Induction chemotherapy (IC) followed by radiotherapy (RT) versus cetuximab plus IC and RT in advanced laryngeal/hypopharyngeal cancer resectable only by total laryngectomy-final results of the larynx organ preservation trial DeLOS-II.

Background: The German multicenter randomized phase II larynx organ preservation (LOP) trial DeLOS-II was carried out to prove the hypothesis that cetuximab (E) added to induction chemotherapy (IC) and radiotherapy improves laryngectomy-free survival (LFS; survival with preserved larynx) in locally advanced laryngeal/hypopharyngeal cancer (LHSCC). Patients and methods: Treatment-naïve patients with stage III/IV LHSCC amenable to total laryngectomy (TL) were randomized to three cycles IC with TPF [docetaxel (T) and cisplatin (P) 75 mg/m2/day 1, 5-FU (F) 750 mg/m2/day days 1-5] followed by radiotherapy (69.6 Gy) without (A) or with (B) standard dose cetuximab for 16 weeks throughout IC and radiotherapy (TPFE). Response to first IC-cycle (IC-1) with ≥30% endoscopically estimated tumor surface shrinkage (ETSS) was used to define early responders; early salvage TL was recommended to non-responders. The primary objective was 24 months LFS above 35% in arm B. Results: Of 180 patients randomized (July 2007 to September 2012), 173 fulfilled eligibility criteria (A/B: larynx 44/42, hypopharynx 41/46). Because of 4 therapy-related deaths among the first 64 randomized patients, 5-FU was omitted from IC in the subsequent 112 patients reducing further fatal toxicities. Thus, IC was TPF in 61 patients and TP in 112 patients, respectively. The primary objective (24 months LFS above 35%) was equally met by arms A (40/85, 47.1%) as well as B (41/88, 46.6%). One hundred and twenty-three early responders completed IC+RT; their overall response rates (TPF/TP) were 94.7%/87.2% in A versus 80%/86.0% in B. The 24 months overall survival (OS) rates were 68.2% and 69.3%. Conclusions: Despite being accompanied by an elevated frequency in adverse events, the IC with TPF/TP plus cetuximab was feasible but showed no superiority to IC with TPF/TP regarding LFS and OS at 24 months. Both early response and 24 months LFS compare very well to previous LOP trials and recommend effective treatment selection and stratification by ETSS. Clinical trial information: NCT00508664.

Establecimiento de un protocolo para el uso de la heparina en pacientes con características especiales / Set up of a protocol for heparin use in special patients

Las HBPMs (heparina de bajo peso molecular) tienen numerosas ventajas sobre la heparina no fraccionada (HNF) como seguridad, eficacia, biodisponibilidad, menor monitorización y una respuesta anticoagulante persistente. Pero, existe cierta preocupación en su manejo para determinados pacientes que requieren un control especial como en insuficiencia renal, mayores de 75 años, obesidad y embarazo. El objetivo de este estudio fue la realización de un protocolo consensuado entre los Servicios de Farmacia, Hematología y Medicina Interna, para el seguimiento y monitorización de HBPM en pacientes que requieren un especial control. Para ello, llevamos a cabo una revisión bibliográfica de las distintas heparinas en las situaciones comentadas. Basándonos en la evidencia disponible y en el consenso entre los miembros del grupo de trabajo, elaboramos el protocolo, recomendando unas dosis para profilaxis, tratamiento y monitorización, mediante la determinación del factoranti-Xa. Además, recogemos unas orientaciones sobre los valores terapéuticos del anti-Xa y unas pautas posológicas para la obtención de un anti-Xa en rango. La heparina seleccionada fue la enoxaparina, por su evidencia y disponibilidad en nuestro centro (AU)

Low-molecular weight (LMW) heparins bring a series of advantages as compared to non-fractionated heparin (NFH), such as safety, efficacy, bioavailability, fewer monitoring, and persistent anti-coagulant response. There exist, however, a concern about their use in particular patients that may require a special control, such as those with renal failure, age over 75 years, obesity, and pregnancy. The aim of this study was the set up between the department of Pharmacy, Hematology, and Internal Medicine of a consensus protocol for the follow-up ad monitoring of LMWH in patients requiring a special control. For this purpose, we carried out a bibliographical review of the different heparins used under de above mentioned conditions. Based on the evidence available and the consensus among the members of the working group, we established a protocol that contained recommendations on prophylaxis, management and monitoring by means of the determination of anti-Xa factor. Besides,we included some clues on the therapeutic figures of anti-Xa and administration schedules for obtaining anti-Xa values within the range. Enoxaparin was the selected heparin given the evidence and its availability at our center (AU)

[Set up of a protocol for heparin use in special patients]. / Establecimiento de un protocolo para el uso de la heparina en pacientes con características especiales.

Low-molecular weight (LMW) heparins bring a series of advantages as compared to non-fractionated heparin (NFH), such as safety, efficacy, bioavailability, fewer monitoring, and persistent anti-coagulant response. There exist, however, a concern about their use in particular patients that may require a special control, such as those with renal failure, age over 75 years, obesity, and pregnancy. The aim of this study was the set up between the department of Pharmacy, Hematology, and Internal Medicine of a consensus protocol for the follow-up ad monitoring of LMWH in patients requiring a special control. For this purpose, we carried out a bibliographical review of the different heparins used under de above mentioned conditions. Based on the evidence available and the consensus among the members of the working group, we established a protocol that contained recommendations on prophylaxis, management and monitoring by means of the determination of anti-Xa factor. Besides, we included some clues on the therapeutic figures of anti-Xa and administration schedules for obtaining anti-Xa values within the range. Enoxaparin was the selected heparin given the evidence and its availability at our center.

Las HBPMs (heparina de bajo peso molecular) tienen numerosas ventajas sobre la heparina no fraccionada (HNF) como seguridad, eficacia, biodisponibilidad, menor monitorización y una respuesta anticoagulante persistente. Pero, existe cierta preocupación en su manejo para determinados pacientes que requieren un control especial como en insuficiencia renal, mayores de 75 años, obesidad y embarazo. El objetivo de este estudio fue la realización de un protocolo consensuado entre los Servicios de Farmacia, Hematología y Medicina Interna, para el seguimiento y monitorización de HBPM en pacientes que requieren un especial control. Para ello, llevamos a cabo una revisión bibliográfica de las distintas heparinas en las situaciones comentadas. Basándonos en la evidencia disponible y en el consenso entre los miembros del grupo de trabajo, elaboramos el protocolo, recomendando unas dosis para profilaxis, tratamiento y monitorización, mediante la determinación del factor anti-Xa. Además, recogemos unas orientaciones sobre los valores terapéuticos del anti-Xa y unas pautas posológicas para la obtención de un anti-Xa en rango. La heparina seleccionada fue la enoxaparina, por su evidencia y disponibilidad en nuestro centro.

DNA replication stress response involving PLK1, CDC6, POLQ, RAD51 and CLASPIN upregulation prognoses the outcome of early/mid-stage non-small cell lung cancer patients.

Lung cancer is the leading cause of cancer deaths worldwide. Clinical staging classification is generally insufficient to provide a reliable prognosis, particularly for early stages. In addition, prognostic factors are therefore needed to better forecast life expectancy and optimize adjuvant therapeutic strategy. Recent evidence indicates that alterations of the DNA replication program contribute to neoplasia from its early stages and that cancer cells are frequently exposed to endogenous replication stress. We therefore hypothesized that genes involved in the replication stress response may represent an under-explored source of biomarkers. Expressions of 77 DNA replication-associated genes implicated in different aspects of chromosomal DNA replication, including licensing, firing of origins, elongation, replication fork maintenance and recovery, lesion bypass and post-replicative repair were determined in primary tumors and adjacent normal tissues from 93 patients suffering from early- or mid-stage non-small cell lung cancer (NSCLC). We then investigated a statistically significant interaction between gene expressions and survival of early-stage NSCLC patients.The expression of five genes, that is, POLQ, PLK1, RAD51, CLASPIN and CDC6 was associated with overall, disease-free and relapse-free survival. The expression levels are independent of treatment and stage classification. Except RAD51, their prognostic role on survival persists after adjustment on age, sex, treatment, stage classification and conventional proliferation markers, with a hazard ratio of 36.3 for POLQ (95%CI 2.6-517.4, P=0.008), 23.5 for PLK1 (95%CI 1.9-288.4, P=0.01), 20.7 for CLASPIN (95%CI 1.5-275.9, P=0.02) and 18.5 for CDC6 (95%CI 1.3-267.4, P=0.03). We also show that a five-gene signature including POLQ, PLK1, RAD51, CLASPIN and CDC6 separates patients into low- and high-risk groups, with a hazard ratio of 14.3 (95% CI 5.1-40.3, P<0.001). This 'replication stress' metamarker may be a reliable predictor of survival for NSCLC, and may also help understand the molecular mechanisms underlying tumor progression.

Aplasia pura de serie roja con cambios mielodisplásicos / No disponible

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[Thrombogenic and endothelial damage markers in patients with ischemic systolic impairment]. / Marcadores de hipercoagulabilidad y daño endotelial en pacientes con disfunción sistólica de origen isquémico.

INTRODUCTION: Anticoagulation is rarely indicated in patients with left ventricular dysfunction who show an increased risk for thromboembolism. In theory, the three arms of the Virchow' triad may be present: abnormal blood flow, endothelial damage and prothrombotic markers. The aim of this study was to identify the last two arms. PATIENTS AND METHOD: We studied 82 consecutive patients with demonstrated ischaemic heart disease and sinus rhythm, and compared them with a control group comprised of 32 healthy subjects matched for age and sex. None or the patients had had an acute coronary event or hemodynamic decompensation within the 3 months prior to inclusion in the study. The plasma concentration or von Willebrand factor and fibrin d-dimer and fibrinogen were determined as endothelial damage and prothrombotic markers, respectively. A fractional shortening less than 29% by echography was defined as ventricular systolic dysfunction. RESULTS: The patients showed significantly higher levels of von Willebrand factor with respect to the control group (109.2 31.9 vs 85.5 32.6%, p < 0.01), with no differences in fibrinogen and fibrin d-dimer values. Twenty-six patients fulfilled criteria of left ventricular systolic dysfunction. Patients with left ventricular dysfunction showed higher fibrinogen (386 118 vs 322 102 mg/dl, p = 0.03) and fibrin d-dimer (0.36 0.22 vs 0.26 0.10 g/ml; p = 0.04) levels, with no differences in von Willebrand factor levels. CONCLUSIONS: After acute coronary events, patients with ischaemic heart disease show markers of endothelial damage. However, patients with left ventricular dysfunction show a hypercoagulable state.

Hipercoagulabilidad y cardiopatía isquémica: potencial interacción entre los anticuerpos antifosfolípidos y elementos celulares implicados en la hemostasia / Hipercoagulability and ischemic cardiopathy: potential interaction between antiphospholipid antibodies and cellular elements related with haemosthasis

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[Subcutaneous preservation of an amputated auricle. Morphological changes]. / Subkutane Konservierung einer abgetrennten Ohrmuschel. Morphologische Veränderungen.

BACKGROUND: Microsurgical replantation of an avulsed auricle remains a challenge in reconstructive surgery. Secondary reconstruction of a traumatic lost auricle is usually performed using a costal cartilage framework according to well documented techniques or with a prosthesis. In order to minimize donor-site morbidity, various efforts can be undertaken to preserve the amputated auricle by implanting the de-epithelialized cartilage framework in a subcutaneous pocket on the surface of the mastoid. Where preservation is successful, this original cartilage could be used for reconstructive treatment. PATIENT AND RESULTS: This study describes the histologic and immunohistologic changes in a complete traumatic avulsion of the auricle with subsequent cartilage conservation for eight months within a skin pocket. Trauma, preparation and preservation were accompanied by morphologic changes that included generation of local ossification centers and infiltration of fibrous tissue. We compared the macroscopic and microscopic morphology of the amputated part to native elastic cartilage following maximal denutrition and temporary heterotopic implantation in conjunction with atypical tension and pressure properties of the retroauricular pocket. CONCLUSION: In this case, the limited success of cartilage conservation in the subcutaneous pocket required conventional auricle reconstruction with autologous costal cartilage.

Ectodermal ablation of the third branchial arch in chick embryos and the morphogenesis of the parathyroid III gland.

The parathyroid glands have been classically considered to be derivatives of the third and fourth pharyngeal pouches in most species, including humans. Furthermore, the presence of neural crest-derived cells in the parathyroid glands connective tissue has been apparently established. However, our previous studies have provided a new hypothesis on the origin of these glands in human and chick embryos. To determine the origin of the parathyroid III (P3) gland, ectoderm of the third branchial arch was cauterized in chick embryos at Hamburger and Hamilton's stage 19 (embryonic day 3). Cauterization of the ventral half of the ectoderm was followed by the non-formation, on the same side, of the P3 gland. When the dorsal half of the ectoderm was cauterized, both the right and left P3 glands formed. Our observations suggest that the ectoderm of the ventral half of the third branchial arch is necessary for the organization of the P3 gland.

[Improvement in fibrinolytic function following anticoagulant treatment in chronic rheumatic atrial fibrillation]. / Mejoría de la función fibrinolítica tras el tratamiento anticoagulante en la fibrilación auricular reumática crónica.

INTRODUCTION AND OBJECTIVES: Patients with rheumatic atrial fibrillation are considered at high risk of systemic embolism and require oral anticoagulation. Fibrinolytic function has been little studied. We evaluated fibrinolytic activation markers before starting anticoagulation, at 1 and 6 months following the introduction of oral anticoagulation therapy. We analyzed the relationship with left atrial diameter and mitral area. METHODS: Tissue plasminogen activator (tPA), its inhibitor (PAI-1), plasmin-antiplasmin complexes (PAP) and D-dimer were measured in 13 patients with rheumatic atrial fibrillation. Basal levels were compared with those found in plasma of 20 healthy subjects matched by sex and age. Transthoracic echocardiography was made. RESULTS: A significant increase for PAI-1 and D-dimer levels were detected in patients with atrial fibrillation group (p < 0.05), with no differences in tPA and PAP concentrations. Significant correlation between left atrial diameter and basal t-PA levels was found. Levels of t-PA, PAI-1 and D-dimer decreased significantly under anticoagulation therapy, whereas PAP levels were significantly increased. CONCLUSIONS: Patients with rheumatic atrial fibrillation show a relative hypofibrinolytic state due to elevated PAI-1 levels with no increase in PAP concentration. At six months of anticoagulation therapy, an improvement of fibrinolytic function markers was observed. This is consistent with the prophylactic effect of oral anticoagulants therapy against thromboembolic risk.

Acute leukemias after treatment with radioiodine for thyroid cancer.

Leukemia is an uncommon complication of exposure to radioiodine (131I), used in treatment of thyroid cancer, because low doses are now used. We report two cases of acute myelogenous leukemia developed after the treatment of a thyroid carcinoma with a small dose of 131I.

[Safety of oral anticoagulation in aged patients with heart diseases]. / Seguridad en la anticoagulación oral en ancianos con cardiopatía.

BACKGROUND: Anticoagulation therapy in the elderly poses some doubts on the possible increase in hemorrhagic risk. The hemorrhagic complications in a population of patients over 70 years of age anticoagulated with acenocoumarol by heart disease were studied. MATERIALS AND METHODS: A study was made of seventy-two patients (43 females and 29 males; mean age: 73 years) anticoagulated for one year and controlled on an outpatient basis by means of INR (international normalized ratio) measurement with a maximal interval of four weeks. INR values above 4.5 or below 2.0 were considered out of range. RESULTS: Nineteen patients had an INR above the recommended value on one occasion and eleven patients on two or more occasions. Sixteen patients had hemorrhagic complications, five were admitted on account of hemorrhages although none of them required transfusional therapy. No cases of brain hemorrhage or peripheral embolism occurred. CONCLUSIONS: Most anticoagulated elderly patients were within their therapeutic range. The percentage of severe hemorrhagic complications was low. Advanced age had did not prove to be a factor against therapy with oral anticoagulants.

Localization of transforming growth factor-beta-expressing cells and comparison with major extracellular components in aural cholesteatoma.

Transforming growth factor-beta (TGF-beta) plays an important role in the regulation of extracellular matrix (ECM) deposition by stimulating the synthesis of individual matrix proteins like tenascin and fibronectin. Cholesteatoma shows significant changes in the ECM, supporting the view of a disturbed cell-matrix interaction. The purpose of our present study was to evaluate the distribution of TGF-beta in comparison to the deposition of tenascin, fibronectin, and collagen as major components of the ECM in cholesteatoma (n = 12) by means of histochemistry and immunohistochemistry. We found TGF-beta in lymphocytes and fibrohistiocytes in the stroma of 7 cholesteatomas. In corresponding sections, a marked expression of tenascin and fibronectin was seen manifesting as a continuous band along the epidermal-stromal junction, extending to the deeper stroma. In addition, in those cases of TGF-beta expression, beginning collagen fibril formation was seen in adjacent deeper stroma layers, indicating beginning stromal fibrosis. These results suggest that TGF-beta may be involved in the stimulation of the synthesis of tenascin, fibronectin, and collagen. Furthermore, the enhanced expression of tenascin and fibronectin provides evidence for a deregulated cell-matrix interaction in cholesteatoma associated with the enhanced proliferative process of cholesteatoma formation.

Overexpression of tenascin in cholesteatoma and external auditory meatal skin compared to retroauricular epidermis.

In the present study the distribution of tenascin in cholesteatoma was immunohistochemically investigated. The results were compared with those in external auditory meatal skin and in retroauricular skin of healthy controls. The staining pattern was additionally correlated to the degree of cell proliferation as detected by the monoclonal antibody MIB-1 (Ki-67 antigen). Retroauricular skin showed a limited distribution of tenascin in the papillary dermis and a sparse reactivity of MIB-1 in only a few epithelial cells. External auditory meatal skin revealed a more pronounced reaction for tenascin and MIB-1. In contrast, cholesteatoma tissue exhibited an abundant and continuous expression of tenascin covering the whole stroma compartment. This coincided with a significant increase of MIB-1-positive cells in the basal and suprabasal epithelial layers. Doublestaining experiments revealed most prominent stromal tenascin-expression in areas with marked signs for epithelial proliferation. This suggests that tenascin is selectively increased in response to epidermal hyperproliferation. This matrix protein thus shows a quantitatively and qualitatively enhanced expression under pathological conditions. Moreover, the abundant reactivity for tenascin in the cholesteatoma provides evidence of a deregulated cell-matrix interaction involved in the hyperproliferative process of cholesteatoma formation.

Grafts of the third branchial arch in chick embryos.

The parathyroid glands have been classically considered derivatives of the third and fourth pharyngeal pouches in most species, including humans. The presence of neural crest-derived cells in parathyroid glands connective tissue has apparently been established. However, our previous studies have provided a new hypothesis on the origin of these glands in human and chick embryos. To determine the true origin of the third parathyroid (parathyroid III) gland in the chick embryo, pieces of the third branchial arch from donor chick embryos at Hamburger and Hamilton's stage 19 (embryonic day 3) were grafted to host chick embryos at the same stage of development. Starting from Hamburger and Hamilton's stage 27 (embryonic day 5), a structure identified as the parathyroid III appeared in the ectodermal (epipharyngeal) placode of the third branchial arch graft, from which it subsequently became separated at Hamburger and Hamilton's stage 28 (embryonic day 5.5) and continued to develop and mature. Our findings suggest the conclusion that the parathyroid III gland begins to develop from the epipharyngeal placode, so that this gland, from our point of view, could be considered ectodermal in nature.

[Intra-arterial cisplatin and sequential radiotherapy. Long-term follow-up]. / Cisplatin intraarteriell und sequentielle Strahlentherapie. Langzeit-Ergebnisse.

BACKGROUND: The objective of this study was to improve the results of irradiation by prior application of intraarterial (i.a.) chemotherapy with cisplatin. METHODS: Sixty-three patients suffering from advanced head and neck cancer without previous treatment were prepared for intraarterial chemotherapy by neck dissection without resection of the primary tumor and by modification of the carotid artery by creating a more inferiorly positioned bifurcation to facilitate intermittent i.a. infusion. The patients received approximately 400 mg cisplatin over a period of four to five weeks followed by irradiation with 60Co (64 Gy HD). RESULTS: The survival rate at five years in all patients with adequate i.a. chemotherapy was 19 of 49 (39%), except those with adenoid-cystic carcinoma, who had a five-year-survival rate of 100%. CONCLUSION: The results indicate that inductive i.a. chemotherapy with cisplatin has a positive influence on the outcome of irradiation even in inoperable head and neck cancer, which is defined by a longer period of remission with the possibility of curing the disease.