The effects of hypercortisolism on the frequency and magnitude of sleep EEG waves in patients with Cushing syndrome: A spectral analysis study.

OBJECTIVES: Our aim was to investigate the effects of endogenous chronic hypercortisolism on sleep electroencephalogram (EEG) and differences between the adrenocorticotropic hormone (ACTH)-dependent and independent Cushing Syndrome (CS) patients through a sleep spectral analysis program. METHODS: A total of 32 patients diagnosed as having endogenous CS (12 ACTH-dependent and 20 ACTH-independent) and a control group comprising 16 healthy individuals were included in the study. Polysomnographic analysis was performed. Blood samples were collected at 08:00 AM for analysis of ACTH and basal cortisol, and at 00:00 AM for midnight cortisol levels. The frequency and power of the slow wave activity (SWA), theta, alpha, and beta waves of the first and last non-rapid eye movement (NREM) cycles were measured with a spectral analysis program. RESULTS: The CS patient group had higher SWA power, especially in the first NREM cycle. In the ACTH-dependent group, SWA maximum and mean power values were higher in the frontal channels in the first NREM, compared to the last NREM sleep stage (p<0.05). CONCLUSION: Cortisol has been found to be associated with SWA waves, making these waves higher in power, especially in the first NREM phase. This difference was much less pronounced in the final NREM sleep stage. The difference between the first and last NREM sleep stages with respect to the power of SWA in the frontal channel in the ACTH-dependent group suggests that not only cortisol but also high levels of ACTH affect the power of slow waves during sleep.

The REM-sleep-related characteristics of narcolepsy: a nation-wide multicenter study in Turkey, the REMCON study.

INTRODUCTION: Narcolepsy type 1 (NT1) is caused by hypocretin deficiency, the pathophysiology of narcolepsy type 2 (NT2) has not been delineated. Except for the hypocretin deficiency and cataplexy, all clinical and laboratory features used in the diagnosis of NT2 are identical to those used for NT1. The aim of this study was to assess the rapid eye movement (REM) sleep-related characteristics in the patients with narcolepsy; the characteristics of REM sleep in polysomnography (PSG) and multiple sleep latency test (MSLT) recordings, the quantification of REM sleep without atonia (RSWA) and atonia index, and the analysis of rapid eye movements (REMs) during REM sleep. MATERIALS AND METHODS: This study was planned by the Sleep Medicine Study Group of the Turkish Neurology Society, and conducted in 11 centers in eight cities in Turkey. The analysis of RSWA was analyzed by reviewing all REM sleep periods on nocturnal PSG and MSLT recordings per standard criteria. The total duration of the increased muscle tone during REM sleep in the chin and bilateral leg electromyography (EMG) recordings was calculated as RSWA index. The REMs index was also investigated the relation to the RSWA. RESULTS: A total of 274 patients were involved; 147 patients (53.6%) were males and 127 patients (46.4%) were females; the mean age was 29.1 ± 12.0 years. The diagnosis of NT1 was made in 166 patients (60.6%), and 108 patients (39.4%) were diagnosed as having NT2. The mean Epworth sleepiness scale score was significantly higher in patients with NT1 than the patients with NT2 (P = 0.001). The diagnosis of REM sleep behavior disorder (RBD) was made in 19.3% of the patients with NT1 versus in 2.8% of the patients with NT2 (P < 0.001). The percentage of SOREMP in PSG recordings was significantly higher in patients with NT1 (37.1%) than those with NT2 (18.9%, P = 0.001). MSLT showed that the mean sleep latency was shorter in patients with NT1 compared to those with NT2 (P < 0.001). The total duration of REMs on electrooculography recordings was also significantly higher in patients with RSWA in comparison with the patients without RSWA (P = 0.002). Total duration of REMs was significantly and positively correlated with the duration of RSWA on chin-EMG and leg-EMG recordings (P = 0.001). ROC analyses showed an RSWA index of ≥2% for the RSWA on chin-EMG with a sensitivity of 86.7% and a specificity of 71.3% (P < 0.001). The REMs index ≥20% was associated with the presence of RSWA with a sensitivity of 70.0% and a specificity of 57.1% (P = 0.008). CONCLUSIONS: In this nation-wide study, we identified for the first time that the increase in REMs density during REM sleep may be a major correlate of the RSWA. Significant positive correlations were demonstrated between the total duration of REMs on electrooculography recordings and the mean durations of RSWA in both chin and leg EMG recordings. A REMs index of >20% was demonstrated to have a moderate sensitivity and specificity in the diagnosis of RSWA. As observed in chin RSWA index, REMs index also showed a significantly high association with RBD, in comparison to RSWA per standard criteria.

Cushing Syndrome is Associated with Increased Stage N2 Sleep and Decreased SWS Partially Reversible After Treatment.

The aim of the present study was to evaluate the sleep parameters of patients with Cushing syndrome (CS) at the time of diagnosis and 12-months after treatment. Thirty four newly diagnosed patients with endogenous CS (17 with ACTH-secreting pituitary adenoma, 17 with adrenal CS) and 23 controls with similar age were included in the study. Two polysomnography (PSG) recordings were performed; one at the time of diagnosis and the other 12 months after resolution of hypercortisolemia. Control group had only baseline PSG. Based on the PSG findings, stage N2 sleep was found to be prolonged, stage N3 and REM sleep were shortened in patients with CS. Average heart rate and mean Apnea Hypopnea Index (AHI) score were higher in patients with CS than the control subjects. Sixteen (47.1%) patients with CS and 4 (17.4%) controls had obstructive sleep apnea (OSA; AHI ≥5). There were no significant differences in sleep parameters of patients according to the etiology of CS (adrenal vs. pituitary) patients. Following 12-months of treatment, a significant decrease in stage N2 sleep and a significant increase in stage N3 sleep were detected, but there was no change in terms of AHI. In conclusion, Cushing syndrome has disturbing effects on sleep structure and these effects are at least partially reversible after treatment. However, the increased risk of OSA was not reversed a year after treatment indicating the importance of early diagnosis and treatment of CS.

Electroencephalogram abnormalities in patients with NREM parasomnias.

OBJECTIVE: Electroencephalographic (EEG) changes in patients with NREM parasomnias (NRP) occur in sleep architecture as changes in slow wave sleep or cyclic pattern, which are not considered abnormal. However, abnormalities in EEG in these patients have recently been reported, indicating that EEG patterns in NRPs are not definitive. Moreover, most of the polysomnography (PSG) findings in NRP patients were reported in the adult population requiring data from pediatric population to avoid bias in conclusion. METHODS: In sum, 39 patients with a NRP were undergone comprehensive assessments including a PSG with additional EEG montages. EEG recordings were evaluated in patients without a history of epilepsy and further compared between pediatric and adult patients. RESULTS: Twenty-three (59%) of the patients were pediatric and 77% were male. The mean age was 18.4 (±13.1) years. Of the patients, 19 (49%) had somnambulism, 13 (33%) had confusional arousal and seven (18%) had sleep terrors. Macrostructure of sleep detected by PSG was normal in all patients. After excluding 11 (28%) patients with a positive history of epilepsy, seven (25%) of 28 showed EEG abnormalities within K-complexes in NREM-II stage, six of whom were pediatric patients compared to only one adult (p < 0.05). CONCLUSION: This study showed that patients with NRP may display EEG abnormalities in NREM-II stage. These abnormalities were more frequent in pediatric patients compared to adults. In NRP patients, utmost care should be taken in EEG evaluations to prevent false diagnosis of epilepsy.

Comparing expression levels of PERIOD genes PER1, PER2 and PER3 in chronic insomnia patients and medical staff working in the night shift.

AIM: This study was done to determine the changes in expression levels of PERIOD family genes in chronic insomnia patients and night shift healthcare staff with irregular sleep hours. METHOD: A total of 24 chronic insomnia patients aged between 25 and 55 that were admitted to Erciyes University Medical Faculty Neurology Polyclinic, 32 medical staff aged between 23 and 42 that work in night shifts with no neurological diagnosis were included as volunteers in the experiment. Additionally, a control group consisting of 29 healthy individuals between 21 and 50 years of age who do not work in shifts was volunteered in the study. Since PERIOD family gene expressions are affected by time of day and season changes, blood samples were taken from the groups within the same week and at the same time periods. RNA isolation followed by cDNA synthesis from leukocytes was performed from blood samples that were kept in 10 cc EDTA tubes. Expression levels of the genes were then determined by quantitative PCR method and analysed. RESULTS: There was a significant decrease in the expression levels of PER1 and PER2 genes in chronic insomnia and night shift healthcare professional groups compared to the control group (p = 0.0001 for PER1; p = 0.0023 for PER2), but no significant change was observed in PER3 gene (p = 0.619). DISCUSSION: The decrease in PER1 and PER2 gene expressions in chronic insomnia and shift working healthcare personnel seems to be more of a result for short sleep periods than a cause.

The correlation between the electroencephalographic spectral analysis and salivary cortisol rhythm in insomnia.

OBJECTIVE: Insomnia is a common sleep disorder that affects many adults either transiently or chronically. This study aimed to establish whether there is a relationship between the electroencephalographic (EEG) spectral analysis and salivary cortisol levels in insomnia and compared to healthy controls. MATERIALS AND METHODS: This case-control study included 15 insomnia patients and 15 healthy control subjects. Insomnia was determined according to the International Classification of Headache Disorders III diagnostic criteria. The EEG data were collected and processed with MATLAB software. Blood and salivary samples were taken for hematological and biochemical measurements. Salivary cortisol levels were calculated and compared statistically with the healthy group. RESULTS: The mean age of the patients was 46.5 ± 11 years. The salivary cortisol levels at 18:00 and 24:00 were found higher in the insomnia than in the healthy subjects (respectively, 0.12 (0.11) µg/dl, 0.07 (0.02) µg/dl). But this difference was not statistically significant (p > 0.05). No significant difference was observed in the spectral analysis of patients between the frontal, central, and occipital channel (p > 0.05). However, in the correlation between the frontal channel spectral analysis and at the 24:00 salivary cortisol of patient and control group, DeltaGmax (p = 0.002), DeltaGmean (p = 0.019) and, in the correlation with 18:00 salivary cortisol DeltaGmax (p = 0.010), were positively correlated. CONCLUSION: In this study, no significant difference was found in spectral analysis and salivary cortisol levels in insomnia patients, but at 18:00 and 24:00, cortisol levels were correlated positively with theta and delta waves in EEG spectral analysis in some channels.

Awareness of Migraine Among Primary Care Physicians in Turkey: A Regional Study.

INTRODUCTION: Migraine is a primary headache that involves genetic and environmental factors. In studies conducted in different countries, migraine was shown to be underdiagnosed, treated insufficiently, and highly related to disability. The primary aim of this study was to identify the competence in making a diagnosis of migraine by primary care physicians who provide basic health care to patients. METHODS: Primary care physicians (266 individuals) working in the primary health service centers located within the borders of Kayseri province were included in our study. The research was conducted by using techniques such as face-to-face meetings with the primary care physicians and by participants filling in questionnaires. A neurologist evaluated the questionnaire form. The information provided by the participants was evaluated according to the migraine without aura diagnostic criteria prepared by the International Headache Society (ICHD-3 Beta). RESULTS: Only 10.5% participants were able to give the complete diagnostic criteria of migraine without aura. The most well-known properties were unilateral (53.4%) and pulsating headaches (47%). CONCLUSION: This study showed that educational programs are required regarding migraines for primary care physicians, supported by complete educational material.

The Relationship Between Blood Pressure and Sleep Duration in Turkish Children: A Cross-Sectional Study.

OBJECTIVE: As in adults, hypertension is also an important risk factor for cardiovascular disease in children. We aimed to evaluate the effect of sleep duration on blood pressure in normal weight Turkish children aged between 11-17 years. METHODS: This cross-sectional study was conducted in the primary and secondary schools of the two central and ten outlying districts of Kayseri, Turkey. Subjects were 2860 children and adolescents (1385 boys, 1475 girls). Systolic and diastolic blood pressures were measured according to the recommendations of the Fourth Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. Sleep duration was classified as follows: ≤8 hours, 8.1-8.9 hours, 9.0-9.9 hours or ≥10 hours. RESULTS: For short sleeper boys and girls (participants with a sleep duration ≤8 h) the prevalence of prehypertension and hypertension was 35.0% and 30.8%, respectively. In univariate binary logistic regression analyses (age-adjusted), each unit increment in sleep duration (hours) in boys and girls, decreased the prehypertension and hypertension risk by 0.89 [odds ratio (OR)] [confidance interval (CI); 0.82-0.98] and 0.88 (OR) (CI; 0.81-0.97), respectively (p<0.05). In multiple binary logistic regression analyses [age- and body mass index (BMI)-adjusted] the location of the school and sleep duration categories were shown to be the most important factors for prehypertension and hypertension in both genders, while household income was the most important factor, only in boys. CONCLUSIONS: A sleep duration ≤8 h is an independent risk factor for prehypertension and hypertension in Turkish children aged 11-17 years.

Determination of restless legs syndrome prevalence in children aged 13-16years in the provincial center of Kayseri.

OBJECTIVE: This study was conducted to determine the prevalence rate of restless legs syndrome (RLS) and associated factors in adolescents aged 13-16years in the provincial center of Kayseri. MATERIALS AND METHODS: The study sample included 5720 adolescents who were selected from among 74,421 grade 7-10 students aged 13-16years in the provincial center of Kayseri. Overall, datas from 4792 subjects were included into analysis. Data were collected by using a self reported questionnaire and the Epworth Sleepiness Scale (ESS). The prevalence rate of RLS was determined by questionnaire datas and phone interviews. The effects of age, gender, economical status and body weight on RLS prevalence rate were analyzed. Mean ESS score was calculated. The effect of RLS on academic success, as measured by grade point average, was also assessed. The subjects were stratified as underweight, normal, overweight and obese according to the body mass index and the RLS prevalence rate was compared among groups. RESULTS: The RLS prevalence rate was determined to be 2.9% among adolescents aged 13-16years in the study group. It was found that gender and economical status had no significant effect on RLS prevalence. Mean age at symptom onset was 11.4years of age. There was a positive family history in 11.3% of subjects. Mean body mass index (BMI) was found to be significantly higher in subjects with RLS (21.5±3.8 vs. 20.5±3.2). Academic success (72.0±11.2 vs. 77.0±12.0) was found to be poorer and daytime sleepiness level, as measured by ESS (11.4±3.9 vs. 6.3±4.0), was found to be higher in subjects with RLS. CONCLUSION: The RLS prevalence rate was 2.9% in the study sample while gender and economical status had no significant effect on prevalence rate. The RLS, which results in decreased sleep quality and academic success, is an important disorder with a considerable prevalence in the population.

Efficiency of a Combination of Pharmacological Treatment and Nondrug Interventions in Childhood Narcolepsy.

Objective Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic and/or hypnopompic hallucinations, and sleep paralysis. It is one of the most important causes of excessive daytime sleepiness in the pediatric population. The aim of this study is to present the clinical and laboratory findings, and treatment results of pediatric patients with narcolepsy. Materials and Methods We studied five unrelated consecutive children with narcolepsy, focusing on clinical and laboratory features, the therapy and outcome over the 33-month follow-up period. Results The study subjects included two boys and three girls. The mean age at diagnosis was 11.8 ± 3.3 years (range: 8-16 years). Three patients had cataplexy. There were no hypnagogic hallucinations and/or sleep paralysis in any patients. All patients were educated about sleep hygiene, appropriate nutrition, and regular exercise. Three patients were treated with modafinil, while two patients received methylphenidate. Sodium oxybate was added to existing treatment in patients with cataplexy. Cataplexy attacks did not respond well to the treatment in one patient; therefore intravenous immunoglobulin therapy was given. Conclusions Early diagnosis is important to help narcoleptic patients in improving their quality of life. A combination of pharmacological treatment and nondrug interventions can greatly improve children's clinical symptoms.

The effect of prophylactic migraine treatment on arterial stiffness.

BACKGROUND: Migraine is a common type of primary headache predominantly seen in women. This study aimed to evaluate endothelial function in patients with migraine using pulse wave velocity (PWV). METHODS: The study included 73 patients with newly diagnosed migraine and 80 healthy subjects. All patients and controls underwent baseline transthoracic echocardiography and PWV measurements. Patients were randomized to three groups to receive propranolol, flunarizine or topiramate, and the measurements were repeated at the end of 1 month. RESULTS: The newly diagnosed migraine patients and the control group exhibited no differences in baseline clinical characteristics, and the measurements showed that PWV was 7.4 ± 1.0 m/s in the patient group and 6.0 ± 1.0 m/s in the control group (p < 0.001). The same measurements were repeated during a control visit at the end of 1 month. Following treatment, a significant decrease was observed in PWV in all patient groups compared to baseline (p < 0.001). Subgroup analysis showed significantly decreased PWV in all drug groups, with the most prominent decrease in the topiramate group. CONCLUSIONS: The increased PWV demonstrated in migraine patients in this study stands out as an additional parameter elucidating endothelial dysfunction in these patients. Decreasing the number of migraine attacks with prophylactic treatment may reduce PWV and decrease cardiovascular risk in long-term follow-up.

Neutrophil to lymphocyte ratio predicts poor prognosis in ischemic cerebrovascular disease.

BACKGROUND: Inflammation plays a role in the pathogenesis of carotid atherosclerosis. Although previous data demonstrated an association between inflammatory biomarkers and stroke, there is no publication reporting the relation of neutrophil to lymphocyte (N/L) ratio with ischemic stroke. We aimed to analyze the predictive ability of N/L ratio in acute ischemic cerebrovascular disease. METHODS: A total of 190 patients including 70 patients with first-ever atherothrombotic acute ischemic stroke (AAIS), 50 patients with transient ischemic attack, and 70 healthy subjects were enrolled in this study. We analyzed the values of white blood cell (WBC), N/L ratio, C-reactive protein (CRP), gamma-glutamyltransferase (GGT), homocysteine (HCY), mean platelet volume (MPV) in patients with ischemic group and compared those with control individuals. RESULTS: WBC, CRP, HCY, N/L ratio were found to increase significantly in AAIS patients than the controls (P < 0.001). With respect to mortality, there were no significant differences between the values of CRP, GGT, HCY, and MPV in patients with AAIS. However, WBC and N/L ratio values were found to increase significantly in dead patients (P = 0.024 and P = 0.029, respectively). A comparison of receiver operating characteristic curves among WBC, CRP, GGT, HCY, MPV, and N/L ratio variables was made. No significant differences were obtained between area under curve values (P > 0.05). A cut-off value of 4.1 for N/L ratio was detected in predicting mortality with a sensitivity of 66.7% and a specificity of 74.1% (κ = 0.299, P = 0.006). CONCLUSIONS: These findings support the role of N/L ratio as a simple inexpensive and readily available marker of prognosis in acute ischemic stroke.

Comparison of motor pattern of periodic limb movements in patients with restless legs syndrome and obstructive sleep apnea syndrome.

BACKGROUND/AIM: Periodic limb movements (PLMs) are repetitive and stereotypical movements of the lower extremities that occur during sleep. The purpose of this study was to analyze the leg muscle activity patterns in PLMs seen in restless legs syndrome (RLS) and obstructive sleep apnea syndrome (OSAS). MATERIALS AND METHODS: In this study, 1260 PLMs from 4 patients with RLS and 4 patients with OSAS were analyzed. The spreading and frequency characteristics of the gastrocnemius, medial hamstring, and vastus muscles were examined separately for each muscle in addition to the tibialis anterior muscle already included in the standard polysomnography recording. RESULTS: A greater number of PLMs (57.34%) were observed in patients with RLS. A greater number of apnea-related PLMs (59.83%) were observed in patients with OSAS. The number of PLMs with spreading characteristics was higher in both patient groups. In both groups, the first muscle to contract was most frequently the tibialis anterior. Analysis of the subsequent contraction patterns showed no regular course in RLS and OSAS patients. CONCLUSION: PLMs may occur with a nonstereotypical muscle spreading pattern generated by different, independent, and, most frequently, unsynchronized spinal generators.

The effect of sleep duration and quality on academical success of the elementary school children in Kayseri Turkey.

OBJECTIVE: To assess the sleeping habits of primary school children and establish link between sleeping hours and academic achievement. METHODS: The cross-sectional study was conducted between April and June 2007, involving 2422 students of 6-8th grades in 12 primary schools located in Kayseri, Turkey. A questionnaire was presented to the students on the basis of probability sampling method. Academic performance was evaluated with regard to their school grades. SPSS 20 was used for statistical analysis. RESULTS: Of the total 2422 questionnaires distributed, 1966 (81.2%) were used for further evaluation. The mean sleeping period of the students during school days was 8.86 +/- 1.10 hours. The number of students having difficulty in waking up in the morning was 940 (47.8%), while 910 (46.3%) were confused when they woke up during the night, and the 886 (45.1%) had nightmares, while 609 (31.0%) were sleepy all day long. As the sleeping period increased, the probability of a mediocre achievement in science lessons increased by 1.33 fold and poor achievement increased by 1.57 fold. Besides, the probability of a mediocre achievement in mathematics lessons increased by 1.36 fold, and poor achievement increased by 1.67 fold. For Turkish language lessons, these increases were found to be 1.40 and 1.60 respectively. Correlation analysis showed a significant negative relationship between sleeping time and successful scores in Turkish (r = -0.65, p < 0.025) and science (r = -0.061, p < 0.036) lessons. CONCLUSION: As the sleeping period increased, the academic achievement of the students was negatively affected. The academic success was low in children who felt sleepy throughout the day.

Obstructive sleep apnoea syndrome is associated with relative hypocortisolemia and decreased hypothalamo-pituitary-adrenal axis response to 1 and 250µg ACTH and glucagon stimulation tests.

OBJECTIVE: The investigations regarding the effect of obstructive sleep apnoea syndrome (OSAS) on hypothalamo-pituitary-adrenal (HPA) axis revealed conflicting results. We aimed to evaluate the effects of OSAS on HPA-axis with dynamic tests. METHODS: This study was carried out on 26 patients with OSAS and 15 subjects without OSAS which, were defined according to the International Classification of Sleep Disorders. Patients were enrolled from either Endocrinology outpatient clinic or Neurology Sleep Center. Participants for the control group were included from the patients admitting to Endocrinology Department with the complaint of obesity or volunteers from hospital staff. All the participants were evaluated by polysomnography (PSG) and dynamic tests of HPA axis (dexamethasone suppression test, 1 and 250µg ACTH and glucagon stimulation tests). RESULTS: Serum basal and peak cortisol levels were found to be lower in OSAS patients when compared to the control group during 1µg ACTH and glucagon stimulation tests. When the area under curve (AUC) of cortisol responses to dynamic stimulation tests were calculated according to trapezoid formula, patients with OSAS were found to have lower values compared to control group. AUC responses of all three dynamic stimulation tests were found to be negatively correlated with AHI. CONCLUSION: OSAS is associated with relative hypocortisolemia in the morning with reduced responses to 1 and 250µg ACTH and glucagon stimulation tests.

Obstructive sleep apnoea prevalence in non-arteritic anterior ischaemic optic neuropathy.

AIMS: The aim of this study was to show the prevalence of obstructive sleep apnoea (OSA) in non-arteritic anterior ischaemic optic neuropathy (NAION). METHODS: 20 patients diagnosed with NAION were included in the study. 20 age and sex matched subjects with similar risk factors for NAION, such as diabetes mellitus (DM) and hypertension (HT), constituted the control group. All cases underwent polysomnography for investigation of the presence of OSA. Cases with an Apnoea-Hypopnoea Index >5 were accepted as having OSA. RESULTS: Mean ages of the patients and controls were 60.90±8.14 and 61.15±7.23 years, respectively. There were no significant differences between the patient and control groups in terms of age, gender, body mass index, smoking/alcohol consumption or systemic diseases. In the patient group, 85% were diagnosed with OSA compared with 65% in the control group (p>0.05). CONCLUSIONS: We found a high prevalence of OSA in patients with NAION but it was also high in the control group (p>0.05). This may be due to the fact that the two groups were matched for the same risk factors for NAION. The study indicates that OSA is not a risk factor for NAION in itself but is the contributing factor as it has effects on the vascular endothelium in DM, HT and atherosclerosis.

Refractory generalized seizures as a possible side effect of bevacizumab in a colon cancer patient.

Bevacizumab, which is a humanized monoclonal antibody against vascular endothelial growth factor, is used to treat metastatic cancers of the colon. Adverse effects common with bevacizumab treatment are hypertension, arterial-venous thrombosis, bleeding, gastrointestinal perforation, and proteinuria. To date, there have been no reports of refractory seizure following treatment with bevacizumab. We describe a patient who presented with refractory generalized tonic-clonic seizures after receiving last dose of bevacizumab for treatment of metastatic colorectal cancer with FOLFIRI and bevacizumab regimen.