines of chemotherapy. No prior epidermal growth factor receptor-targeted therapy was allowed. Patients received 50-mg afatinib once daily until disease progression. Tumor assessment was performed at every other 28-day treatment course. The primary endpoint was clinical benefit (CB) for ≥4 treatment courses in triple-negative (Cohort A) metastatic breast cancer (TNBC) and objective responses measured by Response Evaluation Criteria in Solid Tumors in patients with HER2-negative, estrogen receptor-positive, and/or progesterone receptor-positive breast cancer (Cohort B). Fifty patients received treatment, including 29 patients in Cohort A and 21 patients in Cohort B. No objective responses were observed in either cohort. Median progression-free survival was 7.4 and 7.7 weeks in Cohorts A and B, respectively. Three patients with TNBC had stable disease for ≥4 treatment courses, one of them for 12 courses (median 26.3 weeks; range 18.9-47.9 weeks). The most frequently observed afatinib-associated adverse events (AEs) were gastrointestinal and skin-related side effects, which were manageable by symptomatic treatment and dose reductions. Afatinib pharmacokinetics were comparable to those observed in previously reported phase I trials. In conclusion, afatinib had limited activity in HER2-negative breast cancer. AEs were generally manageable and mainly affected the skin and the gastrointestinal tract.

Safety and pharmacokinetics of sorafenib combined with capecitabine in patients with advanced solid tumors: results of a phase 1 trial.

Sorafenib (twice daily [bid]) plus capecitabine (2 weeks on schedule/1 week off schedule) safety and pharmacokinetics were investigated in patients with advanced solid tumors (N = 35). Cohort 1 (n = 13) included sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid; cohort 2 (n = 4), sorafenib 400 mg bid and capecitabine 1050 mg/m(2) bid; cohort 3 (n = 6), sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid (cycles 1 and 2), then 400 mg bid and capecitabine 1050 mg/m(2) bid (cycle 3 onwards); and cohort 4 (n = 12), sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid. The combination of sorafenib and capecitabine was generally well tolerated. Most frequent drug-related adverse events were hand-foot skin reaction (HFSR, 89%), diarrhea (71%), and fatigue (69%). The HFSR was dose-limiting toxicities in 6 patients. Sorafenib exposure (C(max) and AUC(0-12)) was unaffected by concomitant capecitabine. Concomitant sorafenib moderately increased capecitabine and 5-fluorouracil (metabolite) exposure when the capecitabine dose was 1050 mg/m(2) bid. Simultaneous administration of 400 mg bid sorafenib and 850 mg/m(2) bid capecitabine, however, had only minor effects on the exposure to capecitabine and 5-fluorouracil. Based on the overall toxicity profile and pharmacokinetic parameters, the recommended phase 2 doses were therefore sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid, as scheduled above.