Exploring the Hidden Complexity: Entropy Analysis in Pulse Oximetry of Female Athletes.

This study examines the relationship between physiological complexity, as measured by Approximate Entropy (ApEn) and Sample Entropy (SampEn), and fitness levels in female athletes. Our focus is on their association with maximal oxygen consumption (VO2,max). Our findings reveal a complex relationship between entropy metrics and fitness levels, indicating that higher fitness typically, though not invariably, correlates with greater entropy in physiological time series data; however, this is not consistent for all individuals. For Heart Rate (HR), entropy measures suggest stable patterns across fitness categories, while pulse oximetry (SpO2) data shows greater variability. For instance, the medium fitness group displayed an ApEn(HR) = 0.57±0.13 with a coefficient of variation (CV) of 22.17 and ApEn(SpO2) = 0.96±0.49 with a CV of 46.08%, compared to the excellent fitness group with ApEn(HR) = 0.60±0.09 with a CV of 15.19% and ApEn(SpO2) =0.85±0.42 with a CV of 49.46%, suggesting broader physiological responses among more fit individuals. The larger standard deviations and CVs for SpO2 entropy may indicate the body's proficient oxygen utilization at higher levels of physical demand. Our findings advocate for combining entropy metrics with wearable sensor technology for improved biomedical analysis and personalized healthcare.

Características sociales de la población con infección COVID-19 de un centro de salud en cuatro olas consecutivas de la pandemia / Social characteristics of the population with COVID-19 infection in a primary care center in four consecutive pandemic waves

El objetivo de este estudio es describir algunas características sociales de la población con enfermedad por coronavirus (COVID-19) de un centro de salud de Fuenlabrada. Se incluyeron todos los pacientes valorados en consulta de forma presencial o telefónica, que fueron atendidos, tras el diagnóstico por prueba de detección de infección activa (PDIA), por las gestoras COVID-19 del centro. Los resultados principales describen una mayoría de hogares compuestos por tres habitaciones, siendo esto acorde al número de convivientes; con un baño de media y con terraza en la mayoría de ellos. Hay una gran incidencia de hogares sin personas activas laboralmente y con escasa ayuda social. Se observa ligeramente una mayor incidencia de mujeres diagnosticadas. Los determinantes sociales de la salud como las condiciones de vivienda, el estado laboral o las ayudas sociales influyen en la distribución de los recursos sanitarios. Este estudio refuerza la importancia de la Atención Primaria y sus recursos en situaciones de emergencia. (AU)

This study aims to describe some social characteristics of the population with Coronavirus Disease (COVID) infection in a Primary Care Centre in Fuenlabrada. All patients assessed in the consultation in person or by telephone, who were attended after the diagnosis by active infection diagnostic test (AIDT), by the centre's COVID tracing team, were included. The main results describe a majority of households comprising three rooms, this being in line with the number of cohabitants; with one bathroom on average and a terrace in the majority. There is a high incidence of households with unemployed people and with little social assistance. There is a slightly higher incidence of diagnosed women. The social determinants of health such as housing conditions, employment status, or social assistance influence the distribution of health resources. This study reinforces the importance of Primary Care and its emergency resources. (AU)

Improving pulse oximetry accuracy in dark-skinned patients: technical aspects and current regulations.

Recent concerns regarding the clinical accuracy of pulse oximetry in dark-skinned patients, specifically in detecting occult hypoxaemia, have motivated research on this topic and recently reported in this journal. We provide an overview of the technical aspects of the issue, the sources of inaccuracy, and the current regulations and limitations. These insights offer perspectives on how pulse oximetry can be improved to address these potential limitations.

Are Activity Wrist-Worn Devices Accurate for Determining Heart Rate during Intense Exercise?

The market for wrist-worn devices is growing at previously unheard-of speeds. A consequence of their fast commercialization is a lack of adequate studies testing their accuracy on varied populations and pursuits. To provide an understanding of wearable sensors for sports medicine, the present study examined heart rate (HR) measurements of four popular wrist-worn devices, the (Fitbit Charge (FB), Apple Watch (AW), Tomtom runner Cardio (TT), and Samsung G2 (G2)), and compared them with gold standard measurements derived by continuous electrocardiogram examination (ECG). Eight athletes participated in a comparative study undergoing maximal stress testing on a cycle ergometer or a treadmill. We analyzed 1,286 simultaneous HR data pairs between the tested devices and the ECG. The four devices were reasonably accurate at the lowest activity level. However, at higher levels of exercise intensity the FB and G2 tended to underestimate HR values during intense physical effort, while the TT and AW devices were fairly reliable. Our results suggest that HR estimations should be considered cautiously at specific intensities. Indeed, an effective intervention is required to register accurate HR readings at high-intensity levels (above 150 bpm). It is important to consider that even though none of these devices are certified or sold as medical or safety devices, researchers must nonetheless evaluate wrist-worn wearable technology in order to fully understand how HR affects psychological and physical health, especially under conditions of more intense exercise.

Skin Pigmentation Influence on Pulse Oximetry Accuracy: A Systematic Review and Bibliometric Analysis.

Nowadays, pulse oximetry has become the standard in primary and intensive care units, especially as a triage tool during the current COVID-19 pandemic. Hence, a deeper understanding of the measurement errors that can affect precise readings is a key element in clinical decision-making. Several factors may influence the accuracy of pulse oximetry, such as skin color, body temperature, altitude, or patient movement. The skin pigmentation effect on pulse oximetry accuracy has long been studied reporting some contradictory conclusions. Recent studies have shown a positive bias in oxygen saturation measurements in patients with darkly pigmented skin, particularly under low saturation conditions. This review aims to study the literature that assesses the influence of skin pigmentation on the accuracy of these devices. We employed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to conduct a systematic review retrospectively since February 2022 using WOS, PubMed, and Scopus databases. We found 99 unique references, of which only 41 satisfied the established inclusion criteria. A bibliometric and scientometrics approach was performed to examine the outcomes of an exhaustive survey of the thematic content and trending topics.

Oxygen Saturation Behavior by Pulse Oximetry in Female Athletes: Breaking Myths.

The myths surrounding women's participation in sport have been reflected in respiratory physiology. This study aims to demonstrate that continuous monitoring of blood oxygen saturation during a maximal exercise test in female athletes is highly correlated with the determination of the second ventilatory threshold (VT2) or anaerobic threshold (AnT). The measurements were performed using a pulse oximeter during a maximum effort test on a treadmill on a population of 27 healthy female athletes. A common behavior of the oxygen saturation evolution during the incremental exercise test characterized by a decrease in saturation before the aerobic threshold (AeT) followed by a second significant drop was observed. Decreases in peripheral oxygen saturation during physical exertion have been related to the athlete's physical fitness condition. However, this drop should not be a limiting factor in women's physical performance. We found statistically significant correlations between the maximum oxygen uptake and the appearance of the ventilatory thresholds (VT1 and VT2), the desaturation time, the total test time, and between the desaturation time and the VT2. We observed a relationship between the desaturation time and the VT2 appearance. Indeed, a linear regression model between the desaturation time and the VT2 appearance can predict 80% of the values in our sample. Besides, we suggest that pulse oximetry is a simple, fairly accurate, and non-invasive technique for studying the physical condition of athletes who perform physical exertion.

Martial arts injuries: a longitudinal study about judo, karate and wushu carried out in the Community of Madrid, Spain.

BACKGROUND: Martial arts are currently being practiced throughout the world by about 100 million people. Considering that sports injuries account for 20% of all emergencies treated in hospitals, this is an issue that should be further studied. Our objective was to determine the prevalence and type of injuries in wushu, judo, and karate practitioners in Community of Madrid, Spain. METHODS: A descriptive epidemiology study was carried out. A questionnaire was used to collect data from 457 men and women practicing karate, judo and/or wushu, including injuries from the past five years, type of injury and occurrence during training or competition. RESULTS: Injuries that disrupted training occurred in 56% of judokas, in 36.7% of karatekas and in 38.9% of wushu practitioners (WP). For judokas, the most common injury site was "shoulder/arm/elbow" (13.43%), for karatekas, it was "lower leg/foot/ankle" (9.95%), and for WP it was "groin/hip/thigh" (9.45%) (P=0.000). The most common injuries in judo and karate were "ankle sprains and joint injuries" (4.98% and 3.98%), while for WP the most common injury were "hamstring strains" (5.47%) (P=0.008). There was no relationship between occurrence of a first injury and sex, age or belt rank. CONCLUSIONS: Judo is the martial art with the highest percentage of injuries, followed by wushu and then karate.

Metastatic Colorectal Cancer. First Line Therapy for Unresectable Disease.

Colorectal cancer (CRC) is a commonly diagnosed malignancy. The prognosis of patients with unresectable, metastatic colorectal cancer (mCRC) is dismal and medical treatment is mainly palliative in nature. Although chemotherapy remains the backbone of treatment, the landscape is changing with the understanding of its heterogeneity and molecular biology. First-line therapy relies on a combination of chemotherapy and targeted therapies, according to clinical patient characteristics and tumor molecular profile. Here we review current evidence from randomized clinical trials for using chemotherapy doublets or triplets, and for the addition of bevacizumab or anti-epidermal growth factor receptor (EGFR) agents. Novel therapies developed for small, selected populations are also discussed.

Phase II randomized trial of capecitabine with bevacizumab and external beam radiation therapy as preoperative treatment for patients with resectable locally advanced rectal adenocarcinoma: long term results.

BACKGROUND: Preoperative chemoradiotherapy with capecitabine is considered as a standard of care for locally advanced rectal cancer. The "Tratamiento de Tumores Digestivos" group (TTD) previously reported in a randomized Ph II study that the addition of Bevacizumab to capecitabine-RT conferred no differences in the pre-defined efficacy endpoint (pathological complete response). We present the follow-up results of progression-free survival, distant relapse-free survival, and overall survival data at 3 and 5 years. METHODS: Patients (pts) were randomized to receive 5 weeks of radiotherapy (45 Gy/25 fractions) with concurrent Capecitabine 825 mg/m2 twice daily, 5 days per week with (arm A) or without (arm b) bevacizumab (5 mg/kg once every 2 weeks). RESULTS: In our study, the addition of bevacizumab to capecitabine and radiotherapy in the neoadjuvant setting shows no differences in pathological complete response (15.9% vs 10.9%), distant relapse-free survival (81.0 vs 80.4 and 76.2% vs 78.2% at 3 and 5 years respectively), disease-free survival (75% vs 71.7 and 68.1% vs 69.57% at 3 and 5 years respectively) nor overall survival at 5-years of follow-up (81.8% vs 86.9%). CONCLUSIONS: the addition of bevacizumab to capecitabine plus radiotherapy does not confer statistically significant advantages neither in distant relapse-free survival nor in disease-free survival nor in Overall Survival in the short or long term. TRIAL REGISTRATION: EudraCT number: 2009-010192-24 . Clinicaltrials.gov number: NCT01043484 .

Is aflibercept an optimal treatment for wt RAS mCRC patients after progression to first line containing anti-EGFR?

PURPOSE: To determine the efficacy and safety data of aflibercept + FOLFIRI in wt RAS mCRC patients after progression to standard chemotherapy + anti-EGFR treatment. METHODS: Retrospective, observational study in real life conducted in wt RAS mCRC patients treated with FOLFIRI-aflibercept after progression to standard first line chemotherapy + anti-EGFR treatment. RESULTS: A total of 120 patients from 12 Spanish hospitals were enrolled. Median age is 60 years (62.5%/37.5%male/female). Primary tumor site is 24.1%/75.9% right/left-side colon, and 40.8% of patients had a prior resection. All patients had wild-type RAS tumors including 5% of patients with BRAF mutations and received anti-EGFR treatment. At the time aflibercept was initiated, ECOG PS is 0/1 in 96% of patients. Median number of FOLFIRI-aflibercept cycles is 12. Efficacy results: Overall response rate is 33%; progression-free survival (PFS) is 6.9 months (95%CI: 6.1-7.8). Primary tumor resection was the only significant variable related to PFS in the multivariate analysis. Median overall survival (OS) is 14.5 months (95%CI: 9.7-19.3). ECOG and number of metastatic sites were related to OS in multivariate analysis. About 54.1% of patients received a third-line therapy including TAS-102 (23%), regorafenib (18.5%), and capecitabine (9.2%). TOXICITY: Grade 3-4 toxicities were observed in 37.5% of the patients (hematologic 16.6%, hypertension 7.5%, asthenia 5.9%, and perforation 2.5%). Aflibercept dose was reduced in 18.3% of patients. CONCLUSIONS: The results show that patients with wt RAS mCRC who received an anti-EGFR as part of the first-line treatment achieved similar RR, PFS, OS, and toxicities to those reported in VELOUR trial. These results suggest that FOLFIRI-aflibercept after first-line treatment with anti-EGFR is an appropriated option for RAS wt mCRC.

Tumour location and efficacy of first-line EGFR inhibitors in KRAS/RAS wild-type metastatic colorectal cancer: retrospective analyses of two phase II randomised Spanish TTD trials.

Purpose: Metastatic colorectal cancer (mCRC) is a group of distinct diseases, with clinical and molecular differences between right-sided and left-sided tumours driving varying prognosis. Methods: Patients with KRAS/RAS-wild type (wt) mCRC treated in first line with epidermal growth factor receptor inhibitors (EGFR-Is) (cetuximab or panitumumab) plus oxaliplatin or irinotecan-based chemotherapy from two phase II randomised trials conducted by the Spanish Cooperative for the Treatment of Digestive Tumours group were included in this retrospective study. The main objective was to analyse the prognostic effect of primary tumour location on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: Patients with KRAS-wt right-sided tumours (n=52) had significantly lower efficacy as compared with patients with KRAS-wt left-sided tumours (n=209); confirmed ORR (25% vs 47%, respectively; OR 0.4, 95% CI 0.2 to 0.8, p=0.004); and shorter median PFS (7.2 vs 9.9 months; HR 0.6, 95% CI 0.4 to 0.9, p=0.0157) and OS (13.6 vs 27.7 months; HR 0.5, 95% CI 0.3 to 0.7, p<0.0001). Similar results were observed in the RAS-wt populations. The further classification of left-sided tumours as colon or rectum delivered similar survival outcomes, as well as a tendency to diminished ORR in patients with rectum tumours. Conclusion: We observed significantly improved efficacy outcomes in patients with KRAS/RAS-wt mCRC treated with first-line EGFR-I plus chemotherapy in left-sided primary tumours as compared with right-sided primary tumours. Trial registration numbers: NCT01161316 and NCT00885885.

Prediction of Progression-Free Survival in Patients With Advanced, Well-Differentiated, Neuroendocrine Tumors Being Treated With a Somatostatin Analog: The GETNE-TRASGU Study.

PURPOSE: Somatostatin analogs (SSAs) are recommended for the first-line treatment of most patients with well-differentiated, gastroenteropancreatic (GEP) neuroendocrine tumors; however, benefit from treatment is heterogeneous. The aim of the current study was to develop and validate a progression-free survival (PFS) prediction model in SSA-treated patients. PATIENTS AND METHODS: We extracted data from the Spanish Group of Neuroendocrine and Endocrine Tumors Registry (R-GETNE). Patient eligibility criteria included GEP primary, Ki-67 of 20% or less, and first-line SSA monotherapy for advanced disease. An accelerated failure time model was developed to predict PFS, which was represented as a nomogram and an online calculator. The nomogram was externally validated in an independent series of consecutive eligible patients (The Christie NHS Foundation Trust, Manchester, United Kingdom). RESULTS: We recruited 535 patients (R-GETNE, n = 438; Manchester, n = 97). Median PFS and overall survival in the derivation cohort were 28.7 (95% CI, 23.8 to 31.1) and 85.9 months (95% CI, 71.5 to 96.7 months), respectively. Nine covariates significantly associated with PFS were primary tumor location, Ki-67 percentage, neutrophil-to-lymphocyte ratio, alkaline phosphatase, extent of liver involvement, presence of bone and peritoneal metastases, documented progression status, and the presence of symptoms when initiating SSA. The GETNE-TRASGU (Treated With Analog of Somatostatin in Gastroenteropancreatic and Unknown Primary NETs) model demonstrated suitable calibration, as well as fair discrimination ability with a C-index value of 0.714 (95% CI, 0.680 to 0.747) and 0.732 (95% CI, 0.658 to 0.806) in the derivation and validation series, respectively. CONCLUSION: The GETNE-TRASGU evidence-based prognostic tool stratifies patients with GEP neuroendocrine tumors receiving SSA treatment according to their estimated PFS. This nomogram may be useful when stratifying patients with neuroendocrine tumors in future trials. Furthermore, it could be a valuable tool for making treatment decisions in daily clinical practice.

Prospective Biomarker Study in Advanced RAS Wild-Type Colorectal Cancer: POSIBA Trial (GEMCAD 10-02).

BACKGROUND: RAS testing is used to select patients with anti-epidermal growth factor receptor (EGFR) therapies sensitivity in metastatic colorectal cancer (mCRC). However, other biomarkers such as BRAF, PIK3CA/PTEN, and p-IGF-1R+/MMP7+ (double positive [DP] phenotype) have not been prospectively assessed to predict anti-EGFR resistance. MATERIALS AND METHODS: We designed a multicenter prospective trial (NCT01276379) to evaluate whether the biomarkers BRAF mutation, PIK3CA mutation/PTEN loss, and DP phenotype can improve the prediction for 12-months progression-free survival (PFS) over the use of clinical variables exclusively in patients with RAS wild-type (WT) mCRC treated with standard chemotherapy plus biweekly cetuximab as first-line therapy. The planned sample size was 170 RAS WT patients to detect a 20% difference in 12-month PFS based on the analysis of clinical and selected biomarkers (α = .05, ß = .2). The discriminatory capacity of the biomarkers was evaluated using receiver operating characteristic curves. RESULTS: We included 181 RAS WT patients. The biomarker distribution was as follows: BRAF mutant, 20 patients (11%); PIK3CA mutated/PTEN loss, 98 patients (58%); DP, 23 patients (12.7%). The clinical variables in the clinical score were progression status >0, left-sided tumor, and resectable liver metastasis as the only metastatic site. The area under the curve (AUC) of the score containing the clinical variables was 0.67 (95% confidence interval [CI], 0.60-0.75). The AUC of the score with clinical variables and BRAF mutational status was 0.68 (0.61-0.75, p = .37). The AUC of the score with clinical variables and PI3KCA mutation/PTEN status was 0.69 (0.61-0.76, p = .32). The AUC of the score with clinical variables and DP phenotype was 0.66 (0.58-0.73, p = .09). CONCLUSION: The addition of BRAF, PIK3CA/PTEN, and DP to a clinical score does not improve the discrimination of 12-month PFS. IMPLICATIONS FOR PRACTICE: This prospective biomarker design study has important clinical implications because many prospective clinical trials are designed with the hypothesis that BRAF mutation per se and MEK and PIK3CA downstream pathways are critical for colorectal tumor survival. The results lead to the question of whether these pathways should be considered as passengers instead of drivers.

Impact of the UGT2B17 polymorphism on the steroid profile. Results of a crossover clinical trial in athletes submitted to testosterone administration.

This article studies the genetic influence of polymorphism of the UGT2B17 gen on the urinary steroid profile and its implications for the anti-doping field. The study presents the results of a triple-blind randomized placebo-controlled crossover trial with healthy athletes submitted to a single dose of 250 mg of testosterone cypionate. Forty urine samples were collected from each participant. Mass spectrometry-based techniques commonly used in Anti-Doping laboratories, were employed to measure the urinary concentration and the Δδ13C values of a selection of target compounds for testosterone (T) administration together with LH. Twelve volunteers were included in the study; the polymorphism was evenly distributed among them. After T administration, the most meaningful change affected the Testosterone/Epitestosterone ratio (T/E) and the urinary concentration of LH. In relation with T/E, the wild type homozygous (ins/ins) group there was a mean relative increase of 30 (CI 95%: 25.2 to 36.7); in the heterozygous mutant (del/ins) group it was 19.8 (CI 95%:15.9 to 24.7); and in the homozygous mutant (del/del) group it was 19.7 (CI 95% 14.9 to 26.2). In the case of LH, it́s observed how LH values decrease significantly after the administration of Testex homogeneously among the three groups. The main outcome was related to the (del/del) group (homozygous mutant), where due to the depressed basal level of the steroid profile, if the longitudinal steroid profile of the athlete was not available, the analysis by GC/MS would not produce an "atypical" result according to the WADA TD2016EAAS despite the T administration. However, the genotyping of the UGT2B17 polymorphism, the follow up of LH and the use of GC-C-IRMS makes it possible to identify most of these samples as Adverse.

Clinical Impact of Circulating Tumor RAS and BRAF Mutation Dynamics in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy Plus Anti-Epidermal Growth Factor Receptor Therapy.

PURPOSE: RAS and BRAF mutations can be detected as a mechanism of acquired resistance in circulating tumor (ct) DNA in patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy. METHODS: RAS and BRAF mutational status was assessed in ctDNA in a baseline plasma sample and a serum sample collected at the time of the last available determination (named secondary extraction) from patients with KRAS exon 2 wild-type metastatic colorectal cancer treated in two first-line prospective biomarker-designed clinical trials (PULSE, ClinicalTrials.gov identifier: NCT01288339; and POSIBA, ClincialTrials.gov identifier: NCT01276379). RESULTS: Analysis of extended RAS and BRAF in tissue and plasma from 178 patients with KRAS exon 2 wild-type metastatic colorectal cancer showed a sensitivity of 64.1% and a specificity of 90%. The median overall survival (OS) of baseline patients with RAS and BRAF mutations in ctDNA was 22.3 months (95% CI, 15.6 to 29 months) and 8.9 months (95% CI, 6.3 to 11.4 months), respectively, which was significantly inferior to the median OS of 40.4 months (95% CI, 35.9 to 44.9 months) in two patients with wild-type disease (P < .001). Acquisition of RAS/BRAF mutations occurred in nine of 63 patients (14%) with progressive disease (PD; ie, blood draw within 1 month before PD or after PD) compared with six of 73 patients (8%) with no PD or blood extraction for ctDNA analysis before 1 month of PD (P = .47). Median OS in patients with RAS/BRAF acquisition was 23.9 months (95% CI, 19.7 to 27.9 months) compared with 40.6 months (95% CI, not reached to not reached) in patients who remained free of mutations (P = .016). CONCLUSION: Our results confirm that baseline RAS and BRAF testing in ctDNA discriminates survival. The emergence of RAS/BRAF mutations has limited relevance for the time to progression to anti-epidermal growth factor receptor therapy.

Coexpression of p-IGF-1R and MMP-7 Modulates Panitumumab and Cetuximab Efficacy in RAS Wild-Type Metastatic Colorectal Cancer Patients.

INTRODUCTION: The coexpression of pIGF-1R and MMP-7 (double-positive phenotype, DP) correlates with poor overall survival (OS) in KRAS wild-type (WT) (exon 2) metastatic colorectal cancer (mCRC) patients treated with irinotecan-cetuximab in second/third line. METHODS: We analyzed two prospective biomarker design trials of newly diagnosed RAS-WT mCRC patients treated with panitumumab-FOLFOX6 (PULSE trial; NCT01288339) or cetuximab plus either FOLFOX6/FOLFIRI (POSIBA trial; NCT01276379). The main exposure was DP phenotype (DP/non-DP), as assessed by two independent pathologists. DP cases were defined by immunohistochemistry as >70% expression of moderate or strong intensity for both MMP-7 and pIGF-1R. Primary endpoint: progression-free survival (PFS); secondary endpoints: OS and response rate. PFS and OS were adjusted by baseline characteristics using multivariate Cox models. RESULTS: We analyzed 67 patients (30 non-DP, 37 DP) in the PULSE trial and 181 patients in the POSIBA trial (158 non-DP, 23 DP). Response rates and PFS were similar between groups in both studies. DP was associated with prolonged OS in PULSE (adjusted HR: 0.23; 95%CI: 0.11-0.52; P=.0004) and with shorter OS in POSIBA (adjusted HR: 1.67; 95%CI: 0.96-2.90; P=.07). CONCLUSION: A differential effect of anti-EGFRs on survival by DP phenotype was observed. Panitumumab might be more beneficial for RAS-WT mCRC patients with DP phenotype, whereas cetuximab might improve OS in non-DP.

Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer.

BACKGROUND: Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. METHODS: We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation. RESULTS: Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R. CONCLUSIONS: Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.

First-line panitumumab plus FOLFOX4 or FOLFIRI in colorectal cancer with multiple or unresectable liver metastases: A randomised, phase II trial (PLANET-TTD).

BACKGROUND: In first-line wild-type (WT)-Kirsten rat sarcoma viral oncogene homologue (KRAS) metastatic colorectal cancer (mCRC), panitumumab (Pmab) improves outcomes when added to FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin] or FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]. However no trial has directly compared these combinations. METHODS: Multicentre, open-label study in untreated patients ≥ 18 years with (WT)-KRAS mCRC and multiple or unresectable liver-limited disease (LLD) randomised to either Pmab-FOLFOX4 or Pmab-FOLFIRI. The primary end-point was objective response rate (ORR). Secondary end-points included liver metastases resection rate (R0 + R1), progression-free survival (PFS), overall survival (OS), adverse events and perioperative safety. Exploratory end-points were: response by RAS status, early tumour shrinkage (ETS) and depth of response (DpR) in WT-RAS patients. RESULTS: Data on 77 patients were analysed (38 Pmab-FOLFOX4; 39 Pmab-FOLFIRI; WT-RAS: 27/26, respectively). ORR was 74% with Pmab-FOLFOX4 and 67% with Pmab-FOLFIRI (WT-RAS: 78%/73%). Out of the above, 45% and 59% underwent surgical resection, respectively (WT-RAS: 37%/69%). The R0-R1 resection rate was 34%/46% (WT-RAS:26%/54%). Median PFS was 13/14 months (hazard ratio [HR] Pmab-FOLFIRI versus Pmab-FOLFOX4: 0.9; 95% confidence interval: [0.6-1.5]; WT-RAS:13/15; HR: 0.7 [0.4-1.3]). Median OS was 37/41 months (HR:1.0 [0.6-1.8]; WT-RAS: 39/49; HR:0.9 [0.4-1.9]). In WT-RAS patients with confirmed response, median DpR was 71%/66%, and 65%/77% of patients showed ETS ≥ 30%/ ≥ 20% at week 8, without significant differences between arms; these patients had longer median PFS and OS and higher resectability rates. Surgery was associated with longer survival. Perioperative and overall safety were similar, except for higher grade 3/4 neutropenia (40%/10%; p = 0.003) and neuropathy (13%/0%; p = 0.025) in the Pmab-FOLFOX4 arm. CONCLUSIONS: In patients with WT-KRAS mCRC and LLD, both first-line Pmab-FOLFOX4 and Pmab-FOLFIRI resulted in high ORR and ETS, allowing potentially curative resection. No significant differences in efficacy were observed between the two regimens. (clinicaltrials.gov:NCT00885885).

Impact of UGT2B17 gene deletion on the steroid profile of an athlete.

The measurement of the testosterone to epitestosterone ratio (T/E ratio) in urine is often used as a marker for testosterone administration in the doping control field. This study examines the frequencies of the different expression forms of the UGT2B17 gene, and assesses their effects on this marker in volunteer subjects. The sample for this descriptive study was composed of male and female athletes aged between 16 and 55 years old who practiced different sports disciplines. All participants underwent a sports-medical physical examination, and subsequently provided 10 urine samples consecutively over a period of 48 h. The dependent variable examined was T/E and the main independent variable was the UGT2B17 gene polymorphism. During 1 year, 1410 urine samples were obtained from 141 athletes. The frequencies of the three genotypes were as follows: wt homozygotes (ins/ins) 48.2% (n = 68), mutant homozygotes (del/del) 12.1% (n = 17), and heterozygotes (ins/del) 39.7% (n = 56). Genotype distributions varied significantly (P < 0.001) according to ethnicity, 80% of Asian subjects being homozygous for the gene deletion (del/del) compared to 6.9% of Caucasian subjects. A multivariate analysis adjusted for genotype, age, sex, and sports discipline revealed that athletes with the del/del polymorphism showed a significantly lower mean T/E than heterozygotes (ins/del). In contrast, homozygous athletes for the gene insertion (ins/ins) showed higher mean T/E ratios than heterozygotes (ins/del). UGT2B17 gene deletion has a strong influence on the T/E ratio in urine, which is the most efficient indicator of testosterone prohormone misuse. Others factors studied seem not to have such an impact. The genotyping of UGT2B17 is an important source of information for understanding steroid profiling in the doping control field; therefore it is suggested that it be included in the Athletes Biological Passport.