Trastuzumab or lapatinib with standard chemotherapy for HER2-positive breast cancer: results from the GEICAM/2006-14 trial.

BACKGROUND: The addition of trastuzumab (T) and lapatinib (L) to neoadjuvant chemotherapy increases the pathological complete response (pCR) rate in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We investigated the efficacy of T or L with neoadjuvant chemotherapy and specific efficacy biomarkers. METHODS: Patients with stages I-III (including inflammatory) HER2-positive breast cancer were randomised to receive epirubicin (E) plus cyclophosphamide (C) × 4 cycles followed by docetaxel (D) plus either T (EC-DT) or L (EC-DL). End points included pCR (primary), clinical response, toxicity, and pCR-predictive biomarkers. RESULTS: We randomised 102 patients to EC-DT (50) and EC-DL (52). Median age was 48, 56% were premenopausal and 58% had oestrogen receptor (ER)-positive tumours. Pathological complete response in breast was 52.1% (95% CI:38.0-66.2%) for EC-DT and 25.5% (95% CI:13.5-37.5%) for EC-DL (P=0.0065). Pathological complete response in breast and axilla was 47.9% for EC-DT and 23.5% for EC-DL (P=0.011). Grade 3-4 toxicity did not differ across treatments, except for diarrhoea (2% in EC-DT vs 13.5% in EC-DL, P=0.030). Multivariate analyses showed that treatment (P=0.036) and ER (P=0.014) were the only predictors of pCR in both groups. CONCLUSION: EC-DT exhibited higher efficacy and lower toxicity than EC-DL. Of the different biomarkers studied, only the absence of ER expression was associated with increased pCR.

SOLIDUSS: Solid-state diffusion software for radiation protection.

The out-diffusion of radionuclides from activated material in case of a fire may represent a non-negligible contribution to the radiological source term of such an event. In order to assess the contribution of this phenomenon, a software package has been designed and implemented. In the present document we briefly introduce the numerical treatment used to tackle the problem prior to the explanation of the software's logic. The document ends with an exemplary simulation and a study carried out to validate the implementation of the algorithm. The presented tool has been named SOLIDUSS, it is mainly written in C++ and uses a Monte Carlo based approach to simulate the diffusion of radioisotopes within solid materials. It is designed to run coupled with CERN-FLUKA, taking advantage of its geometry kernel to carry out diffusion calculations in arbitrarily complex geometries. The user can provide 3D temperature maps along with many other parameters that allow the program to target a wide range of different scenarios. As results SOLIDUSS provides 3D radionuclide concentration maps as well as the amount of radionuclides out-diffused from the selected materials. So far, this software has undergone numerical validation which will be discussed in this paper. Benchmarking against experimental data is currently ongoing.

Exploring neutron capture therapy with 33S and 10B.

The 33S(n,α)30Si reaction was proposed as cooperative neutron capturer to 10B(n,α)7Li in Neutron Capture Therapy (NCT). At that moment, the available 33S(n,α)30Si cross-section data were scarce and discrepant in key energy ranges for its use in NCT. Since then, three experiments have been carried out at n_TOF facility at CERN and at Institut Laue-Langevin. These new data are used for the calculation of the dose rate on ICRU-4 tissue by using kerma factors, a simplified model of tissue and a 13.45 keV neutron beam, energy of the most important 33S(n,α)30Si resonance. A significant enhancement of the dose rate due to the presence of 33S is shown. In spite of the limitations, the cooperative action of 33S and 10B is an interesting possibility to be studied for accelerator-based neutron sources with non-moderated neutrons.

SEOM clinical guideline thyroid cancer (2019).

Thyroid carcinoma is the most frequent endocrine malignancy and accounts for around 3% of global cancer incidence. Different histologies and clinical scenarios make necessary a multidisciplinary approach that includes new diagnostic methods and surgical, radiopharmaceutical and systemic therapies. This guideline updates several aspects of management of thyroid cancer.

BNCT research activities at the Granada group and the project NeMeSis: Neutrons for medicine and sciences, towards an accelerator-based facility for new BNCT therapies, medical isotope production and other scientific neutron applications.

The Granada group in BNCT research is currently performing studies on: nuclear and radiobiological data for BNCT, new boron compounds and a new design for a neutron source for BNCT and other applications, including the production of medical radioisotopes. All these activities are described in this report.

[Study into the use of cetuximab in metastatic colorectal cancer in a third level hospital]. / Estudio de utilización de cetuximab en cáncer colorrectal metastásico en un hospital de tercer nivel.

OBJECTIVES: In this study we will analyse the use of cetuximab in the treatment of metastatic colorectal cancer (MCC) in a third level hospital. We will establish the usage conditions in our centre in keeping with those approved in current technical records. We will also record the treatment duration under the different usage conditions and use the information available in material that has been published to date. METHODS: An indication-prescription study of cetuximab in MCC was carried out on all patients treated with cetuximab for colorectal cancer in the period between 2004 and 2007 in our hospital. The number of prescriptions that do not fit the approved recommendations for cetuximab in MCC treatment (and why they do not fit) is determined. Descriptive statistical analysis was carried out for the different variables collected, and a Kaplan-Meier analysis was carried out for the treatment duration variable, so as to determine whether there is a difference in effectiveness for the common uses in our hospital. RESULTS: Data was recorded for 74 patients treated with cetuximab. The average cost per patient was 14,399 Euro and on average, 15.3 dosages were administered per patient. The average initial dosage was 710 mg with an average dosage of 446 mg after that. The average duration of the treatments was 15.4 weeks. cetuximab was administered to 7 patients as first-line treatment and to 32 patients who had not used Irinotecan previously. Irinotecan was not associated with cetuximab treatment in 9 patients, and it was used in 14 patients resulting in a negative outcome for the EFGR test. Treatment duration was longer in the case of its use as first-line treatment (27.7 weeks), if Irinotecan had not been used before (23.3 weeks), if Irinotecan was used (20.5 weeks) and in patients with positive EFGR results (19.6 weeks.) The median treatment duration, under the different conditions, was less than the average but with no major differences between them. 70.3 % of prescriptions did not fit with the data sheet. CONCLUSIONS: The use of cetuximab under different conditions to those approved on the technical data sheet creates an increase in the number of patients treated and a longer duration of the treatments which implies an increase in intake. The average and the mean treatment times for the usage conditions found did not present any significant statistical differences. There are a small number of patients who benefit from this treatment which can be seen by the large average, in comparison with the mean, without any of the conditions in which the analysis was carried out seeming to determine a higher response. The treatment duration in our study was similar to the durations recorded in relevant literature for these usage conditions.

Enhancement of neutron radiation dose by the addition of sulphur-33 atoms.

The use of neutrons in radiotherapy allows the possibility of producing nuclear reactions in a specific target inserted in the medium. (10)B is being used to induce reactions (n, alpha), a technique called boron neutron capture therapy. I have studied the possibility of inducing a similar reaction using the nucleus of (33)S, for which the reaction cross section presents resonances for keV neutrons, the highest peak occurring at 13.5 keV. Here shown, by means of Monte Carlo simulation of point-like sources of neutrons in this energy range, is an enhancement effect on the absorbed dose in water by the addition of (33)S atoms. In addition to this, as the range of the alpha particle is of the order of a mammalian cell size, the energy deposition via this reaction results mainly inside the cells adjacent to the interaction site. The main conclusion of the present work is that the insertion of these sulphur atoms in tumoral cells would enhance the effect of neutron irradiation in the keV range.

Simple analytical expressions for the dose of point photon sources in homogeneous media.

The contributions to the dose of a point photon source in homogeneous media due to primary and first, second, ..., nth scattered photons are investigated. Assuming a simple statistical model, an analytical form comes out for each of these contributions. It includes a polynomial and a single exponential and depends on three parameters which have a physical meaning. The values of these parameters for different energies and for water, as a test case, are obtained from numerical fits to the results of a Monte Carlo simulation with the code PENELOPE. The average differences between the model and the Monte Carlo results, after the fitting process, are below 1%. Our model permits to obtain improved versions of the classical approach of Berger in a straightforward way. The expressions obtained also describe the dose build-up of the primary photons.

DOSE EFFECT OF THE 33S(n,α) 30SI REACTION IN BNCT USING THE NEW n_TOF-CERN DATA.

33S is a stable isotope of sulphur which is being studied as a potential cooperative target for Boron Neutron Capture Therapy (BNCT) in accelerator-based neutron sources because of its large (n,α) cross section in the epithermal neutron energy range. Previous measurements resolved the resonances with a discrepant description of the lowest-lying and strongest one (at 13.5 keV). However, the evaluations of the major databases do not include resonances, except EAF-2010 which shows smaller values in this range than the experimental data. Furthermore, the glaring lack of data below 10 keV down to thermal (25.3 meV) has motivated a new measurement at n_TOF at CERN in order to cover the whole energy range. The inclusion of this new 33S(n,α) cross section in Monte Carlo simulations provides a more accurate estimation of the deposited kerma rate in tissue due to the presence of 33S. The results of those simulations represent the goal of this work.

Deficit irrigation and rootstock: their effects on water relations, vegetative development, yield, fruit quality and mineral nutrition of Clemenules mandarin.

Differences between rootstocks, 'Cleopatra' mandarin and 'Carrizo' citrange, in soil-plant water relations and the influence of these factors on vigor, crop yield, fruit quality and mineral nutrition were evaluated in field-grown Clemenules mandarin trees irrigated at 100% of potential seasonal evaporation (ET(c)) (control treatment), or irrigated at 100% ET(c), except during Phases I and III of fruit growth and post-harvest when no irrigation was applied (deficit irrigation (DI) treatment), for 3 years. Differences between rootstocks in plant-soil water relations were the primary cause of differences among trees in vegetative development and fruit yield. After 3 years of DI treatment, trees on 'Cleopatra' showed more efficient soil water extraction than trees on 'Carrizo', and maintained a higher plant water status, a higher gas exchange rate during periods of water stress and achieved faster recovery in gas exchange following irrigation after water stress. The DI treatment reduced vegetative development more in trees on 'Carrizo' than in trees on 'Cleopatra'. Cumulative fruit yield decreased more in DI trees on 'Carrizo' (40%) than on 'Cleopatra' (27%). The yield component most affected by DI in 'Cleopatra' was the number of fruit, whereas in 'Carrizo' it depended on the severity of water stress reached in each phase (severe water stress in Phase I affected mainly the number of fruit, whereas it affected fruit size the most in Phase III). In the third year of DI treatment, water-use efficiency decreased sharply in trees on 'Carrizo' (70%) compared to trees on 'Cleopatra' (30%). Thus, trees on 'Cleopatra' were able to tolerate moderate water stress, whereas trees on 'Carrizo' were more sensitive to changes in soil water content.

Using a Tandem Pelletron accelerator to produce a thermal neutron beam for detector testing purposes.

Active thermal neutron detectors are used in a wide range of measuring devices in medicine, industry and research. For many applications, the long-term stability of these devices is crucial, so that very well controlled neutron fields are needed to perform calibrations and repeatability tests. A way to achieve such reference neutron fields, relying on a 3 MV Tandem Pelletron accelerator available at the CNA (Seville, Spain), is reported here. This paper shows thermal neutron field production and reproducibility characteristics over few days.

Phase II trial of gemcitabine/doxorubicin/paclitaxel administered every other week in patients with metastatic breast cancer.

The present trial was designed to determine the efficacy of the combination of gemcitabine/doxorubicin/paclitaxel (GAT) delivered every other week as first-line therapy in patients with metastatic breast cancer. From February 1998 to September 1999, 41 patients were included in this trial. Doses delivered were doxorubicin 30 mg/m2 on day 1 and paclitaxel 135 mg/m2 plus gemcitabine 2500 mg/m2 both given on day 2, every 14 days. Doses were selected from a previous phase I trial conducted at our institution. Eligibility criteria for the phase II trial included histologically confirmed metastatic breast cancer with bidimensionally measurable lesions; no prior therapy for metastatic disease; adjuvant or neoadjuvant chemotherapy was allowed if given more than 1 year before and cumulative doses of doxorubicin or epirubicin were less than 200 mg/m2 or 360 mg/m2, respectively; Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less; and adequate hematological, hepatic, and renal function. Prophylactic use of granulocyte colony-simulating factor (G-CSF) was allowed if patients were not fully recovered (absolute neutrophil count greater than 1500/microL) from chemotherapy administration before the next dose. Left ventricular ejection fraction was determined initially, at the end of the study, and every 6 months thereafter. The patients' median age was 55 years (range, 33-68 years), and their median ECOG performance status was 0 (range, 0-1). Twenty-eight patients had received adjuvant therapy, 17 with epirubicin (none with doxorubicin). Metastases were present in the bone (19 patients), lung (19 patients), liver (11 patients), and soft tissues (18 patients). Twenty patients had one metastatic site and 21 had two or more sites. Efficacy was assessed on an intent-to-treat basis. A total of 216 cycles of GAT were given. Twenty-two percent of the courses were delayed or given at reduced doses mostly due to neutropenia or thrombocytopenia. G-CSF was required in 58% of the cycles. Grade 3/4 neutropenia was the main toxicity and appeared in 17 patients, one of whom had an episode of febrile neutropenia. Nonhematological toxicities consisted mainly of neurotoxicity and myalgias. A drop of 10%-20% in the left ventricular ejection fraction was detected in two patients and another patient had a decrease greater than 20%, although none developed symptoms of heart failure. Overall response rate was 80.4% (95% confidence interval: 68.3-92.5), with 15 patients (36.6%) achieving a complete response. Median survival time was 27 months and median time to progression was 15 months. The GAT combination is feasible and very active in patients with metastatic breast cancer, with an encouraging response rate including a high rate of complete responses. No congestive heart failure was documented and other toxicities were mild, with the exception of neutropenia.

Biweekly gemcitabine, doxorubicin, and paclitaxel as first-line treatment in metastatic breast cancer. Final results from a phase II trial.

In a single-center, open, phase II trial, we assessed the toxicity and activity of a triple combination therapy--doxorubicin at 30 mg/m2 (day 1), paclitaxel (Taxol) at 135 mg/m2 (day 2), and gemcitabine (Gemzar) at 2,500 mg/m2 (day 2 after paclitaxel)--administered biweekly in a 28-day cycle for six cycles. This was given as first-line treatment in 41 patients with metastatic breast cancer. Granulocyte colony-stimulating factor was used in 27 patients to permit maintenance of dose density. Hematologic toxicity was moderate. Nonhematologic adverse events were generally mild. The objective response rate was 82.9% (34/41) with 18 patients (43.9%) achieving complete response and 16 (38%) achieving partial response; progressive disease was observed in 4 patients (9.8%). Responses were observed at all metastatic sites, including complete responses in lung, liver, bone, and soft tissue. Median duration of response was 14.1 months and median time to progression was 13.9 months. Median survival was 26.2 months. The biweekly combination of gemcitabine, doxorubicin, and paclitaxel is safe and highly active as first-line treatment in metastatic breast cancer.

Submammary median sternotomy.

A vertical skin incision is used as routine approach for sternotomy. The resulting scar is often disappointing and the top is visible and unpleasant, especially for young women. In 35 women ranging from 10 to 48 years (mean 29.2 years), median sternotomy was performed via a submammary skin incision. In all cases an open heart surgical procedure was performed. Adequate exposure of the heart was achieved in every case and there were no technical problems related to this approach, no hospital mortality or major complications. The cosmetic result is excellent and this approach is certainly justified in open heart surgery for young women.

[Pharmacobezoar in a patient operated on for pyloric stenosis]. / Farmacobezoar en un paciente intervenido de estenosis pilórica.

Bezoars are concretions made up of a variety of partially digested materials seen in several portions of the gastrointestinal tract; they may result in gastrointestinal obstruction. Bezoar types described in the scientific literature include bezoars resulting from drugs. Their development is usually associated with some predisposing risk factor. The case of a patient is described, who was admitted to the hospitals Emergency Department because of a clinical event suggesting a gastrointestinal bleeding episode. After admission, endoscopy demonstrated the presence of a bezoar whose components included a great number of Adalat Oros tablets. A review of the drugs that induced bezoar formation is made, and associated risk factors, formation mechanisms, bezoar appearance, and treatments used are all described.

[Intrapulmonary short-circuit during coronary or aortic valve heart surgery]. / Cortocircuito intrapulmonar en cirugía cardíaca coronaria o de válvula aórtica.

BACKGROUND: The alterations in gas exchange during cardiac surgery was studied by the measurement of the perioperative intrapulmonary shunt. PATIENTS AND METHODS: Forty patients divided into two groups were studied. Group 1 consisted of 20 patients undergoing myocardial vascularization and group 2 consisted of 20 patients undergoing aortic valve replacement. The anesthetic technique was similar in both groups but the patients in group 1 received a continuous perfusion of nitroglycerin from the beginning of surgery plus a bolus of intranasal nifedipine 30 minutes prior to the exit of extracorporeal circulation. The measurement of the shunt was performed 5 times: following the induction of anesthesia, prior to and after extracorporeal circulation, upon termination of surgery and one hour following admission to the ICU. RESULTS: In both groups an increase of the shunt was produced at the end of extracorporeal circulation which later returned to basal levels. The increase was greater in patients of group 1 during the different phases of surgery although significant differences only existed at the beginning and end of extracorporeal circulation. The variations of the shunt were not related with the state of preoperative pulmonary function or with the duration of extracorporeal circulation. CONCLUSIONS: Although intrapulmonary shunt increases during cardiac surgery, especially coronary, its clinical transcendence is nul and no special measures are required.

(33)S as a cooperative capturer for BNCT.

(33)S is a stable isotope of sulfur for which the emission of an α-particle is the dominant exit channel for neutron-induced reactions. In this work the enhancement of both the absorbed and the equivalent biologically weighted dose in a BNCT treatment with 13.5keV neutrons, due to the presence of (33)S, has been tested by means of Monte Carlo simulations. The kerma-fluence factors for the ICRU-4 tissue have been calculated using standard weighting factors. The simulations depend crucially on the scarce (33)S(n,α)(30)Si cross-section data. The presence of a high resonance at 13.5keV was established by previous authors providing discrepant resonance parameters. No experimental data below 10keV are available. All of this has motivated a proposal of experiment at the n_TOF facility at CERN. A setup was designed and tested in 2011. Some results of the successful test will be shown. The experiment is scheduled for the period November to December 2012.

[Analysis of several containment measures of pharmaceutical expenditure in an Ambulatory Surgery Centre]. / Análisis de varias medidas de contención del gasto farmacéutico ambulatorio en una Unidad de Cirugía Mayor Ambulatoria.

OBJECTIVE: In the context of the current crisis, sustainability of National Health Service must be considered a priority issue. To compare several cost saving measures in drug expenditure due to outpatient drug treatment after surgery in an Ambulatory Surgical Centre. MATERIAL AND METHOD: Pharmaco-economic analysis of cost minimization of ambulatory pharmaceutical services during the year 2011. A total of 3,346 patients were operated on and discharged on the same day, were included. Treatments were collected from the discharge report of each patient. We compared changes in real outpatient drug spending after separately applying each of the following measures: 1) increasing the co-payment; 2) improving the quality of prescribing; 3) dispensing by units of drugs through pharmacies, and 4) dispensing through the hospital pharmacy service. RESULTS: The real outpatient pharmaceutical expenditure was 29,454.21€. Increasing the co-payment mean a transfer of 2,091.82€ from the funding institutions to users. Improving the quality of prescriptions, dispensing through units of drugs in the pharmacy, and dispensing through the hospital pharmacy service led to a pharmaceutical expenditure of 24,215.14€, 21,766.24€ and 7,827.71€, respectively. CONCLUSIONS: Only considering co-payment to contain pharmaceutical expenditure arising from prescribing in an Ambulatory Surgical Centre is the least effective measure. The most effective measure, for this purpose, is the supply of drugs through the hospital pharmacy service.

Bevacizumab plus preoperative chemotherapy in operable HER2 negative breast cancer: biomarkers and pathologic response.

PURPOSE: The primary aim of this trial was to assess the rate of pathologic complete responses (pCR) of doxorubicin/cyclophosphamide (AC) followed by bevacizumab/docetaxel (BT), as neoadjuvant therapy for breast cancer (BC). Furthermore, the association between biomarkers and the pCR was explored. METHODS: Patients with HER-negative operable stage II-III BC ≥ 2 cm were enrolled. Four cycles of AC (A 60 mg/m(2) and C 600 mg/m(2), every 3 weeks) followed by 4 cycles of BT (B 15 mg/kg and T 75 mg/m(2), every 3 weeks), were planned. A core-biopsy was performed for biological markers assessment. RESULTS: Seventy-two women were included. Forty-three (63 %) patients were hormone receptor-positive. Sixty-four (89 %) completed the planned treatment, and 66 evaluable patients underwent surgery (92 %): a pCR was achieved in 16 of them (24, 95 % CI 15-36 %). pCR was significantly higher in tumors hormone receptor-negative, and in those with Angiotensin II type 1 receptor (AGTR1) protein overexpression. The overall clinical response rate was 86 % (95 % CI 76-93 %), including 42 complete responses. No unexpected toxicities or treatment-related deaths were observed. CONCLUSION: This regimen showed a remarkable clinical and pathological activity: the suggested relation between pCR and AGTR1 overexpression should be confirmed in larger trials.

Sulfur-33 nanoparticles: a Monte Carlo study of their potential as neutron capturers for enhancing boron neutron capture therapy of cancer.

In this paper, the potential effect of enhancing BNCT near the surface of the target volume by means of the addition of the sulfur isotope (33)S is studied. By means of Monte Carlo simulations, it is found a noticeable enhancement effect (local increase of the dose at the isotope site) when it is present at local concentrations that in principle can be reached by means of sulfur nanoparticles. A neutron beam with a high component of 13.5 keV would be required to produce this effect. Some open problems are discussed.