Parental genetically predicted liability for coronary heart disease and risk of adverse pregnancy outcomes: a cohort study.

BACKGROUND: Adverse pregnancy outcomes (APO) may unmask or exacerbate a woman's underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls). METHODS: We studied up to 83,969‬ women (and up to 55,568‬ male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967-2019) in the Medical Birth Registry of Norway (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value < 5 × 10-8, not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis. RESULTS: One standard deviation higher GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10), pre-eclampsia (OR 1.08, 95% CI 1.05-1.11), and small for gestational age (OR 1.04, 95% CI 1.01-1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96-1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98-1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners' GRS and restricting analyses to stable couples. Associations for other APOs were close to the null. There was weak evidence of an association of paternal genetically predicted liability for CHD with spontaneous preterm birth in female partners (OR 1.02, 95% CI 0.99-1.05), but not with other APOs. CONCLUSIONS: Hypertensive disorders of pregnancy, small for gestational age, and stillbirth may unmask women with a genetically predicted propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth in female partners needs further exploration.

The TEOGIC study project: a comprehensive characterization of early onset gastrointestinal cancer in the Northern area of Spain.

BACKGROUND: Gastrointestinal cancers represent one of the most prevalent diseases worldwide. Strikingly, the incidence of Early Onset Gastrointestinal Cancer (EOGIC) has been rising during the last decades and changes in lifestyle and environmental exposure seem to play a role. EOGIC has been defined as a different entity compared to on-average gastrointestinal cancer, with distinct clinical and molecular characteristics. Inherent to the particularities of younger age, there is an unmet need for a tailored approach for the management of these patients. The TEOGIC proposes a comprehensive study to characterize EOGIC patients in the northern of Spain. METHODS: Patients with histologically confirmed new diagnosis of colorectal, gastroesophageal and pancreatic adenocarcinoma will be considered for two cohorts: EOGIC (≤ 50 years old) and non-EOGIC (60-75 years old), with a ratio of 1:2. Two hundred and forty patients will be recruited in 4 Public Hospitals from northern Spain. After receiving unified informed consent, demographic and clinical data of the patients will be collected in a REDCap database. Lifestyle related data will be obtained in questionnaires assessing diet, physical activity and the general quality of life of the patients before diagnosis. Biological samples prior to any onco-specific treatment will be obtained for the analyses of circulating inflammatory proteins, gut microbiota, and the proteome of the tumor microenvironment. Histologic characteristics and routine biomarkers will be also collected. Thereafter, data will be integrated and analyzed to assess tumor specific, pan-tumor and sex-associated differential characteristics of EOGIC. DISCUSSION: The underlying risk factors and differential characteristics of EOGIC remain poorly studied, particularly in our geographical area. Although limited by the exploratory nature and the small sample size estimated to be recruited, TEOGIC represents the first attempt to comprehensively characterize these young patients, and thus attend to their special needs. Findings derived from this study could contribute to raise awareness and preventive behaviors in the population. In parallel, molecular studies could lead to the identification of potential novel non-invasive biomarkers and therapeutic targets that would help in the development of the tailored clinical management of these patients, focusing on screening programs for early diagnosis and precision medicine.

High-Dose Methylphenidate and Carboxylesterase 1 Genetic Variability in Patients With Attention-Deficit/Hyperactivity Disorder: A Case Series.

PURPOSE/BACKGROUND: Methylphenidate (MPH) is widely used to reduce symptoms of attention-deficit/hyperactivity disorder. Methylphenidate is metabolized by the carboxylesterase 1 (CES1) enzyme. Some patients need a very high dose of MPH to reach desired clinical effects, without having adverse effects. This may be due to differences in MPH pharmacokinetics (PK), potentially caused by DNA variants in CES1 , the gene encoding the enzyme that metabolizes MPH. Here we describe 3 patients requiring high-dose MPH and investigated the CES1 gene. METHODS/PROCEDURES: The 3 patients were using short-acting MPH in a dose of 180 to 640 mg instead of the maximum advised dose of around 100 mg MPH in the Netherlands. Plasma concentrations of MPH were determined at scheduled time points (day-curve). Methylphenidate plasma concentrations were used for PK analysis using an earlier published 2-compartment PK population model of MPH. Individual data of the 3 patients were compared with simulated population data, when equivalent doses were used. In addition, CES1 was genotyped (number of gene copies and single nucleotide polymorphisms) using real-time polymerase chain reaction. FINDINGS/RESULTS: Pharmacokinetic analysis in all 3 patients showed lower plasma concentrations of MPH in comparison with the population data. The mean absorption time and volume of distribution of the central compartment were equal, but the elimination clearance was higher. However, CES1 genotyping revealed no variations that could explain a higher metabolism of MPH. IMPLICATIONS/CONCLUSIONS: In these 3 cases, we could not demonstrate a correlation between MPH clearance and known genetic variants of the CES1 gene.

Identification and characterization of migraine in pregnancy: A Norwegian registry-based cohort study.

BACKGROUND: Migraine is common in women of reproductive age. Migraine's episodic manifestation and acute and preventive pharmacological treatment options challenge studying drug safety for this condition during pregnancy. To improve such studies, we aimed to develop algorithms to identify and characterize migraines in electronic healthcare registries and to assess the level of care. METHODS: We linked four registries to detect pregnancies from 2009-2018 and used three algorithms for migraine identification: i) diagnostic codes, ii) triptans dispensed, and iii) a combination of both. We assessed migraine severity using dispensed drugs as proxies. ICD-10 diagnostic subcodes of migraine (G43) allowed the allocation of four subtypes: complicated and/or status migrainosus; with aura; without aura; other/unspecified. RESULTS: We included 535,089 pregnancies in 367,908 women with available one-year lookback. The prevalence of migraines identified was 2.9%-4.3% before, and 0.8%-1.5% during pregnancy, depending on algorithm used. Pregnant women with migraine were mostly managed in primary care. CONCLUSIONS: Primary care data in combination with drug dispensation records were instrumental for identification of migraine in electronic healthcare registries. Data from secondary care and drug dispensations allow better characterization of migraines. Jointly, these algorithms may contribute to improved perinatal pharmacoepidemiological studies in this population by addressing confounding by maternal migraine indication.

Associations between endometriosis and adverse pregnancy and perinatal outcomes: a population-based cohort study.

PURPOSE: To examine the association between endometriosis and adverse pregnancy and perinatal outcomes (preeclampsia, placenta previa, and preterm birth). METHODS: A population-based retrospective cohort study was conducted among 468,778 eligible women who contributed 912,747 singleton livebirths between 1980 and 2015 in Western Australia (WA). We used probabilistically linked perinatal and hospital separation data from the WA data linkage system's Midwives Notification System and Hospital Morbidity Data Collection databases. We used a doubly robust estimator by combining the inverse probability weighting with the outcome regression model to estimate adjusted risk ratios (RR) and 95% confidence intervals (CIs). RESULTS: There were 19,476 singleton livebirths among 8874 women diagnosed with endometriosis. Using a doubly robust estimator, we found pregnancies in women with endometriosis to be associated with an increased risk of preeclampsia with RR of 1.18, 95% CI 1.11-1.26, placenta previa (RR 1.59, 95% CI 1.42-1.79) and preterm birth (RR 1.45, 95% CI 1.37-1.54). The observed association persisted after stratified by the use of Medically Assisted Reproduction, with a slightly elevated risk among pregnancies conceived spontaneously. CONCLUSIONS: In this large population-based cohort, endometriosis is associated with an increased risk of preeclampsia, placenta previa, and preterm birth, independent of the use of Medically Assisted Reproduction. This may help to enhance future obstetric care among this population.

Health-related quality of life before and during the COVID-19 pandemic in Switzerland: a cross-sectional study.

INTRODUCTION: The COVID-19 pandemic forced people to give up their daily routines and adjust to new circumstances. This might have affected health-related quality of life (HRQOL). We aimed to compare HRQOL during the first COVID-19 wave in 2020 to HRQOL before the pandemic and to identify determinants of HRQOL during the pandemic in Switzerland. METHODS: We conducted a cross-sectional online survey during the pandemic (between May and July 2020; CoWELL sample; convenience sample). Before the pandemic (2015-2016), we had conducted a cross-sectional paper-based survey among a representative random sample of the Swiss general population (SGP sample). In both samples, we assessed physical and mental HRQOL (Short Form-36) and socio-demographic characteristics. In the CoWELL sample, we additionally assessed health- and COVID-19-related characteristics. Data were analysed using linear regressions. RESULTS: The CoWELL sample included 1581 participants (76% women; mean age = 43 years, SD = 14 years) and the SGP sample 1209 participants (58% women, mean age = 49 years, SD = 15 years). Adjusted for sex, age, and education, the CoWELL sample reported higher physical HRQOL (PCS, +5.8 (95% CI: 5.1, 6.6), p < 0.001) and lower mental HRQOL (MCS, -6.9 (-7.8, -6.0), p < 0.001) than the SGP sample. In the CoWELL sample, especially persons with lower health literacy, who had no support network or who have had COVID-19, reported lower HRQOL. DISCUSSION: Aspects unique to the COVID-19 pandemic affected HRQOL. Vulnerable persons such as those having had COVID-19, less support opportunities, and with lower health literacy are especially prone to impaired HRQOL during the COVID-19 pandemic.

I've got you under my skin: inflammatory response to elephant seal's lice.

Seals (Phocidae) undergo an annual cycle of moulting that implies hair regeneration, and in the case of southern elephant seals, it also involves the superficial strata of the epidermis. Therefore, surviving the moulting period is crucial for their obligate and permanent ectoparasites. Throughout evolutionary time, sucking lice (Echinophtiriidae) have developed morphological, behavioural and ecological adaptations to cope with the amphibious lifestyle of their hosts. Lepidophthirus macrorhini, the Southern elephant seal louse species, faces the additional challenge of surviving attached to the host during the moulting period. Since lice live on the skin, L. macrorhini has developed a unique survival strategy by piercing the skin of their host, thus keeping them protected from moulting. During fieldwork in Patagonia and Antarctica, skin samples with lice within were collected for histological analysis to assess whether these parasites caused damage to the host. Lice generate an inflammatory process in the host's dermis, and these lesions could alter the normal chemical and mechanical protective properties of the skin facilitating secondary infections. Further studies that analyse the potential pathogens in those skin lesions are necessary to properly assess the real impact of ectoparasites on their host health.

Oral anticoagulation and left atrial appendage closure: a new strategy for recurrent cardioembolic stroke.

BACKGROUND AND PURPOSE: There are no recommendations regarding how to treat cardioembolic recurrent strokes when patients are well anticoagulated. We evaluated the safety and efficacy of combining oral anticoagulation (OAC) with percutaneous left atrial appendage closure (LAAC) in patients with well-anticoagulated atrial fibrillation (AF) with recurrent strokes. METHODS: In an explorative, prospective, observational study, LAAC was performed in patients with AF with at least two ischaemic strokes in the previous year, despite good anticoagulation using the Amplatzer Cardiac Plug (St Jude Medical, St Paul, MN, USA) or Amulet Abbot device (Abbot Vascular, Santa Clara, CA, USA). We recorded age, type of AF, CHA2 DS2 -VASC and HAS-BLED scores, types of OAC and risk factors. After closure, treatment with aspirin (100 mg/day) was continued for 3 months in combination with indefinite OAC. Clinical status, recurrent embolisms and bleeding complications were recorded during follow-up. RESULTS: A total of 19 patients were included (mean age, 72.1 ± 9.6 years; mean CHA2 DS2 -VASC score, 5.3 ± 1.48; mean number of previous strokes, 2.78 ± 1.15). Thirteen had spontaneous echocardiographic contrast and all had dilatation of the left atrium. Eighteen patients had a multilobulated left atrial appendage, 17 with 'chicken-wing' morphology and one patient had a left atrial appendage thrombus. There were no complications during the procedure. Only one patient had a transient ischaemic attack and no major bleeding occurred during a mean follow-up of 17.4 ± 11.5 months. CONCLUSION: Combination therapy with indefinite OAC plus LAAC in patients with AF with recurrent strokes despite good anticoagulation should be considered in order to prevent a new stroke.

The greater incidence of small-for-gestational-age newborns after gonadotropin-stimulated in vitro fertilization with a supraphysiological estradiol level on ovulation trigger day.

INTRODUCTION: Reproductive scientists have postulated various risk factors for lower birthweight following conventional gonadotropin-stimulated in vitro fertilization compared with spontaneously conceived children: parental factors (age, health, duration of subfertility and smoking habits); ovarian stimulation; laboratory procedures; the number of oocytes retrieved and the number of embryos transferred. Our aim was to investigate the impact of gonadotropin stimulation and serum estradiol level on the risk of a newborn being small-for-gestational-age. MATERIAL AND METHODS: We conducted a cohort study (2010-2016) of singletons (n = 155) born either after conventional gonadotropin-stimulated in vitro fertilization (using ≥150 IU/d human gonadotropin for stimulation) or after natural cycle in vitro fertilization without any stimulation. We analyzed perinatal outcomes using birthweight percentiles, adjusted for gestational age and sex. RESULTS: The proportion of small-for-gestational-age was 11.8% following conventional gonadotropin-stimulated in vitro fertilization and 2.9% after natural cycle in vitro fertilization (P = 0.058). The odds of small-for-gestational-age were significantly higher with supraphysiological estradiol levels in maternal serum on ovulation trigger day (unadjusted odds ratio 4.58; 95% confidence interval 1.35-15.55; P = 0.015). It remained significant after adjusting for maternal height, age and body mass index (adjusted odds ratio 3.83; 95% confidence interval 1.06-13.82; P = 0.041). CONCLUSIONS: We found an associated risk of children being born small-for-gestational-age after conventional gonadotropin-stimulated in vitro fertilization compared with natural cycle in vitro fertilization. This higher risk is significantly associated with supraphysiological estradiol levels. We propose a reduction in the dosage of gonadotropin to minimize the risk of small-for-gestational-age and future health consequences.

Diversity of scale insects (Hemiptera, Coccomorpha) in ten varieties of olive trees (Olea europaea L.) in Southern Brazil.

Olive production (Olea europaea L.) is a recent activity in Brazil and studies on the adaptability of olive trees varieties in the States are required. One of the problems that can hamper the development of olive trees is the incidence of pests, such as scale insects (Hemiptera, Coccomorpha). In this study, the associated scale insect species were found in ten varieties in an olive grove located at the Research Center of the Serra do Sudeste Region (30º33'15"S, 52º23'45"W) in Brazil. The surveys were carried out twice in each season (2013-2014). Six species of armored scale insect (Diaspididae) and two soft scales (Coccidae) were determined. Saissetia oleae (Coccidae) with 88.15% and Aspidiotus nerii (Diaspididae) with 5.85% occurred in all varieties of olive trees. The varieties Arbequina, Frantoio and Cipressino were with greater richness of scale insects, the highest values of diversity occurred in Frantoio, Arbequina and Picual; in Alfafara, Arbosana and Coratina there was a high dominance of one species (S. oleae).

Dynamic soluble changes in sVEGFR1, HGF, and VEGF promote chemotherapy and bevacizumab resistance: A prospective translational study in the BECOX (GEMCAD 09-01) trial.

Despite initial responsiveness, acquired resistance to both bevacizumab and chemotherapy in metastatic colorectal cancer is universal. We have recently published that in vitro, chronically oxaliplatin resistance upregulates soluble vascular endothelial growth factor receptor 1, downregulates vascular endothelial growth factor, and also promotes c-MET, b-catenin/transcription factor 4, and AKT activation. We tested whether variation in three serum biomarkers such as the natural c-MET ligand (hepatocyte growth factor), soluble vascular endothelial growth factor receptor 1, and vascular endothelial growth factor-A was associated with efficacy in metastatic colorectal cancer patients treated in the prospective BECOX study. Serum levels of vascular endothelial growth factor-A165, soluble vascular endothelial growth factor receptor 1, and hepatocyte growth factor were assessed by enzyme-linked immunosorbent assay method basally and every 3 cycles (at the time of computed tomography evaluation) in a preplanned translational study in the first-line BECOX trial in metastatic colorectal cancer patients treated with CAPOX plus bevacizumab. Response was evaluated by routine contrast-enhanced computed tomography by RECIST 1.1 by investigator assessment and by three blinded independent radiologists. Ratios between soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A and hepatocyte growth factor/vascular endothelial growth factor-A were established and variations through time were related to RECIST 1.1 by investigator assessment and independent radiologist. The BECOX trial included 68 patients, and 27 patients were analyzed in the translational trial. A total of 80 RECIST 1.1 evaluations were done by investigator assessment and 56 by independent radiologist. We found that a 3.22-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by investigator assessment and a 3.06-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by independent radiologist from previous determination were associated with responses compared with 1.38-fold increase by investigator assessment and 1.59 by independent radiologist in non-responders (p = 0.0009 and p = 0.03, respectively). Responders had a 3.36-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A from previous determination by investigator assessment and 3.66-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A by independent radiologist compared with 1.43-fold increase by investigator assessment and 1.53 by independent radiologist for non-responders (p = 0.002 and 0.003, respectively). In conclusion, a decrease in vascular endothelial growth factor-A and an increase in soluble vascular endothelial growth factor receptor 1 during chemotherapy and bevacizumab exposure can contribute to both chemotherapy (due to c-MET/b-catenin activation) and bevacizumab (due to low vascular endothelial growth factor requirements) resistance. Because hepatocyte growth factor levels decrease also during acquired resistance, alternative strategies to hepatocyte growth factor-ligand inhibition should be investigated.

Bone Marrow Cell Transplant From Donors With Cardiovascular Risk Factors Increases the Pro-atherosclerotic Phenotype in the Recipients.

Improvement of long-term survival after hematopoietic stem cell transplantation has revealed that these patients have an increased appearance of de novo cardiovascular risk factors. Even though in these clinical studies no relation to transplant-related factors has been found, no attention has been paid to the influence of cardiovascular risk factors affecting the bone marrow donors on the cardiovascular risk of the recipients. Thus, the aim of this study was to analyze, using an animal model, whether transplantation of bone marrow from donors with cardiovascular risk factors increases cardiovascular risk in healthy recipients. Results from transplantation experiments have shown that bone marrow from donors with cardiovascular risk factors induced pro-atherogenic modifications in the cholesterol profile of healthy recipients, increasing the low-density lipoprotein cholesterol fraction in comparison to those transplanted with control bone marrow. Moreover, bone marrow from donors with cardiovascular risk factors induced significant alterations in liver pro-inflammatory state and lipid metabolism-related gene expression that could contribute to alter cholesterol homeostasis. Altogether, these results suggest that cardiovascular risk factors in the donor confer a cardiometabolic alteration to their bone marrow cells that is transferred to noncardiovascular disease transplant recipients, affecting their liver function and increasing their cardiovascular risk.

The syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis mimicking an acute stroke.

BACKGROUND AND PURPOSE: The syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) can present as sudden onset of focal neurological deficits which are clinically and radiologically indistinguishable from an ischaemic stroke. Its diagnosis requires a lumbar puncture (LP), which contraindicates intravenous thrombolytic therapy (IV-tPA). METHODS: All patients referred to our stroke centre as a stroke code resulting in a final diagnosis of HaNDL syndrome from June 2005 to June 2015 were retrospectively analysed. RESULTS: Nine cases were identified: seven women and two men (mean age 27.6 years, range 15-51). Clinical onset consisted of isolated aphasia (two) and aphasia with right hemiparesis/hemiparaesthesia (seven). All patients had headache in the acute setting, lasting 2-12 h. Cranial computed tomography (CT) and CT angiography (CTA) were normal in all patients. Perfusion CT was performed in seven patients, showing left hemispheric focal hypoperfusion in five cases; the remaining two were normal. Five patients were initially diagnosed as stroke and treated uneventfully with IV-tPA. Cranial magnetic resonance imaging within 48 h was normal in all cases. LP performed in all patients showed pleocytosis (range 17-351 cells/mm(3) ), high protein levels (range 0.4-1.6 g/l) and normal glucose levels. All cases recovered within 12 h and suffered a second episode within 72 h. Patients were asymptomatic between episodes and after remission. CONCLUSIONS: The decision to thrombolyse or perform an LP in HaNDL patients mimicking a stroke is difficult in the acute setting. Perfusion CT can provide misleading results and CTA may be useful in ruling out occlusion of a cerebral vessel.

Microbial, physical and chemical properties of irrigation water in rice fields of Southern Brazil.

This paper presents the results of the statistical analysis of microbiological, physical and chemical parameters related to the quality of the water used in rice fields in Southern Brazil. Data were collected during three consecutive crop years, within structure of a comprehensive monitoring program. The indicators used were: potential hydrogen, electrical conductivity, turbidity, nitrogen, phosphorus, potassium, calcium, total and fecal coliforms. Principal Component and Discriminant Analysis showed consistent differences between the water irrigation and drainage, as the temporal variation demonstrated a clear reduction in the concentration of most of the variables analyzed. The pattern of this reduction is not the same in the two regions - that is, the importance of each of the different variables in the observed differentiation is modified in two locations. These results suggested that the variations in the water quality utilized for rice irrigation was influenced by certain specific aspects of each rice region in South Brazilian - such as anthropic action or soil/climate conditions in each hydrographic basin.

Erratum:Quality of life in long-term premenopausal early-stage breast cancer survivors from Spain. Effects of surgery and time since surgery.

In this article published in Volume 21, issue 5, the authors' names were incorrectly stated in the Pubmed abstract as: "Ignacio Arraras J(1), Juan Illarramendi J, de la Cruz S, Asin G, Manterola A, Ibanez B, Salgado E, Cambra K, Zarandona U, Angel Dominguez M, Vera R.". The correct authors' names are: "Arraras JI(1), Illarramendi JJ, de la Cruz S, Asin G, Manterola A, Ibanez B, Salgado E, Cambra K, Zarandona U, Dominguez MA, Vera R.". This error appeared only in the PubMed database and not in the print form of the Journal.

Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trial†.

BACKGROUND: The primary results of our phase II randomized trial suggested that compared with conventional preoperative chemoradiation (CRT), the addition of chemotherapy (CT) before CRT and surgery allows most patients receive their planned treatment with a better toxicity profile without compromising the pathological complete response and complete resection rates. We now report the 5-year outcomes. PATIENTS AND METHODS: Patients with distal or middle third, T3-T4 and/or N+ rectal adenocarcinoma selected by magnetic resonance imaging, were randomly assigned to arm A-preoperative CRT followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)-or arm B-four cycles of CAPOX followed by CRT and surgery. The following 5-year actuarial outcomes were assessed: the cumulative incidence of local relapse (LR) and distant metastases (DM), disease-free (DFS) and overall survival (OS). RESULTS: A total of 108 eligible patients were randomly assigned to arm A (n = 52) or arm B (n = 56). With a median follow-up of 69.5 months, 5-year DFS was 64% in arm A and 62% in arm B (P = 0.85) and 5-year OS was 78% in arm A and 75% in arm B (P = 0.64). The 5-year cumulative incidence of LR was 2% and 5% (P = 0.61) and 5-year cumulative incidence of DM was 21% and 23%; (P = 0.79) in arms A and B, respectively. CONCLUSION: Both treatment approaches yield similar outcomes. Given the lower acute toxicity and improved compliance with induction CT compared with adjuvant CT, integrating effective systemic therapy before CRT and surgery is a promising strategy and should be examined in phase III trials.

Role of circulating tumor cells as prognostic marker in resected stage III colorectal cancer.

BACKGROUND: The prognostic role of circulating tumor cells (CTC) in early colorectal cancer (CRC) has not been determined yet. We evaluated the potential prognostic value of CTC in stage III CRC patients. PATIENTS AND METHODS: Prospective multicenter study of 519 patients with stage III CRC recruited between January 2009 and June 2010. CTC were enumerated with the CellSearch System after primary tumor resection and before the start of adjuvant therapy. A total of 472 patients were included in the analysis. RESULTS: CTC ≥1, ≥2, ≥3 and ≥5 were detected in 166 (35%), 93 (20%), 57 (12%) and 34 (7%) patients, respectively. Median follow-up was 40 months. In the overall population, CTC ≥1 (disease-free survival (DFS): HR 0.97, P = 0.85; overall survival (OS): HR 1.03, P = 0.89), ≥2 (DFS: HR 1.07, P = 0.76; OS: HR 1.02, P = 0.95), ≥3 (DFS: HR 0.96, P = 0.87; OS: HR 0.74, P = 0.41) and ≥5 (DFS: HR 0.72, P = 0.39; OS: HR 0.48, P = 0.21) were not associated with worse DFS and OS. No clinicopathological characteristics were significantly associated with the presence of CTC. In patients with disease relapse, the proportion with CTC ≥1 was not significantly different between those with single versus multiple metastatic locations (37.9% versus 31.4%, P = 0.761). In the multivariate analysis, CTC ≥1 was not an independent prognostic factor for DFS (HR 0.97, P = 0.87) and OS (HR 0.96, P = 0.89). CONCLUSION: CTC detection was not associated with worse DFS and OS in patients with stage III CRC. Given the scarcity of CTC in these patients, it is likely that CTC determined by CellSearch system does not have a prognostic role in this setting. However, a longer follow-up is needed.

First-line bevacizumab and capecitabine-oxaliplatin in elderly patients with mCRC: GEMCAD phase II BECOX study.

BACKGROUND: Subgroup analyses of clinical studies suggest that bevacizumab plus XELOX is effective and tolerable in elderly patients with metastatic colorectal cancer (mCRC). The prospective BECOX study examined the efficacy and safety of bevacizumab plus XELOX, followed by bevacizumab plus capecitabine in elderly patients with mCRC. METHODS: Patients aged ⩾70 years with Eastern Cooperative Oncology Group performance status 0 out of 1 and confirmed mCRC were included. Patients received bevacizumab 7.5 mg kg(-1) and oxaliplatin 130 mg m(-2) on day 1, plus capecitabine 1000 mg m(-2) bid orally on days 1-14 every 21 days; oxaliplatin was discontinued after 6 cycles. The primary end point was time to progression (TTP). RESULTS: The intent-to-treat population comprised 68 patients (65% male, median age 76 years). Median TTP was 11.1 months; median overall survival was 20.4 months; overall response rate was 46%. Grade 3 or 4 adverse events included diarrhoea (18%) and asthenia (16%). Grade 3 or 4 adverse events of special interest for bevacizumab included deep-vein thrombosis (6%) and pulmonary embolism (4%). CONCLUSIONS: Bevacizumab plus XELOX was effective and well tolerated in elderly patients in the BECOX study. The adverse-event profile was similar to previous reports; no new safety concerns were identified. Fit elderly patients with mCRC should be considered for treatment with bevacizumab plus XELOX.

Adjuvant therapy with cetuximab for locally advanced squamous cell carcinoma of the oropharynx: results from a randomized, phase II prospective trial.

BACKGROUND: Cetuximab combined with radiotherapy (RT) is a treatment option for head and neck cancer. The objectives of this randomized, phase II trial were to evaluate the efficacy and safety of cetuximab maintenance therapy following definitive RT with concomitant cetuximab in patients with oropharyngeal cancer. PATIENTS AND METHODS: Ninety-one patients with stage III-IV M0 oropharyngeal tumors were randomly assigned to the treatment with accelerated concomitant boost RT (69.9 Gy) + cetuximab or the same treatment with the addition of 12 consecutive weeks of cetuximab maintenance therapy. The primary end point was locoregional control (LRC) at 1 year. RESULTS: LRC at 1 year was superior among patients in the experimental arm, treated with cetuximab maintenance (59% versus 47%). However, LRC was similar between both arms after 2 years of follow-up, as a result of increased locoregional recurrences after the first year in the maintenance group. Patients treated with adjuvant cetuximab do recover very soon from toxic effect after combined treatment. CONCLUSIONS: Twelve weeks of cetuximab maintenance therapy after concomitant cetuximab + RT in locally advanced oropharyngeal carcinoma is feasible and improves clinical outcomes measured at 1 year. This improvement is not maintained after the second year suggesting that epidermal growth factor receptor blockade is not sufficient to completely eliminate the minimal residual disease.