Validation of the Upper Limb Functional Index on Breast Cancer Survivor.

Breast cancer survivors (BCS) may face functional alterations after surgical intervention. Upper Limb Disorders (ULDs) are highly prevalent even years after a diagnosis. Clinicians may assess the upper limbs after breast cancer. The Upper Limb Functional Index (ULFI) has been validated across different populations and languages. This study aimed to assess the psychometric properties of the Upper Limb Functional Index Spanish version (ULFI-Sp) in the BCS. METHODS: A psychometric validation study of the ULFI-Sp was conducted on 216 voluntary breast cancer survivors. The psychometric properties were as follows: analysis of the factor structure by maximum likelihood extraction (MLE), internal consistency, and construct validity by confirmatory factor analysis (CFA). RESULTS: The factor structure was one-dimensional. ULFI-Sp showed a high internal consistency for the total score (α = 0.916) and the regression score obtained from MLE (α = 0.996). CFA revealed a poor fit, and a new 14-item model (short version) was further tested. The developed short version of the ULFI-SP is preferable to assess upper limb function in Spanish BCS. CONCLUSIONS: Given the high prevalence of ULD in this population and the broader versions of ULFI across different languages, this study's results may be transferred to clinical practice and integrated as part of upper limb assessment after breast cancer.

Forearm Muscle Activity During the Handgrip Test in Breast Cancer Survivors: A Cross-Sectional Study.

INTRODUCTION/BACKGROUND: Breast cancer survivors (BCS) frequently show upper limb dysfunctions. The forearm muscle activity measured by surface electromyography (sEMG) in this population has not been studied. This study aimed to describe forearm muscle activity in BCS, as well as to assess its possible relationship with other variables related to upper limb functionality and cancer-related fatigue (CRF). MATERIALS AND METHODS: A cross-sectional study was carried out including 102 BCS as volunteers at a secondary care in Malaga, Spain. BCS were included if they were aged between 32 and 70 years old, without evidence of cancer recurrence at the time of recruitment. The forearm muscle activity (microvolts, µV) was assessed by sEMG during the handgrip test. The handgrip strength was assessed by dynamometry (kg), the upper limb functionality (%) was measured by the upper limb functional index (ULFI) questionnaire and the CRF was also assessed by revised Piper Fatigue Scale (0-10 points). RESULTS: BCS reported reduced forearm muscle activity (287.88 µV) and reduced handgrip strength (21.31 Kg), a good upper limb functionality (68.85%), and a moderate cancer-related fatigue (4.74). Forearm muscle activity showed a poor significant correlation (r = -0.223, P = .038) with the CRF. Handgrip strength showed a poor correlation with the upper limb functionality (r = 0.387, P < .001) and age (r=-0.200, P = .047). CONCLUSION: BCS showed a reduced forearm muscle activity. BCS also presented a poor correlation between forearm muscle activity and handgrip strength. Both outcomes tended to lower values with higher levels of CRF, while preserving a good upper limb functionality.

PD-L1 immunoexpression and molecular characterization of histological subtypes in urothelial carcinoma.

INTRODUCTION: Urothelial carcinoma (UC) has histological subtypes whose phenotype reflects their molecular diversity, behavior and response to conventional therapy. Immune checkpoint inhibitors (ICIs) have improved the management of UC by evaluation of PD-L1. In the case of PD-L1 22C3, the initiation of ICI is considered from a combined positive score (CPS) greater than 10. However, UC subtypes with absent PD-L1 22C3 expression in cases with CPS>10 may not respond to these treatments. This study aims to establish a correlation between the PD-L1 immunoexpression and molecular alterations in divergent differentiation and histological subtypes of UC (UC-s). MATERIAL AND METHODS: Twenty-six samples of UC were detected from a total of 24 patients. Two pathologists performed separately an assessment of UC-s on hematoxylin-eosin as well as PD-L1 expression. Molecular study of each case was performed by next generation sequencing (NGS). A descriptive analysis of the variables included was conducted. RESULTS: Nine cases (34.61%) showed a CPS>10, some with negative PD-L1 immunoexpression in aggressive UC-s. The molecular study revealed alterations in genes belonging to the p53/cell cycle control, RAS, and DNA repair pathways, among others. None of the alterations were exclusive to any histological subtype. DISCUSSION: Special attention should be paid to CPS>10 cases that include histological subtypes of UC with divergent expression for PD-L1 as they may not respond to treatment with ICI. We recommend examining the proportion and PD-L1 status of each subtype, especially if it has aggressive behavior.

PD-L1 immunoexpression and molecular characterization of histological subtypes in urothelial carcinoma / Inmunoexpresión de PD-L1 y caracterización molecular de subtipos histológicos de carcinoma urotelial

Introduction: Urothelial carcinoma (UC) has histological subtypes whose phenotype reflects their molecular diversity, behavior and response to conventional therapy. Immune checkpoint inhibitors (ICIs) have improved the management of UC by evaluation of PD-L1. In the case of PD-L1 22C3, the initiation of ICI is considered from a combined positive score (CPS) greater than 10. However, UC subtypes with absent PD-L1 22C3 expression in cases with CPS>10 may not respond to these treatments. This study aims to establish a correlation between the PD-L1 immunoexpression and molecular alterations in divergent differentiation and histological subtypes of UC (UC-s). Material and methods: Twenty-six samples of UC were detected from a total of 24 patients. Two pathologists performed separately an assessment of UC-s on hematoxylin–eosin as well as PD-L1 expression. Molecular study of each case was performed by next generation sequencing (NGS). A descriptive analysis of the variables included was conducted. Results: Nine cases (34.61%) showed a CPS>10, some with negative PD-L1 immunoexpression in aggressive UC-s. The molecular study revealed alterations in genes belonging to the p53/cell cycle control, RAS, and DNA repair pathways, among others. None of the alterations were exclusive to any histological subtype. Discussion: Special attention should be paid to CPS>10 cases that include histological subtypes of UC with divergent expression for PD-L1 as they may not respond to treatment with ICI. We recommend examining the proportion and PD-L1 status of each subtype, especially if it has aggressive behavior.(AU)

Introducción: El carcinoma urotelial (CU) presenta subtipos histológicos cuyo fenotipo refleja su diversidad molecular, su comportamiento y su respuesta al tratamiento. Los inhibidores de puntos de control inmunitario (ICI) han mejorado el manejo del CU mediante la evaluación de PD-L1. En el caso de PD-L1 22C3, se considera el inicio de ICI a partir de una puntuación positiva combinada (combined positive score [CPS]) mayor de 10. Sin embargo, los subtipos de CU con ausencia de expresión de PD-L1 22C3 en casos con CPS>10 podrían no responder a estos tratamientos. Este estudio pretende establecer una correlación entre la inmunoexpresión de PD-L1 y las alteraciones moleculares en áreas con diferenciación divergente y subtipos histológicos de CU (CU-s). Material y métodos: Se obtuvieron 26 muestras con CU de 24 pacientes. Dos patólogos evaluaron de manera independiente las CU-s en hematoxilina-eosina y la expresión de PD-L1. Se realizó el estudio molecular mediante Next Generation Sequencing (NGS). Se realizó un análisis descriptivo de las variables incluidas. Resultados: Nueve casos (34,61%) mostraron un CPS>10, algunos con PD-L1 negativo en los CU-s de comportamiento agresivo. El estudio molecular reveló alteraciones en genes de las vías de p53/control del ciclo celular, RAS y reparación del ADN, entre otras. Ninguna alteración fue exclusiva de algún CU-s. Discusión: Debe prestarse especial atención a los casos con CPS>10 que incluyan subtipos histológicos con expresión divergente para PD-L1, ya que podrían no responder al tratamiento con ICI. Se recomienda cuantificar la proporción y el estado de PD-L1 de cada subtipo, especialmente si es de comportamiento agresivo.(AU)

The Benefits of a Therapeutic Exercise and Educational Intervention Program on Central Sensitization Symptoms and Pain-Related Fear Avoidance in Breast Cancer Survivors.

BACKGROUND: Central sensitization symptoms and pain-related fear avoidance are two common problems in breast cancer survivors. Non-pharmacologic interventions such as therapeutic exercise and patient education can be effective in this population. AIMS: This study aimed to: (1) analyze the benefits of a therapeutic exercise and educational program on central sensitization symptoms and pain-related fear avoidance in breast cancer survivors, and (2) explore the association between pain-related fear avoidance and central sensitization symptoms. DESIGN: A single group pre-post intervention study was conducted. METHODS: Patients were recruited from the service of Medical Oncology of the University Clinical Hospital Virgen de la Victoria, in Málaga (Spain). The intervention consisted of a therapeutic exercise and educational program that lasted 12 weeks, twice a week, for 1 hour. Two instruments were used: the Spanish version of the Central Sensitization Inventory and the Spanish Fear Avoidance Components Scale. RESULTS: A total of 82 breast cancer survivors participated in the study. Pre-post change on Central Sensitization Inventory was statistically significant (p = .007). There was a trend towards a significant difference for the Spanish Fear Avoidance Components Scale (p = .062). There was a statistically significant correlation between pain-related fear avoidance and central sensitization symptoms (r = 0.536, p < .001). CONCLUSIONS: The current study has provided preliminary evidence on the benefits of this intervention in pain-related fear avoidance and central sensitization symptoms in breast cancer survivors. The Spanish version of the Central Sensitization Inventory and the Spanish Fear Avoidance Components Scale demonstrated responsiveness to change.

The economic cost of not coding disease-related malnutrition: A study in cancer inpatients.

BACKGROUND & AIMS: Disease-related malnutrition (DRM) coding rate is usually low in hospitalised patients. The objective of our study was to estimate the percentage of correct DRM coding in cancer inpatients and to calculate the economic losses caused by such lack of coding. METHODS: This was an observational, prospective study that was conducted in patients hospitalised in the Medical Oncology Unit of our hospital. A nutritional assessment was performed through subjective global assessment (SGA). The all patient refined-diagnosis related group (APR-DRG) weights were obtained at the moment of discharge; moreover, recalculation was done after including the diagnosis of malnutrition in the medical record of those patients in whom it had not been initially coded. The associated cost reimbursement were calculated based on the weight before and after revising the diagnosis of DRM. RESULTS: A total of 266 patients were evaluated. From them, 220 (82.7%) suffered from DRM according to the SGA. In 137 (51.5%) of these patients, diagnosis was coded, as opposed to 83 (31.2%) cases (33 subjects with moderate and 50 with severe DRM) in whom it was not coded. The sum of the APR-DRG weights before revising the diagnosis of malnutrition was 343.4 points (mean: 1.29 ± 0.89). Whereas, after revising the diagnosis, it increased up to 384.3 (1.44 ± 0.96). The total cost reimbursement for the hospital before revising the diagnosis of malnutrition was 1,607,861.21€ and after revision it increased up to 1,799,199.69€, which means that 191,338.48€ were not reimbursed to the hospital due to the lack of coding of malnutrition. The cost reimbursement for each admission increased an average of 719.32€. CONCLUSION: The prevalence of DRM in cancer inpatients is high. Nevertheless, the diagnosis is not coded in one third of patients, which results in important economic losses for the hospitals.

Subclinical Arteriosclerosis is Associated With Common Vascular Risk Factors in Long-Term Survivors of Testicular Cancer.

Cardiovascular disease risk is increased in survivors of testicular cancer because of exposure to treatment (chemotherapy and radiotherapy), as well as modification in lifestyle. Our aim was to assess the presence of subclinical arteriosclerosis in survivors of testicular cancer in comparison with a control group. This was a cross-sectional, observational, case-control study including 50 survivors of Germ Cell Tumor (GCT) (14 years of follow-up) and 53 age-matched controls with no cancer. We registered clinical data, cardiovascular risk factors, physical and Mediterranean questionnaires, intima-media thickness and plaque at carotid and femoral arteries by ultrasound, calcium score at the abdominal aorta, and liver steatosis by computed tomography, and applied analytical tests to quantify metabolic risk factors and inflammation markers. Patients showed a trend toward greater intima-media thickness (IMT) and plaques than controls, as well as a higher calcium score in the abdominal aorta. Remarkably, patients had higher waist circumference, insulin resistance (HOMA-IR), and liver steatosis, but lower physical activity and high-density lipoprotein (HDL) cholesterol than controls (all p < 0.05). In multivariate analyses, only common vascular risk factors were associated with subclinical arteriosclerosis. As a conclusion, in our study, a higher rate of subclinical arteriosclerosis in testicular cancer survivors was associated with classical metabolic risk factors and lifestyle, but not with exposure to chemotherapy.

New insights into the role of the immune microenvironment in breast carcinoma.

Recently, immune edition has been recognized as a new hallmark of cancer. In this respect, some clinical trials in breast cancer have reported imppressive outcomes related to laboratory immune findings, especially in the neoadjuvant and metastatic setting. Infiltration by tumor infiltrating lymphocytes (TIL) and their subtypes, tumor-associated macrophages (TAM) and myeloid-derived suppressive cells (MDSC) seem bona fide prognostic and even predictive biomarkers, that will eventually be incorporated into diagnostic and therapeutic algorithms of breast cancer. In addition, the complex interaction of costimulatory and coinhibitory molecules on the immune synapse and the different signals that they may exert represent another exciting field to explore. In this review we try to summarize and elucidate these new concepts and knowledge from a translational perspective focusing on breast cancer, paying special attention to those aspects that might have more significance in clinical practice and could be useful to design successful therapeutic strategies in the future.

The role of immunohistochemistry in breast cancer patients treated with neoadjuvant chemotherapy: an old tool with an enduring prognostic value.

BACKGROUND: To assess the molecular subtypes determined by hormonal receptors (HR) and human epidermal growth factor receptor 2 (HER2) status and the role of proliferation measured by the Ki-67 marker as predictive and prognostic factors in breast cancer patients treated with neoadjuvant chemotherapy. METHODS: A total of 127 breast cancer patients were treated with neoadjuvant chemotherapy every 2 weeks as part of 2 studies. Study A consisted of the administration of Adriamycin (40 mg/m(2)) on day 1 plus paclitaxel (150 mg/m(2)) and gemcitabine 2000 mg/m(2)) on day 2 for 6 cycles (n = 54). Study B consisted of the administration of epirubicin (90 mg/m(2)), cyclophosphamide (600 mg/m(2)) on day 1 for 3 cycles, followed by the administration of paclitaxel (150 mg/m(2)) and gemcitabine 2500 (mg/m(2)) on day 1 with or without trastuzumab according to HER2 status (n = 73). In study A, patients did not receive trastuzumab regardless of HER2 status. The molecular subtypes of the patients with breast cancer were classified as 49% HR(+)/HER2(-), 17.5% HR(+)/HER2(+), 13.5% HR(-)/HER2(+), and 20% HR(-)/HER2(-). RESULTS: Pathologic complete response (pCR), defined as the absence of invasive cells in the breast and the lymph nodes, was achieved in 35 (28%) patients. The pCR rate was significantly different between the molecular subtypes of breast cancer, with 9% in HR(+)/HER2(-), 23% in HR(+)/HER2(+), 50% in HR(-)/HER2(+), and 56% in HR(-)/HER2(-) tumors (P < .001). The pCR rate was significantly higher in tumors that had high Ki-67 (≥20%) expression and were HR(-). HER2(+) was associated with a higher trend of pCR but did not reach statistical significance. The median follow-up was 81 months (r = 15-150 months). Patients who achieved a pCR had a significantly lower recurrence (P = .01) and higher overall survival (P = .02) compared with those who did not achieve pCR. A multivariate analysis revealed that pCR (hazard ratio 0.24 [95% CI, 0.07-0.7]; P = .019), the molecular subtype (hazard ratio 0.3 [95% CI, 0.1-0.8]; P = .02), and the Ki-67 index (hazard ratio 3.2 [95% CI, 1.4-7.1]; P = .004) were significant independent predictors of disease-free survival. Similar results were obtained for overall survival, in which the pCR rate (hazard ratio 0.119 [95% CI, 0.028-0.5]; P = .004), the molecular subtype (hazard ratio 0.17 [95% CI, 0.03-0.86]; P = .02), and the Ki-67 index (hazard ratio 3.6 [95% CI, 1.3-9.7]; P = .01) also displayed a significant influence on survival. CONCLUSIONS: Molecular subtypes and Ki-67 index were independent prognostic factors for disease-free survival and overall survival in breast cancer patients treated with neoadjuvant chemotherapy. A high rate of Ki-67 and HR(-) expression were predictors of pCR.

Spanish Society of Medical Oncology consensus on the use of erythropoietic stimulating agents in anaemic cancer patients.

Treatment of anaemia is a very important aspect in the management of cancer patients. In order to carry out a consensus process about the use of erythropoietic stimulating agents (ESAs) in cancer patients, the Spanish Society of Medical Oncology (SEOM) elaborated a working group which coordinated a panel of medical oncology specialists. This working group has reviewed the main issues about the use of ESAs. In addition a consensus meeting was held in Madrid on 25 April 2007. The following conclusions were made: Since ESA treatment increases the haemoglobin (Hb) level and decreases the red blood cell (RBC) transfusion requirements, ESAs should be used within the approved indications in patients undergoing chemotherapy treatment, beginning at a Hb level below 11 g/dl and maintaining it around 12 g/dl, with iron supplements if necessary. Neither increasing the ESA dose in nonresponders nor the use of ESAs in the treatment of chronic cancer-related anaemia is recommended.

Targeted therapy of metastatic breast cancer.

Breast cancer is a heterogeneous disease characterised by a dysregulation of multiple pathways related to cell differentiation, cell cycle control, apoptosis, angiogenesis and development of metastasis. Acting against these pathways provides therapeutic targets for new targeted biologic therapies, which, in the future, might constitute a key for fighting cancer. The development of molecular technology in recent years has allowed a further comprehension of these mutations and dysregulated pathways leading to oncogenesis. New targeted biologic therapies will block essential functions of cancer cells and tumour stroma. A growing number of therapy options, alone or in combination with background treatments (chemotherapy, hormone therapy, radiotherapy), will allow oncologists a better adaptation of treatment to patients and disease characteristics. Examples of approved targeted agents in breast cancer include agents targeting the human epidermal growth factor receptor 2 (HER2), such as trastuzumab, lapatinib and the anti-VEGF bevacizumab. In addition, there are other therapy classes under evaluation, including novel antiEGFR or antiHER2 therapies; agents fighting other tyrosine kinases, including the Src and the insulinlike growth factor receptor; agents interfering critically relevant pathways, such as PI3K/AKT/mTOR inhibitors; and agents promoting apoptosis, such as PARP inhibitors (for particular breast cancer subtypes, such as basal-like, or breast cancer with BRCA mutations) and others. The better selectivity against malignant cells of these therapies, when compared to conventional chemotherapy, gives, a priori, at least two advantages to biologic treatments: fewer side effects and a more individualised treatment of cancer depending on the tumour's molecular characteristics. The ability to identify patients' subgroups and response predicting factors will be crucial in obtaining the greatest benefit with minimal toxicity levels. Unsolved questions remain, such as appropriate patient selection based on the expression of the therapeutic target in the tumour, the study of the efficacy of the drug in not so extensively pretreated populations and with a greater chance of response, the use of new pharmacodynamic models to help to define new response predicting factors for a specific new biologic therapy, the combined and rational use of different biologic therapies having different molecular targets and fighting the same target through a complementary mechanism of action that might improve clinical efficacy.

Current status of anti-angiogenic agents in the treatment of ovarian carcinoma.

During the last decade we have assisted in the development of new therapeutic strategies for the treatment of ovarian cancer, based on the best knowledge of molecular biology. One of the most promising strategies under investigation is antiangiogenic therapy. Bevacizumab is a monoclonal humanised antibody targeting vascular endothelial growth factor (VEGF), which has shown antitumour activity in ovarian cancer in preclinical models as well as in clinical trials, both in monotherapy and in combination with other therapies. Currently, ongoing phase III trials are testing bevacizumab as a front-line therapy with carboplatin and paclitaxel. Bevacizumab has been generally well tolerated with mild frequent toxicities (proteinuria, hypertension and bleeding). However, the drug may result in other uncommon, but potentially life-threatening side effects, such as arterial thromboembolism, wound healing complications, and gastrointestinal perforation or fistulae, which should be considered when the drug is administered. Other new therapeutic antiangiogenic strategies that include small-molecule tyrosine kinase inhibitors, antibodies neutralising the VEGF receptor (VEGFR) and soluble VEGFR hybrids (VEGF Trap) are being investigated with promising early results.

A combined neural network and decision trees model for prognosis of breast cancer relapse.

The prediction of clinical outcome of patients after breast cancer surgery plays an important role in medical tasks such as diagnosis and treatment planning. Different prognostic factors for breast cancer outcome appear to be significant predictors for overall survival, but probably form part of a bigger picture comprising many factors. Survival estimations are currently performed by clinicians using the statistical techniques of survival analysis. In this sense, artificial neural networks are shown to be a powerful tool for analysing datasets where there are complicated non-linear interactions between the input data and the information to be predicted. This paper presents a decision support tool for the prognosis of breast cancer relapse that combines a novel algorithm TDIDT (control of induction by sample division method, CIDIM), to select the most relevant prognostic factors for the accurate prognosis of breast cancer, with a system composed of different neural networks topologies that takes as input the selected variables in order for it to reach good correct classification probability. In addition, a new method for the estimate of Bayes' optimal error using the neural network paradigm is proposed. Clinical-pathological data were obtained from the Medical Oncology Service of the Hospital Clinico Universitario of Málaga, Spain. The results show that the proposed system is an useful tool to be used by clinicians to search through large datasets seeking subtle patterns in prognostic factors, and that may further assist the selection of appropriate adjuvant treatments for the individual patient.

El razonamiento clínico como fuente de error / Clinical reasoning as a source of error

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