Peripheral neuropathy in patients with gout, beyond focal nerve compression: a cross-sectional study.

Neuropathies secondary to tophus compression in gout patients are well known; however, limited data exist on other types of peripheral neuropathies (PN). Our aim was to describe PN frequency, characteristics, distribution, patterns, and associated factors in gout patients through clinical evaluation, a PN questionnaire, and nerve conduction studies (NCS). This cross-sectional descriptive study included consecutive gout patients (ACR/EULAR 2015 criteria) from our clinic. All underwent evaluation by Rheumatology and Rehabilitation departments, with IRB approval. Based on NCS, patients were categorized as PN + (presence) or PN- (absence). PN + patients were further classified as local peripheral neuropathy (LPN) or generalized somatic peripheral neuropathy (GPN). We enrolled 162 patients, 98% male (72% tophaceous gout). Mean age (SD): 49.4 (12) years; mean BMI: 27.9 (6.0) kg/m2. Comorbidities included dyslipidemia (53%), hypertension (28%), and obesity (23.5%). Abnormal NCS: 65% (n = 106); 52% LPN, 48% GPN. PN + patients were older, had lower education, and severe tophaceous gout. GPN patients were older, had lower education, and higher DN4 scores compared to LPN or PN- groups (p = 0.05); other risk factors were not significant. Over half of gout patients experienced neuropathy, with 48% having multiplex mononeuropathy or polyneuropathy. This was associated with joint damage and functional impairment. Mechanisms and risk factors remain unclear. Early recognition and management are crucial for optimizing clinical outcomes and quality of life in these patients. Key Points Peripheral neuropathies in gout patients had been scarcely reported and studied. This paper report that: • PN in gout is more frequent and more diverse than previously reported. • Mononeuropathies are frequent, median but also ulnar, peroneal and tibial nerves could be injured. • Unexpected, generalized neuropathies (polyneuropathy and multiplex mononeuropathy) are frequent and associated to severe gout. • The direct role of hyperuricemia /or gout in peripheral nerves require further studies.

Síndrome de Rapunzel: atadura sicológica y simulación orgánica / Rapunzel syndrome: psychological bondage and organic simulation

Introducción. El síndrome de Rapunzel es una entidad infrecuente, que se presenta como un tricobezoar a causa de una aglomeración de cabello acumulado dentro del tracto gastrointestinal, por lo que simula otras patologías quirúrgicas. Caso clínico. Paciente femenina de 10 años de edad, con tricotilomanía y tricofagia, dolor abdominal y síntomas inespecíficos de obstrucción intestinal de ocho meses de evolución. Al examen físico se encontró abdomen con distensión y masa palpable en epigastrio y mesogastrio. La ecografía permitió hacer el diagnóstico de tricobezoar gástrico extendido hasta el intestino delgado, por lo que se llevó a cirugía para gastrotomía y se extrajo el tricobezoar, con evolución satisfactoria de la paciente. El abordaje integral permitió conocer la atadura sicológica por posible maltrato infantil. Resultado. La paciente tuvo una evolución satisfactoria y se dio egreso al quinto día de hospitalización. Actualmente se encuentra en seguimiento por sicología, siquiatría infantil y pediatría. Discusión. El caso clínico denota la importancia en reconocer situaciones de presentación infrecuente en pediatría, que puedan estar asociadas a alteraciones sicológicas o presunción de maltrato infantil y que se presenten como una condición orgánica recurrente que simule otras patologías abdominales frecuentes en la infancia. El retraso diagnóstico puede conducir a un desenlace no deseado con complicaciones. Conclusión. Se hace mandatorio el manejo integral del paciente pediátrico y aumentar la sensibilidad para reconocer situaciones de presunción de maltrato infantil, sobre todo en pacientes con una condición orgánica quirúrgica recurrente.

Introduction. Rapunzel syndrome is an uncommon condition that manifests as trichobezoars, which are hair bundles in the stomach or small intestine that can mimics other surgical illnesses. Multiple complications can arise from delayed diagnosis and treatment. Clinical case. A 10-year-old female patient with trichotillomania and trichophagia, with abdominal pain and nonspecific symptoms of intestinal obstruction of eight months of evolution. Physical examination revealed epigastric tenderness and a solid mass was palpable in the mesogastric and epigastric region. An abdominal ultrasound showed gastric trichobezoar that extended into the small intestine. A gastrotomy was performed and the trichobezoar was extracted with satisfactory evolution of the patient. The comprehensive approach allowed knowing the psychological bond due to possible child abuse. Results. The patient had a satisfactory evolution and was discharged on the fifth day of hospitalization. He is currently being monitored by psychology, child psychiatry and pediatrics. Discussion. This clinical case highlights the importance of recognizing situations that seldom present in pediatrics, which may have a psychological aspect due to the presumption of child abuse, and which present as a recurrent organic condition simulating other frequent abdominal pathologies in childhood; all of which may lead to an unwanted outcome due to diagnostic delay. Conclusion. The comprehensive management of the pediatric patient is mandatory to recognize situations of presumed child abuse, in the face of a recurrent surgical conditions.

Usefulness of an Easy, Structured, and Home-Based Exercise Program to Improve Physical Performance and Quality of Life in a Patient's Cohort with Obesity.

INTRODUCTION: The benefits of exercise in patients with obesity are clear; physical performance and quality of life improve after exercise programs in patients with obesity. Our aim was to evaluate the usefulness of an easy, structured, and home-based exercise program to improve physical performance and quality-of-life in patients with obesity. METHODS: A cohort of patients with obesity (BMI ≥30 kg/m2) was recruited during 2017-2020. Patients who met the inclusion criteria were invited and those who accepted signed informed consent. Patients were evaluated by the same team of physicians who performed the 6-min walking test and collected the clinical and biochemical variables, also applied quality-of-life questionnaire at baseline and 3 months after starting the exercise program that was divided in two levels: level 1: active mobilization of four limbs (15 min) + cardiovascular exercise (15 min walking), 5 days/week; level 2: eight strengthening exercises for upper and lower limbs with an elastic band + cardiovascular exercise (15 min walking), 5 days/week. This study used means (SD), frequencies (percent), Student's t test, and Pearson correlation test. RESULTS: We included 151 patients, mostly women (81.5%), age 46.3 ± 9.8 years old, BMI 40.3 ± 8.56 kg/m2, 34.4% performed some type of exercise, and the most frequents comorbidities were dyslipidemia and diabetes. After 3 months, 86 patients (57%) remained in the study and attended the final evaluation. Evident changes in physical performance were reported (distance traveled, speed walking and VO2max); however, improvement in quality of life was remarkable. CONCLUSION: An easy, structured, and home-based exercise program improves physical performance and quality of life in patients with obesity, without losing its benefits for the health.

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part I: non-small cell lung cancer and breast cancer

Oligometastatic disease (OMD) defines a cancer status that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While diagnostic imaging tools have considerably improved in recent years, unidentified micrometastases can still evade current detection techniques, allowing the disease to progress. The various OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of early disease control. In view of increasing OMD detection rates in current real-world clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies might translate into promising treatment options. This expert review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of non-small cell lung cancer and breast cancer (Part I), and prostate cancer and colorectal cancer (Part II), aiming to offer specialists a pragmatic framework to help improve patient management (AU)

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part II: prostate cancer and colorectal cancer

Oligometastatic disease (OMD) defines a status of cancer that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While imaging diagnostic tools have considerably improved in recent years, unidentified micrometastases can still escape from current detection techniques allowing disease to progress. The variety of OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of an early disease control. Based on increasing detection rates of OMD in the current real clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies may translate into promising treatment options. This experts’ review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of Non-Small Cell Lung Cancer and Breast Cancer (Part I), and Prostate Cancer and Colorectal Cancer (Part II), aiming to offer specialists a pragmatic framework that might contribute to the improved management of patients (AU)

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part II: prostate cancer and colorectal cancer.

Oligometastatic disease (OMD) defines a status of cancer that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While imaging diagnostic tools have considerably improved in recent years, unidentified micrometastases can still escape from current detection techniques allowing disease to progress. The variety of OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of an early disease control. Based on increasing detection rates of OMD in the current real clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies may translate into promising treatment options. This experts' review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of Non-Small Cell Lung Cancer and Breast Cancer (Part I), and Prostate Cancer and Colorectal Cancer (Part II), aiming to offer specialists a pragmatic framework that might contribute to the improved management of patients.

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part I: non-small cell lung cancer and breast cancer.

Oligometastatic disease (OMD) defines a cancer status that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While diagnostic imaging tools have considerably improved in recent years, unidentified micrometastases can still evade current detection techniques, allowing the disease to progress. The various OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of early disease control. In view of increasing OMD detection rates in current real-world clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies might translate into promising treatment options. This expert review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of non-small cell lung cancer and breast cancer (Part I), and prostate cancer and colorectal cancer (Part II), aiming to offer specialists a pragmatic framework to help improve patient management.

Initial clinical and treatment patterns of advanced differentiated thyroid cancer: ERUDIT study.

Background: Up to 30% of differentiated thyroid cancer (DTC) will develop advanced-stage disease (aDTC) with reduced overall survival (OS). Objective: The aim of this study is to characterize initial diagnosis of aDTC, its therapeutic management, and prognosis in Spain and Portugal. Methods: A multicentre, longitudinal, retrospective study of adult patients diagnosed with aDTC in the Iberian Peninsula was conducted between January 2007 and December 2012. Analyses of baseline characteristics and results of initial treatments, relapse- or progression-free survival ((RP)FS) from first DTC diagnosis, OS, and prognostic factors impacting the evolution of advanced disease were evaluated. Results: Two hundred and thirteen patients (median age: 63 years; 57% female) were eligible from 23 hospitals. Advanced disease presented at first diagnosis (de novo aDTC) included 54% of patients, while 46% had relapsed from early disease (recurrent/progressive eDTC). At initial stage, most patients received surgery (98%) and/or radioiodine (RAI) (89%), with no differences seen between median OS (95% CI) (10.4 (7.3-15.3) years) and median disease-specific-survival (95% CI) (11.1 (8.7-16.2) years; log-rank test P = 0.4737). Age at diagnosis being <55 years was associated with a lower risk of death (Wald chi-square (Wc-s) P < 0.0001), while a poor response to RAI to a higher risk of death ((Wc-s) P < 0.05). In the eDTC cohort, median (RP)FS (95% CI) was of 1.7 (1.0-2.0) years after RAI, with R0/R1 surgeries being the only common significant favourable factor for longer (RP)FS and time to aDTC ((Wc-s) P < 0.05). Conclusion: Identification of early treatment-dependent prognostic factors for an unfavourable course of advanced disease is possible. An intensified therapeutic attitude may reverse this trend and should be considered in poor-performing patients. Prospective studies are required to confirm these findings.

Impaired condensin complex and Aurora B kinase underlie mitotic and chromosomal defects in hyperdiploid B-cell ALL.

B-cell acute lymphoblastic leukemia (ALL; B-ALL) is the most common pediatric cancer, and high hyperdiploidy (HyperD) identifies the most common subtype of pediatric B-ALL. Despite HyperD being an initiating oncogenic event affiliated with childhood B-ALL, the mitotic and chromosomal defects associated with HyperD B-ALL (HyperD-ALL) remain poorly characterized. Here, we have used 54 primary pediatric B-ALL samples to characterize the cellular-molecular mechanisms underlying the mitotic/chromosome defects predicated to be early pathogenic contributors in HyperD-ALL. We report that HyperD-ALL blasts are low proliferative and show a delay in early mitosis at prometaphase, associated with chromosome-alignment defects at the metaphase plate leading to robust chromosome-segregation defects and nonmodal karyotypes. Mechanistically, biochemical, functional, and mass-spectrometry assays revealed that condensin complex is impaired in HyperD-ALL cells, leading to chromosome hypocondensation, loss of centromere stiffness, and mislocalization of the chromosome passenger complex proteins Aurora B kinase (AURKB) and Survivin in early mitosis. HyperD-ALL cells show chromatid cohesion defects and an impaired spindle assembly checkpoint (SAC), thus undergoing mitotic slippage due to defective AURKB and impaired SAC activity, downstream of condensin complex defects. Chromosome structure/condensation defects and hyperdiploidy were reproduced in healthy CD34+ stem/progenitor cells upon inhibition of AURKB and/or SAC. Collectively, hyperdiploid B-ALL is associated with a defective condensin complex, AURKB, and SAC.

The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC).

BACKGROUND: Bevacizumab, a VEGF-A inhibitor, in combination with chemotherapy, has proven to increase progression-free survival (PFS) and overall survival in multiple lines of therapy of metastatic colorectal cancer (mCRC). The angiogenic factor angiopoetin-2 (Ang-2) is associated with poor prognosis in many cancers, including mCRC. Preclinical models demonstrate improved activity when inhibiting both VEGF-A and Ang-2, suggesting that the dual VEGF-A and Ang-2 blocker vanucizumab (RO5520985 or RG-7221) may improve clinical outcomes. This phase II trial evaluated the efficacy of vanucizumab plus modified (m)FOLFOX-6 (folinic acid (leucovorin), fluorouracil (5-FU) and oxaliplatin) versus bevacizumab/mFOLFOX-6 for first-line mCRC. PATIENTS AND METHODS: All patients received mFOLFOX-6 and were randomized 1:1 to also receive vanucizumab 2,000 mg or bevacizumab 5 mg/kg every other week. Oxaliplatin was given for eight cycles; other agents were continued until disease progression or unacceptable toxicity for a maximum of 24 months. The primary endpoint was investigator-assessed PFS. RESULTS: One hundred eighty-nine patients were randomized (vanucizumab, n = 94; bevacizumab, n = 95). The number of PFS events was comparable (vanucizumab, n = 39; bevacizumab, n = 43). The hazard ratio was 1.00 (95% confidence interval, 0.64-1.58; p = .98) in a stratified analysis based on number of metastatic sites and region. Objective response rate was 52.1% and 57.9% in the vanucizumab and bevacizumab arm, respectively. Baseline plasma Ang-2 levels were prognostic in both arms but not predictive for treatment effects on PFS of vanucizumab. The incidence of adverse events of grade ≥3 was similar between treatment arms (83.9% vs. 82.1%); gastrointestinal perforations (10.8% vs. 8.4%) exceeded previously reported rates in this setting. Hypertension and peripheral edema were more frequent in the vanucizumab arm. CONCLUSION: Vanucizumab/mFOLFOX-6 did not improve PFS and was associated with increased rates of antiangiogenic toxicity compared with bevacizumab/mFOLFOX-6. Our results suggest that Ang-2 is not a relevant therapeutic target in first-line mCRC. IMPLICATIONS FOR PRACTICE: This randomized phase II study demonstrates that additional angiopoietin-2 (Ang-2) inhibition does not result in superior benefit over anti-VEGF-A blockade alone when each added to standard chemotherapy. Moreover, the performed pharmacokinetic and pharmacodynamic analysis revealed that vanucizumab was bioavailable and affected its intended target, thereby strongly suggesting that Ang-2 is not a relevant therapeutic target in the clinical setting of treatment-naïve metastatic colorectal cancer. As a result, the further clinical development of the dual VEGF-A and Ang-2 inhibitor vanucizumab was discontinued.

Effects of Subsequent Systemic Anticancer Medication Following First-Line Lenvatinib: A Post Hoc Responder Analysis from the Phase 3 REFLECT Study in Unresectable Hepatocellular Carcinoma.

INTRODUCTION: Understanding the relationship between subsequent-line therapies and overall survival (OS) is important for maximizing OS for patients with hepatocellular carcinoma. OBJECTIVE: In this post hoc analysis, we investigated OS in lenvatinib- and sorafenib-treated patients from the REFLECT study, who then received subsequent anticancer medication during the survival follow-up period. METHODS: The follow-up period commenced at the first off-treatment visit after stopping the study medication and continued until study termination, withdrawal of consent, or death. OS and objective response rate were calculated for patients who did or did not receive poststudy anticancer medication for both treatment arms, as well as for the overall cohort. We investigated the subset of patients who responded to first-line treatment and subsequently received anticancer medication. RESULTS: The OS for patients initially randomized to first-line lenvatinib (versus first-line sorafenib) and who then received any subsequent anticancer medication was 20.8 vs. 17.0 months (hazard ratio [HR] 0.87; 95% CI 0.67-1.14). The OS for patients who initially received first-line lenvatinib (versus first-line sorafenib) and who did not receive any subsequent anticancer medication was 11.5 vs. 9.1 months (HR 0.90; 95% CI 0.75-1.09). Responders to first-line lenvatinib who received subsequent medication had a median OS of 25.7 months (95% CI 18.5-34.6); responders to first line-sorafenib who received subsequent medication had a median OS of 22.3 months (95% CI 14.6-not evaluable). CONCLUSIONS: In this post hoc analysis of all patients in the REFLECT study who received subsequent anticancer medication, OS was increased compared with patients who did not receive any subsequent anticancer medication. In a subset analysis of responders who had received subsequent anticancer medication, use of first-line lenvatinib led to a slightly longer median OS; more research is needed on the benefits of using first-line lenvatinib compared with sorafenib.

Are Target Urate and Remission Possible in Severe Gout? A Five-year Cohort Study.

OBJECTIVE: Determine the proportion of patients achieving target serum urate (SU), defined as < 6 mg/dl for patients with non-severe gout and < 5 mg/dl for patients with severe gout, as well as the proportion of patients achieving remission after 5 years of followup. METHODS: Patients from the Gout Study Group (GRESGO) cohort were evaluated at 6-month intervals. Demographic and clinical data were obtained at baseline. Visits included assessments of serum urate, flares, tophus burden, health-related quality of life using the EQ-5D, activity limitations using the Health Assessment Questionnaire adapted for gout, and pain level and patient's global assessment using visual analog scales. Treatment for gout and associated diseases was prescribed according to guidelines and available drugs. RESULTS: Of 500 patients studied, 221 had severe gout (44%) and 279 had non-severe gout (56%) at baseline. No significant differences were observed across the study in percentages of severe gout versus non-severe gout patients achieving SU 6 mg/dl or 5 mg/dl. The highest proportion of patients achieving target SU (50-70%) and remission (39%) were found after 3-4 years of followup. In the fifth year, these proportions decreased and 28% of the patients were in remission, but only 40 patients remained in the study. None of the patients with severe gout achieved remission. CONCLUSION: In patients with severe gout, target SU was hard to achieve and remission was not possible. The main obstacles for target SU and gout remission include poor medication adherence, persistent tophi, and loss to followup.

Peripheral neuropathies in rheumatic diseases: More diverse and frequent than expected. A cross-sectional study.

BACKGROUND/OBJECTIVE: Peripheral neuropathies (PN) are heterogeneous nerve disorders; frequently rheumatic patients have neuropathic symptoms. In some rheumatic diseases (RD) PN are secondary to nerve compression while others are related to metabolic abnormalities, inflammation or vasculitis. Our aim was to explore the frequency of neuropathic symptoms with three neuropathy questionnaires (NQ) and nerve conduction studies (NCS) in RD. METHODS: This is a cross-sectional study in patients with any RD attending for the first time to a rheumatology outpatient clinic. We included all patients who accepted to participate and who answered three NQ and received a physical evaluation. Twenty patients were randomly selected to perform NCS and 10 healthy subjects were included as controls. The topographic diagnoses were: mononeuropathy, multiplex mononeuropathy, and/or polyneuropathy. STATISTICAL ANALYSIS: descriptive statistics (mean, median, standard deviation, interquartile range and frequency, odds ratios and Pearson correlation test). RESULTS: One hundred patients and 10 healthy subjects were included. Sixty-nine were female, mean age 40.6 ± 15.7 years. Rheumatic diagnoses were: systemic lupus erythematosus (26%), rheumatoid arthritis (16%), gout (14%), and osteoarthritis (11%). Fifty-two patients had neuropathic signs during physical examination and 67% had positive questionnaires with variable scores among several RD. Abnormal NCS was reported in 14 patients (70%): 6 (42.8%) median nerve mononeuropathies, 4 (28.5%) multiplex mononeuropathies and 4 (28.5%) polyneuropathies. None of the healthy subjects had neuropathy (NQ, physical evaluation, or NCS). Risk of being NCS positive is higher when the patients were NQ positive. CONCLUSION: PN has variable distribution and high frequency in patients with RD; NQ+ increases the risk of presenting NCS+ for PN.

Effect of Resistance Exercise Plus Cholecalciferol on Nutritional Status Indicators in Adults With Stage 4 Chronic Kidney Disease.

OBJECTIVE: Decreased serum concentrations of 25-hydroxyvitamin D (25(OH)D) affect people with chronic kidney disease (CKD); lower concentrations of 25(OH)D have been associated with decrease in nutritional status indicators. On the other hand, muscle resistance exercise has improved the nutritional status of patients with CKD.The aim of this study was to evaluate the effect of resistance exercise and dietary supplementation with cholecalciferol on nutritional status indicators in adults with stage 4 CKD. METHODS: Patients with an estimated glomerular filtration rate between 15 and 29 mL/min/1.73 m2 in an open-label clinical trial were followed for 12 weeks. The intervention group received exercise resistance training sessions three times per week with oral cholecalciferol supplementation each day. The control group only received standard medical care. The outcomes were anthropometric measurements, handgrip strength, and bioelectrical impedance analysis. RESULTS: Thirty-nine patients of a median age of 48 (36-52) years had an estimated glomerular filtration rate of 21.8 ± 6.5 mL/min/1.73 m2. A total of 57.5% of the patients were women. In 41% of the patients, the etiology of CKD was diabetes. After 12 weeks, in the intervention group, the adherence to the resistance training was 77%, and the adherence to the supplementation with cholecalciferol was 96.2%. Significant improvements in 25(OH)D serum concentrations and in handgrip strength were detected in the intervention group (P < .05). In the control group, a decrease in 25(OH)D serum concentrations and a loss in handgrip strength were observed, although the difference was not statistically significant. Anthropometrics and biochemical and dietary indicators, but not bioelectrical impedance data, exhibited changes. CONCLUSION: Supplementation with cholecalciferol improves serum concentrations of 25(OH)D and, when combined with resistance exercise, improved muscle function as measured by handgrip strength in a study of patients with CKD not on dialysis.

Epigenetic EGFR Gene Repression Confers Sensitivity to Therapeutic BRAFV600E Blockade in Colon Neuroendocrine Carcinomas.

PURPOSE: The limited knowledge of the molecular alterations that characterize poorly differentiated neuroendocrine carcinomas has limited the clinical development of targeted agents directed to driver mutations. Here we aim to identify new molecular targets in colon neuroendocrine carcinomas (co-NEC) and proof the efficacy of matching drugs. EXPERIMENTAL DESIGN: We performed a multi-omic analysis of co-NEC to identify genetic or epigenetic alterations that could be exploited as effective drug targets. We compared co-NEC samples with colorectal carcinomas (CRC) to identify neuroendocrine-specific traits. Patients with co-NEC and patient-derived xenografts were treated with a BRAFV600E-blocking drug to demonstrate sensitivity. RESULTS: co-NEC and CRC are similar in their mutational repertoire, although co-NECs are particularly enriched in BRAFV600E mutations. We report for the first time that V600EBRAF-mutant co-NECs may benefit from BRAF inhibition in monotherapy and how EGFR status is essential to predict innate sensitivity and acquired resistance by a differential methylation of its gene regulatory regions. CONCLUSIONS: The identification of V600E BRAF mutations in high-grade co-NECs has allowed the description of radiological responses to combination therapy of BRAF and MEK inhibitors in basket clinical trials. However, the molecular rationale for this treatment combination was based on the presence of the BRAF mutation and the efficacy observed in other cancer types such as melanoma. Future drug development in this setting should test BRAF inhibitors upfront and the addition of anti-EGFR antibodies instead of MEK inhibitors for an efficient blockade of acquired resistance.

Tumor Growth Rate as a Validated Early Radiological Biomarker Able to Reflect Treatment-Induced Changes in Neuroendocrine Tumors: The GREPONET-2 Study.

PURPOSE: Tumor growth rate (TGR) represents the percentage change in tumor volume per month (%/m). Previous results from the GREPONET study showed that TGR measured after 3 months (TGR3m) of starting systemic treatment (ST) or watch and wait (WW) was an early biomarker predicting progression-free survival (PFS) in neuroendocrine tumors (NET). EXPERIMENTAL DESIGN: Patients from 7 centers with advanced grade (G) 1/2 NETs from the pancreas (P)/small bowel (SB) initiating ST/WW were eligible. Computed tomography (CT)/MRI performed at prebaseline, baseline, and 3(±1) months of study entry were retrospectively reviewed. Aim-1: explore treatment-induced changes in TGR (ΔTGR3m-BL; paired T test), and Aim-2: validate TGR3m (<0.8%/m vs. ≥0.8%/m) as an early biomarker in an independent cohort (Kaplan-Meier/Cox regression). RESULTS: Of 785 patients screened, 127 were eligible. Mean (SD) TGR0 and TGR3m were 5.4%/m (14.9) and -1.4%/m (11.8), respectively. Mean (SD) ΔTGR3m-BL paired-difference was -6.8%/m (19.3; P < 0.001). Most marked ΔTGR3m-BL [mean (SD)] were identified with targeted therapies [-11.3%/m (4.7); P = 0.0237] and chemotherapy [-7.9%/m (3.4); P = 0.0261]. Multivariable analysis confirmed the absence of previous treatment (OR = 4.65; 95% CI, 1.31-16.52; P = 0.018) and low TGR3m (continuous variable; OR 1.09; 95% CI, 1.01-1.19; P = 0.042) to be independent predictors of radiologic objective response. When the multivariable survival analysis for PFS (Cox regression) was adjusted to grade (P = 0.004) and stage (P = 0.017), TGR3m ≥ 0.8 (vs. <0.8) maintained its significance as a prognostic factor (P < 0.001), whereas TGR0 and ΔTGR3m-BL did not. TGR3m ≥ 0.8%/m was confirmed as an independent prognostic factor for PFS [external validation; Aim-2; multivariable HR 2.21 (95% CI, 1.21-3.70; P = 0.003)]. CONCLUSIONS: TGR has a role as a biomarker for monitoring response to therapy for early identification of treatment-induced changes and for early prediction of PFS and radiologic objective response.

Prognostic Nomogram and Patterns of Use of FOLFIRI-Aflibercept in Advanced Colorectal Cancer: A Real-World Data Analysis.

INTRODUCTION: The VELOUR study evaluated the efficacy and safety of adding aflibercept to FOLFIRI (fluorouracil, leucovorin, irinotecan) in second-line therapy for metastatic colorectal cancer (mCRC). However, a nomogram that can stratify patients according to prognosis is unavailable, and the frequency and effect of the pragmatic use of modified schedules in actual practice remains unknown. METHOD: The sample consists of 250 patients with mCRC treated with aflibercept and irinotecan-based chemotherapy at nine Spanish academic centers between January 2013 and September 2015. The result of a Cox proportional hazards model regression for overall survival (OS), adjusted for covariates available in daily practice, was represented as a nomogram and web-based calculator. Harrell's c-index was used to assess discrimination. RESULTS: The prognostic nomogram for OS includes six variables: Eastern Cooperative Oncology Group performance status, tumor location, number of metastatic sites, mutational status, better response to previous treatment(s), and carcinoembryonic antigen. The model is well calibrated and has acceptable discriminatory capacity (optimism-corrected c-index, 0.723; 95% confidence interval [CI], 0.666-0.778). Median OS was 6.1 months (95% CI, 5.1-8.8), 12.4 months (95% CI, 9.36-14.8), and 22.9 months (95% CI, 16.6-not reached) for high-, intermediate-, and low-risk groups, respectively. Age, comorbidity, or use of modified FOLFIRI regimens did not affect prognosis in this series. Grade 3-4 adverse events were less common following modified schedules. The admission rate because of toxicity was higher in ≥65 years (9.7% vs. 19.6%; odds ratio, 2.26; p = .029). CONCLUSION: We have developed and internally validated a prognostic model for use in individuals with colorectal cancer initiating therapy with FOLFIRI-aflibercept to predict both OS and the effect of pragmatic modifications of the classic regime on efficacy and safety. This can aid in decision making and in designing future trials. IMPLICATIONS FOR PRACTICE: In this study, the authors developed and conducted the internal validation of a prognostic nomogram that makes it possible to stratify patients who are eligible for second-line FOLFIRI-aflibercept based on their probability of survival. This model was developed in a multicenter sample from nine Spanish hospitals. Furthermore, to increase the study's validity, the practical use of aflibercept in this setting was investigated, including doses or pragmatic modifications. The results suggest that the modified schedules often used in this daily clinical practice-based patient population are associated with less severe toxicity without apparent detriment to survival endpoints. It is believed that these data complement the information provided by the VELOUR trial and are relevant for the oncologist in treating colon cancer in the second-line setting.

Value of Tumor Growth Rate (TGR) as an Early Biomarker Predictor of Patients' Outcome in Neuroendocrine Tumors (NET)-The GREPONET Study.

INTRODUCTION: Tumor growth rate (TGR; percent size change per month [%/m]) is postulated to be an early radiological biomarker to overcome limitations of RECIST. This study aimed to assess the impact of TGR in neuroendocrine tumors (NETs) and potential clinical and therapeutic applications. MATERIALS AND METHODS: Patients (pts) with advanced grade (G) 1/2 NETs from the pancreas or small bowel initiating systemic treatment (ST) or watch and wait (WW) were eligible. Baseline and follow-up scans were retrospectively reviewed to calculate TGR at pretreatment (TGR0), first follow-up (TGRfirst), and 3(±1) months of study entry (TGR3m). RESULTS: Out of 905 pts screened, 222 were eligible. Best TGRfirst (222 pts) cutoff was 0.8 (area under the curve, 0.74). When applied to TGR3m (103 pts), pts with TGR3m <0.8 (66.9%) versus TGR3m ≥ 0.8 (33.1%) had longer median progression-free survival (PFS; 26.3 m; 95% confidence interval [CI] 19.5-32.4 vs. 9.3 m; 95% CI, 6.1-22.9) and lower progression rate at 12 months (7.3% vs. 56.8%; p = .001). WW (vs. ST) and TGR3m ≥ 0.8 (hazard ratio [HR], 3.75; 95% CI, 2.21-6.34; p < .001) were retained as factors associated with a shorter PFS in multivariable Cox regression. TGR3m (HR, 3.62; 95% CI, 1.97-6.64; p < .001) was also an independent factor related to shorter PFS when analysis was limited to pts with stable disease (81 pts). Out of the 60 pts with TGR0 data available, 60% of pts had TGR0 < 4%/month. TGR0 ≥ 4 %/month (HR, 2.22; 95% CI, 1.15-4.31; p = .018) was also an independent factor related to shorter PFS. CONCLUSION: TGR is an early radiological biomarker able to predict PFS and to identify patients with advanced NETs who may require closer radiological follow-up. IMPLICATIONS FOR PRACTICE: Tumor growth rate at 3 months (TGR3m) is an early radiological biomarker able to predict progression-free survival and to identify patients with advanced neuroendocrine tumors who may require closer radiological follow-up. It is feasible to calculate TGR3m in clinical practice and it could be a useful tool for guiding patient management. This biomarker could also be implemented in future clinical trials to assess response to therapy.

Combining Russian stimulation with isometric exercise improves strength, balance, and mobility in older people with falls syndrome.

One of the main causes of falls in older people is muscle strength loss associated with aging. Russian stimulation can improve muscle strength in healthy individuals, but the effect has never been tested in older individuals with falls syndrome. The aim of this study was to evaluate the usefulness of Russian stimulation plus isometric exercise to improve muscular strength, balance, and mobility in older people with falls syndrome. The recruited participants (older than 60 years, at least one fall in the past year) were evaluated by a physiatrist, who collected clinical data and performed baseline and final evaluations (muscle strength, Berg balance scale, Tinetti mobility test, get up and go test, and 6-min walk test). A physical therapist applied the 10/50/10 protocol for Russian stimulation, stimulating the quadriceps and tibialis anterior muscles separately; simultaneously, the participants performed isometric exercise at a frequency of three sessions per week for 12 weeks. Descriptive statistics, the paired-sample t-test, and the χ-test were performed. The study included 25 participants (96% women, mean age 65.2±5.5 years). After the intervention, there was a significant improvement in the strength of the quadriceps (~30%) and tibialis anterior (~40%) muscles as well as the results of the balance (Tinetti 22%, Berg 10%) and mobility (get up and go 25%, 6-min distance 20%) tests. On the basis of the improvements in the Tinetti and Berg scores, significantly fewer participants were classified as being at increased risk for falls. The muscle strength correlated with several clinical evaluation results, but not with the Tinetti test score. Russian stimulation plus isometric exercise improves strength, balance, and mobility, which may decrease the fall risk.

Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There is increasing interest in developing specific markers to serve as predictors of response to sorafenib and to guide targeted therapy. Using a sequencing platform designed to study somatic mutations in a selection of 112 genes (HepatoExome), we aimed to characterize lesions from HCC patients and cell lines, and to use the data to study the biological and mechanistic effects of case-specific targeted therapies used alone or in combination with sorafenib. We characterized 331 HCC cases in silico and 32 paired samples obtained prospectively from primary tumors of HCC patients. Each case was analyzed in a time compatible with the requirements of the clinic (within 15 days). In 53% of the discovery cohort cases, we detected unique mutational signatures, with up to 34% of them carrying mutated genes with the potential to guide therapy. In a panel of HCC cell lines, each characterized by a specific mutational signature, sorafenib elicited heterogeneous mechanistic and biological responses, whereas targeted therapy provoked the robust inhibition of cell proliferation and DNA synthesis along with the blockage of AKT/mTOR signaling. The combination of sorafenib with targeted therapies exhibited synergistic anti-HCC biological activity concomitantly with highly effective inhibition of MAPK and AKT/mTOR signaling. Thus, somatic mutations may lead to identify case-specific mechanisms of disease in HCC lesions arising from multiple etiologies. Moreover, targeted therapies guided by molecular characterization, used alone or in combination with sorafenib, can effectively block important HCC disease mechanisms.