Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody-drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study.

BACKGROUND: Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors. PATIENTS AND METHODS: Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. RESULTS: Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2. CONCLUSIONS: Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W.

Early-drug development in the era of immuno-oncology: are we ready to face the challenges?

The classical development of drugs has progressively faded away, and we are currently in an era of seamless drug-development, where first-in-human trials include unusually big expansion cohorts in the search for early signs of activity and rapid regulatory approval. The fierce competition between different pharmaceutical companies and the hype for immune combinations obliges us to question the current way in which we are evaluating these drugs. In this review, we discuss critical issues and caveats in immunotherapy development. A particular emphasis is put on the limitations of pre-clinical toxicology studies, where both murine models and cynomolgus monkeys have underpredicted toxicity in humans. Moreover, relevant issues surrounding dose determination during phase I trials, such as dose-escalation methods or flat versus body-weight dosing, are discussed. A proposal of how to face these different challenges is offered, in order to achieve maximum efficacy with minimum toxicity for our patients.

Targeting the fibroblast growth factor receptor 2 in gastric cancer: promise or pitfall?

Gastric cancer is the third leading cause of death from cancer worldwide. Systemic chemotherapy remains the mainstay therapeutic option for this poor prognosis cancer. Trastuzumab, the epidermal growth factor receptor 2 (ERBB2 or HER2)-antibody, is the only biological agent approved for the molecularly selected population of HER2-positive gastric cancer patients. Over the last decade, several groups have been working for deepening into the molecular characterization of gastric cancer, shedding some light into the heterogeneity of this tumour. The published data have broadened the landscape towards a future molecular classification into several subtypes of gastric cancer, enabling a better selection of the optimal therapeutic strategy. The fibroblast growth factor receptor (FGFR) pathway plays a key role in gastric cancer pathogenesis, with 1.2%-9% of gastric cancer patients harbouring FGFR2 amplifications. Several selective FGFR inhibitors have been developed in the last years, with promising efficacy signals. However, there is still scarce evidence of the most reliant molecular determinants of response to these targeted agents. Homogeneous high-level clonal FGFR2-amplification, high FGFR2 mRNA or protein levels, specific FGFR2 C3 isoform expression, FGF ligand co-overexpression or detection of FGFR2 copy number in plasma circulating tumour DNA, are considered some of the potential predictive biomarkers to the FGFR inhibition. The successful development of highly specific FGFR inhibitors will rely on our capacity of establishing new personalized strategies, based on a deeper knowledge of the key alterations that drive oncogenesis in gastric cancer. Further efforts seem mandatory in order to implement accurate predictive biomarkers in the next stages of the FGFR inhibitors development.

[Outcome of posterior anorectal myectomy for the treatment of idiopathic chronic constipation]. / Resultados de la miectomía anorrectal posterior en el tratamiento del estreñimiento crónico idiopático.

OBJECIVES: The aim of this study is to assess the outcome of surgery (Lynn's myectomy) in patients with chronic persistent constipation and failure of medical treatment. MATERIAL AND METHODS: Descriptive study of patients with severe chronic constipation treated by posterior anorectal myectomy (Lynn's technique). We report data from the last 15 years, with a minimum postoperative follow-up of one year. Patients included in the study suffered from a long-term constipation refractory to medical management. Data regarding contrast enema, anorectal manometry and rectal biopsy were recorded. The procedure's outcome is classified following clinical criteria: Asymptomatic: >3 bowel movements per week, with no soiling/incontinence and with no medical treatment; Improvement: >3 bowel movements per week, with no soiling/incontinence but using laxatives occasionally. RESULTS: Nineteen myectomies were performed (median age of 8.47 years). Median time of constipation before surgery was 7.89 years. Rectal biopsy findings: 10 with ganglion cells, 4 without ganglion cells and other abnormalities in 5. Anorectal manometry was performed in 6 patients, 4 presented rectoanal inhibitory reflex. Four patients were diagnosed of Hirschsprung's disease (1 was asymptomatic after myectomy, 2 needed further surgery and 1 was lost in follow-up). Of the remaining 15 patients, 8 were asymptomatic (53.3%), 4 experienced improvement (26.6%) and 1 without clinical changes is on pelvic floor physiotherapy. Two were lost in follow-up. There were no other postoperative complications after long term follow-up. CONCLUSIONS: Lynn's myectomy is an effective and safe procedure in patients suffering from persistent chronic constipation despite of medical treatment. It is also the definitive treatment for patients with ultrashort-segment Hirschsprung's disease.

OBJETIVO: Evaluar los resultados clínicos del tratamiento quirúrgico de pacientes con estreñimiento crónico incontrolable con tratamiento médico. MATERIAL Y METODOS: Estudio descriptivo de pacientes con estreñimiento crónico severo tratados mediante miectomía anorrectal posterior (técnica de Lynn). Se recogen los resultados de los últimos 15 años, con periodo de seguimiento postoperatorio mínimo de 1 año. Se incluyen pacientes con larga historia de estreñimiento, refractarios a tratamiento médico. Pruebas complementarias: enema opaco, manometría anorrectal y biopsias rectales. El resultado clínico de la técnica se clasifica según los siguientes criterios: Curación: >3 movimientos intestinales por semana, sin incontinencia/encopresis y sin necesidad de tratamiento médico; Mejoría: >3 movimientos intestinales por semana, sin incontinencia/encopresis y con necesidad de laxante. RESULTADOS: Se realizaron 19 miectomías (edad media de 8,47 años). Tiempo medio de estreñimiento previo de 7,89 años. Los hallazgos en la anatomía patológica fueron: presencia de células ganglionares en 10, ausencia de células ganglionares en 4 y otras alteraciones en 5. Manometría en 6 pacientes, 4 presentaron reflejo inhibitorio anal. Cuatro pacientes se diagnosticaron de enfermedad de Hirschsprung (uno se curó con la miectomía, dos precisaron cirugía correctora y uno no acudió a revisiones). En los 15 restantes, cumplieron criterios de curación 8 pacientes (53,3%), 4 mejoraron (26,6%), 1 sin mejoría sigue tratamiento fisioterápico. Dos pacientes no continuaron las revisiones. No se registró incontinencia fecal ni otras complicaciones. CONCLUSIONES: La miectomía de Lynn es un procedimiento eficaz y seguro para los pacientes con estreñimiento crónico severo refractario al tratamiento médico. También resulta el tratamiento definitivo en la enfermedad de Hirschsprung de segmento ultracorto.

[Implementation of "fast-track" treatment in paediatric complicated appendicitis]. / Aplicación de un modelo terapéuticofast-track en la apendicitis aguda complicada del paciente pediátrico.

OBJECTIVE: Acute appendicitis is the most common emergency surgical pathology in childhood and there is no consensus on its management. Fast-track treatment, based on optimizing perioperative care has reduced morbidity and mortality of surgical pathologies, including simple acute appendicitis. The aim of our study was to assess the effects of a fast-track protocol in complicated acute appendicitis. METHODS: Ambispective cohort study. Historical unexposed cohort: children with complicated appendicitis and appendectomy in our hospital during 2008-2009. Exposed cohort: children operated in 2010-2011 and who performed protocol. The protocol treatment was done after a literature review, adapting the principles of fast-track to a potentially severe urgent disease: early mobilization, limited drainage-tubes and short antibiotic regimens Taking hospital stay as the resulting variable, the calculated sample size for alpha = 0.05 and power = 90% was 54, being X1 = 7 +/- 3DS and X2=5. RESULTS: We included 151 patients, historical cohort 81 and current cohort 70, which excluded 31 children who did not meet protocol because of surgeon choice. Both groups showed homogeneity due to the absence of differences in sex, age, weight, type of appendicitis (gangrenous, perforated, generalized peritonitis) or surgical approach. The average stay decreased 2.71 days (p <0.001) due to the protocol, without any complication increase (abscess, postoperative ileus, readmission). CONCLUSIONS: Complicated appendicitis in children is common and potentially serious, and optimization of treatment should be a primary goal of our practice. Application of a fast-track protocol can provide clinical and economic benefits, although this requires an appropriate multidisciplinary management.

[Appendectomy and Crohn's disease]. / Apendicectomía y enfermedad de Crohn.

UNLABELLED: We analyzed the relationship between Crohn's disease and appendectomy in paediatric age. METHOD AND MATERIAL: We studied the patients diagnosed with Crohn's disease and appendectomy (under 20) between 1999 and 2011. We retrieved their previous medical histories and carried out an histological re evaluation of those appendix. RESULTS: 11 patients out of 137 (8,02%) had an appendectomy before the development of Crohn's disease. An average age in which the appendectomy took place and the development of Crohn's disease was diagnosed 14 (5-20 years), having 90% of the patients diagnosed in the early post-surgical stages. A patient did not develop any symptoms until a year later. There were no more appendectomies carried out in comparison with the adult population. The initial anatomopathologic diagnosis and the histological re evaluation agreed in just one case, compatible with Crohn's disease. CONCLUSION: The majority of appendectomies carried out in paediatric patients that later develop Crohn's disease are realized by a bias diagnosis of acute appendicitis and the relation between the two of them can be explained as the not yet developed Crohn's disease at the moment of the appendectomy. Appendectomies at a paediatric age are not associated with a potential development of Crohn's disease. There is no evidence of histological changes compatible with Crohn's disease in the first episode.

[Testicular cancer and cryptorchidism: myth or reality]. / Cáncer testicular y criptorquidia. Mito o realidad.

OBJECTIVE: To evaluate the previous history of cryptorchidism in patients with testicular cancer. MATERIALS AND METHODS: We carried out a study using 175 patients diagnosed with testicular cancer, in our hospital, from 1999 to 2010. We analyzed the previous history of cryptorchidism and its characteristics, testicular placing, histology and intervention age. RESULTS: 5 out of the 175 patients (2,8%) with testicular neoplasm presented a history of cryptorchidism, The average age was 31 years old, an orchidopexy was only carried out in 2 patients. The histology was different depending on the treatment chosen to battle cryptorchidism and in 2 cases it developed in the adjoining testicle. The average ratio was of 1,9. CONCLUSIONS: Our results reflect that the association of cryptorchidism with testicular neoplasm is in fact lower than in the past. A good and proper handling of cryptorchidism can prevent it from turning malignant, presenting these patients similar incidences to the rest of the population.

[Evaluation of quality of life in patients operated on for gastroesophageal reflux in the pediatric age]. / Valoración de la calidad de vida en los pacientes intervenidos por reflujo gastroesofágico en la edad pediátrica.

AIM: To assess the quality of life and symptoms of GER patients who underwent laparoscopy in our hospital before and after surgery. MATERIAL AND METHODS: We collect data from patients operated laparoscopically for gastroesophageal reflux disease (GER) in our center before and after surgery in 3 items: nutritional studies, diagnostic methods, interviews with the families of patients about symptoms (preferably differing in digestive or respiratory symptoms) and quality of life; also, determined the age, gender, personal history and surgical technique of patients. RESULTS: 30 patients have been operated for GER, 22 men and 8 women, 11 months to 14 years (median age 5 years) of whom 12 (40%) had some degree of encephalopathy. The most common surgical technique used is Nissen (73% cases). Most patients had significant alterations in their daily activities before surgery. The most common symptom was gastrointestinal (70% cases), although all showed improvement, families of children with respiratory symptoms related predominantly greater reduction in the clinic after surgical correction. All improved in its growth curve. CONCLUSIONS: Surgery for GER patients have a significant improvement in their quality of life, not only by the reduction of their symptoms but also in enhancing from the nutritional status. Patients with respiratory symptoms have a higher satisfaction with surgical treatment than those with gastrointestinal clinical.

[Congenital solitary infantile myofibroma: report of two cases]. / Miofibroma infantil solitario congénito. Presentación de dos casos.

UNLABELLED: The infantile myofibromatosis is a rare pathology usually affecting children under 2 years. More than half are congenital, located in head and neck in a 30% of the cases. Myofibroma is a benign mesenchymal tumor that appear an isolated lesion or multiple, with or without visceral involvement. Case 1: A newborn girl that presents lump in scalp suspected of encefalocele. Ultrasound and RM: solid and heterogeneous mass 4 x 2 cm with increased peripheral vascularisation. Case 2: A 7-month-old baby boy with lump in right occipital zone detected at 4 months. Ultrasound and RM: injury 1 x 1.5 cm in head esplenio muscle suggestive of hemangioma. RESULTS: After surgical total resection, the histological study and immunohistochemical identified the lesion as myofibroma. The evaluation of disease dissemination was normal and the recovery of the patients was favorable. The differential diagnosis of myofibroma must be carried out with other mesenchymal tumors and with non neoplastic injuries characteristics of the region affects. The visceral location and multiple forms worsen the prognosis, so is important do an exhaustive study. Treatment is conservative surgery, but if there is no risk to the child, the possibility of spontaneous regression makes the abstention therapeutic a correct alternative.

[Structural alterations of the smooth muscle and of the EGFR expression and C-kit in congenital pyeloureteral stenosis. Relationship with its pathogenesis]. / Alteraciones estructurales del músculo liso y de la expresión de EGFR y C-kit en la estenosis pieloureteral congénita. Relación con su patogénesis.

PURPOSE: To assess the role that the muscular dysplasia, epidermal growth factor (EGFR) and interstitial cells of Cajal (ICC) C-kit +, may have in the pathophysiology of pyeloureteral stenosis (EPU). MATERIALS AND METHODS: 30 samples were studied UPJ (ureteropelvic junction), with 25 UPJ obstruction and 5 controls. Performed with Masson's trichrome staining and immunohistochemical techniques for smooth muscle actin, EGFR (epidermal growth factor) and CD117 (C-kit) (Dako). We compared the results statistically. RESULTS: The control group was diffuse positivity of EGFR in the muscle layer in samples of EPU was positive in 4%, weak in 16% and negative in 80%. The controls are C-kit + ICC between the muscle cells showed a decreased density in the samples of obstruction. Masson's trichrome highlighted the increase of inter-and intramuscular collagen and attenuated muscle fibers, thinner and individualized, in the inner muscular layer of the cases of EPU also evident with the actin. Differences between groups were statistically significant (p < 0.001). CONCLUSIONS: Our results suggest that dysplastic changes in the muscle layer, the low expression of EGFR and the decrease or absence of C-kit + ICC, may participate in the pathophysiology of UPJ obstruction.

Isquemia mesentérica: manejo endovascular

La isquemia mesentérica es una condición que puede volverse muy grave y ser letal, más aún en los casos agudos. Un tratamiento precoz es muy importante. Se presentaron cuatro casos consecutivos tratados por nuestro equipo con trombosis, o disección o aneurismas de arterias mesentérica superior y tronco celíaco, se revisaron las indicaciones y se evaluaron los tratamientos llevados a cabo. Se utilizaron procedimientos endovasculares en todos, técnicamente en forma exitosa, evitando que progrese a un desenlace peligroso. Hubo diversidad de técnicas endovasculares adaptándolas a cada caso. En ningún paciente se requirió un acceso quirúrgico abierto para completar el tratamiento realizando las intervenciones prontas. El manejo endovascular de las lesiones mesentéricas es factible y replicable, y en nuestros casos podría haber prevenido una necrosis intestinal así como la necesidad de cirugías resectivas.

SUMMARY Mesenteric ischaemia is a condition that may be very severe and potentially lethal particularly in the acute presentation. Early treatment is crucial. We present four consecutive cases managed by our team with thrombosis or dissection or aneurysm of the superior mesenteric artery and the celiac trunk reviewing indications and treatment implemented. Multiple successful endovascular procedures were used in all cases avoiding progression to lethal consequences. None of the patients required an open surgical procedure. Therefore, endovascular procedures are feasible in these patients avoiding intestinal necrosis as well as the need for open surgeries.

Hodgkin's disease of middle ear and mastoid.

We present a case of Hodgkin's disease of the mastoid associated with upper cervical lymph node involvement without disseminated disease. This patient was treated with chemotherapy alone and lesions responded rapidly. At present the patient is well, with no evidence of recurrence or extension of this disease. Hodgkin's disease of the middle ear and mastoid is an extremely rare disease. After a wide search in the literature no cases of Hodgkin's disease arising in the middle ear and mastoid have been found.

[Producing intravenous medications in a pharmacy]. / Elaboración en farmacia de los medicamentos intravenosos. Repercusiones en el personal de enfermería del hospital.

The authors explain the different intravenous mixtures and the types of preloaded syringes elaborated in a centralized unit, analysing their profitability and evaluating their repercussion on the daily work nurses have to perform. This study was carried out in the Hospital de Poniente in Almeria, a county hospital which has 165 beds. The hospital authorities defined those medications which were chosen to be prepared in a centralized unit in the Pharmacy Service of the hospital and they drew up a list/guide of their corresponding conservation conditions. The authorities determined the time which nursing personnel in the various hospital units would employ in the elaboration of these medications and compared that with the time employed in the Pharmacy Service.

Puesta al día en el manejo del hipospadias / Update on the management of hypospadias

El hipospadias es la malformación congénita más frecuente del pene. el diagnóstico se realiza al nacimiento y es primordial explicar a los padres las características de la malformación, su repercusión funcional y el plan terapéutico a seguir. el tratamiento es quirúrgico y se recomienda llevarlo a cabo antes de la edad escolar. los objetivos de la cirugía son funcionales además de estéticos. puesto que hay una gran variabilidad en cuanto a presentación clínica y severidad, existen múltiples técnicas quirúrgicas

Hypospadias is the most common congenital malformation of the penis. the diagnosis is made at birth and it is essential to explain to the parents the characteristics of the malformation, its functional repercussion and the therapeutic objectives. Surgical treatment is recommended before school age. the objectives of the surgery are functional as well as aesthetic. Because there is great variability in clinical presentation and severity, there are multiple surgical techniques

Focal nodular hyperplasia on accessory lobe of the liver: preoperative diagnosis and management.

We report the case of a 13 year-old girl transferred to our department with a one month history of vomiting, weight loss, and abdominal mass that was diagnosed as Focal Nodular Hyperplasia in an accessory lobe of the liver. Accessory liver lobe is a rare congenital anomaly whose preoperative diagnosis is difficult and usually presents as an incidental finding intraoperatively. Depending on their location and size, they can present as acute abdomen or abdominopelvic mass. In the literature reviewed, we found no association of focal nodular hyperplasia and accessory liver lobe in children.