Participación de residentes de cirugía plástica de Chile en la publicación científica: revisión de los últimos 20 años / Participation of chilean plastic surgery residents in scientific publications: review of the last 20 years

Resumen Objetivo: Analizar la participación de los residentes de cirugía plástica de Chile en la publicación científica de los últimos 20 años y evaluar su experiencia durante la residencia. Materiales y Método: Revisión de la literatura desde 1998-2018 bajo los términos: Cirugía Plástica, Plastic Surgery y Chile. Se incluyeron aquellos con al menos un autor cirujano plástico con filiación en Chile. Se registró la participación reportada de residentes y analizaron sus autores según su período de residencia y fecha de publicación, agregándolos como residentes no reportados. Se analizó tema, año de publicación y revista. Se aplicó una encuesta a residentes de cirugía plástica y postbecados recientes para conocer la percepción sobre su participación en actividades científicas. Se comparó la participación entre residentes con y sin año de investigación mediante el test exacto de Fisher. Resultados: Predominó la temática reconstructiva (48,2%), en adultos (68,6%) y en centros universitarios (48,7%). La participación reportada de residentes fue de 8,4%, subiendo a 38,2% al ampliarla a los no explicitados como residentes. Los encuestados expusieron la falta de tiempo como principal impedimento a la publicación y participación en congresos. Discusión: La participación en actividades científicas resulta beneficiosa para residentes, sus tutores y la reputación académica de sus centros. La mayoría de los residentes cree que su participación podría haber sido mayor en caso de que se hubiesen dado más facilidades. Conclusiones: La participación de residentes de cirugía plástica se encuentra subreportada. Programas de investigación, tiempos protegidos y mayor tutorización podrían aumentar esta cifra.

Aim: Evalúate the participation of Chilean plastic surgery residents in scientific publication in the last 20 years and assess their experience during residency. Materials and Method: Literature review from 1998-2018 under the terms: Cirugia Plastica AND Plastic Surgery AND Chile. Publications with at least one plastic surgeon author with filiation reported in Chile were considered. Those with reported participation of residents were registered and their authors were also analyzed according to their period of residence and date of publication, adding them as unreported residents. Subjects, year of publication and journals were analyzed. A survey was applied to plastic surgery residents and recent plastic surgery graduates to evaluate the perception of their participation in scientific activities. Residents participation with and without a previous research fellow was compared using Fisher's exact test. Results: Reconstructive themed studies (48.2%), in adults (68.6%) and in university centers (48.7%) prevailed among the included articles. The reported participation of residents was 8.4%, which rised to 38.2% when it was extended to those not explicitly reported as residents among the authors. Residents exposed the lack of time as the main barrier to publication and congress participations. Discussion: Participation in scientific activities is beneficial for residents, their mentors and the academic reputation of their centers. The majority of residents believe that their participation could have been greater if more facilities had been given. Conclusions: Participation of plastic surgery residents in scientific publications is under reported. The implementation of research programs, protected times and active mentoring could increase this number.

Alternativas de cierre de fasciotomías en extremidades / Alternatives for the closure of extremity fasciotomy

Resumen La fasciotomía es el pilar del tratamiento y prevención del síndrome compartimental agudo. Una vez resuelto el cuadro agudo que derivó en la necesidad de ésta, el cierre de la herida resultante genera un importante desafío reconstructivo para el cirujano dado el importante edema residual de los tejidos. El objetivo de este artículo es entregar una actualización respecto a las alternativas de cierre de una fasciotomía de extremidades, para lo cual se realizó una búsqueda de artículos indexados en PubMed, Epistemonikos y Scielo. Se encontraron al menos 6 técnicas disponibles, cada una de ellas con determinadas ventajas y desventajas. Recomendamos que la elección sea de acuerdo a la experiencia del cirujano, los recursos disponibles y el contexto de cada paciente.

Fasciotomy is the mainstay of treatment and prevention of acute compartment syndrome. Given the important deep tissue edema, closure of the resulting wound generates a significant reconstructive challenge for the surgeon. The aim of this article is to provide an update concerning alternatives for closure of fasciotomy of limbs, for which a search of articles indexed in PubMed, Scielo and Epistemonikos databases was performed. At least 6 techniques were found, each of them with specific advantages and disadvantages. We recommend that the choice should be according to the surgeons experience, resources and context of each patient.

Uso de doble colgajo diep para reconstrucción de extremidad inferior / Double diep flap for lower extremities reconstruction

Introduction: A soft tissue defect considering the extent, location, depth and involved structures can be a complex task, leading to search for unusual reconstructive alternatives. Case report: Puerperal woman, 21 years, previously healthy, admitted for septic shock and skin necrosis of both extremities secondary to purpura fulminans. Escharectomy was performed and the final defect was 27 percent of total body surface, corresponding to necrotic areas of both superior and lower extremities. Is remarkable the presence of musculocutaneous perforating vessels thrombosis and segmental muscular necrosis in legs and interosseous muscles necrosis in hands. In upper extremity coverage was performed with dermoepidermal grafts. To cover peroneal malleolus and feet dorsum, whereas there were no regional or local alternatives, we realize a double DIEP flap. Flap elevation of bilateral DIEP flap was performed simultaneously for two surgical teams. The patient had no complications and was discharged with complete soft tissue coverage.

Introducción: Un defecto de cobertura extenso de extremidades inferiores (EEII), considerando ubicación, profundidad y estructuras involucradas es de una alta complejidad y puede llevar a buscar alternativas reconstructivas poco habituales. Caso Clínico: Paciente de 21 años, puérpera, ingresa por shock séptico y necrosis cutánea extensa de extremidades secundario a un purpura fulminans. Se realiza escarectomía y el defecto resultante es de 27 por ciento de superficie corporal, correspondiendo a zonas necróticas en ambas extremidades, superiores e inferiores. Destaca la presencia de trombosis de vasos perforantes musculocutáneos, necrosis muscular segmentaria en piernas y de musculatura interósea en manos. En extremidades superiores se realizó cobertura con injertos dermoepidérmicos. Para la exposición de ambos maléolos peroneos y dorso de pies, considerando que no existen alternativas locales ni regionales, se decide realizar un colgajo DIEP bilateral; se eleva en un tiempo, con dos equipos quirúrgicos simultáneos. La anastomosis microquirúrgica se realizó a los vasos tibiales de cada extremidad. La evolución postoperatoria fue favorable. La paciente es dada de alta en buenas condiciones generales, extubada, con cobertura cutánea completa.

Cirugía de banco y autotrasplante en aneurisma complejo de arteria renal / Complex renal artery aneurysm: ex vivo repair and reimplantation

Introduction: True incidence of renal artery aneurysms is unknown but it has been estimated to be around 1 percent. They are usually asymptomatic and diagnosed through imaging studies done for other medical reasons. Those that are more than 2 cm in diameter or any aneurysm in pregnant women should be treated because of an elevated risk of rupture. We present a case of a man with a complex 2.5 cm renal artery aneurysm, successfully treated with ex vivo repair and reimplantation by a multidisciplinary team.

Introducción: La incidencia real de los aneurismas de arteria renal es desconocida, pero se ha estimado en aproximadamente un 1 por ciento. Normalmente los pacientes son asintomáticos y su diagnóstico es habitualmente un hallazgo de estudios de imágenes solicitados por otras causas. El riesgo principal de los aneurismas mayores de 2 cm de diámetro o aquellos en mujeres embarazadas es la rotura. Caso clínico: Presentamos el caso de un hombre con diagnóstico de aneurisma complejo de arteria renal izquierda, que fue sometido a reparación exitosa.

Cirugía plástica y sus complicaciones: ¿en qué debemos fijarnos? / Plastic surgery and its complications: what we should look?

Plastic surgeries are becoming more popular, being performed on a varied type of population and often as office-based procedures. Despite being highly elective procedures, they have risks and complications, which should be reported to patients by the health personnel. The most frequently performed procedures are breast augmentation and body liposuction. The most relevant complications associated with plastic surgery are pulmonary embolism and deep vein thrombosis, which is the leading cause of mortality in this type of surgery. Other complications are local anesthetics intoxication secondary to the use of tumescent solution in body liposuction, inadequate management of perioperative intravenous fluids, mild hypothermia and severe pain after surgery caused by poor postoperative analgesia. It is essential to prevent the described complications, which significantly increase morbidity, mortality and hospital stay. The perioperative measures that have demonstrated effectiveness in reducing perioperative risk are thromboprophylaxis, depending on the thrombotic risk categorization of each patient and the use of adequate concentrations of lidocaine and vasoconstrictor in the tumescent solution. Appropriate temperature monitorization and use of conservation measures in patients with exposure of large body surfaces is also an important issue, as is diligence in intraoperative fluid balance and administration of intravenous multimodal analgesia, adjusted to the magnitude of the surgery. In order to achieve this, proper communication between the surgical team, anesthesiologists and nurses is vital, as it permits implementation of specific measures that permit adequate monitorization, prevention of complications and analgesic management described above.

Las cirugías plásticas son cada vez más frecuentes, abarcando todo tipo de población y realizándose incluso en la consulta médica. Las cirugías estéticas más frecuentemente realizadas son aumento mamario y liposucción corporal. Son procedimientos quirúrgicos sumamente electivos, pero poseen riesgos y complicaciones asociados, los cuales deben ser debidamente informados a los pacientes. La complicación más relevante es el tromboembolismo pulmonar, generalmente asociado a trombosis venosa profunda, el cual es la primera causa de mortalidad en este tipo de cirugías. Otras complicaciones destacadas son intoxicación por anestésicos locales secundaria al uso de solución tumescente para liposucción corporal, inadecuado manejo de fluidos endovenosos perioperatorios, hipotermia inadvertida y dolor intenso por deficiente analgesia postoperatoria. Estas complicaciones aumentan significativamente la morbimortalidad y estadía hospitalaria, por lo que su prevención es fundamental. Las medidas que han demostrado disminución significativa de los riesgos y complicaciones perioperatorios en cirugía plástica son tromboprofilaxis según categorización del riesgo trombótico de cada paciente, revisar que la solución tumescente administrada para liposucciones tenga concentraciones adecuadas de lidocaína (idealmente utilizando vasoconstrictores coadyuvantes), utilizar medidas adecuadas de monitorización y conservación de temperatura en pacientes con gran superficie corporal expuesta, ser acuciosos en el balance intraoperatorio de fluidos endovenosos y administrar analgesia postoperatoria multimodal, balanceada y acorde a la magnitud del dolor. Es vital una adecuada comunicación entre el equipo de cirujanos, anestesiólogos, enfermeros e instrumentadores quirúrgicos con el objetivo de conocer las particularidades de las distintas cirugías plásticas e implementar las medidas de monitorización, prevención de complicaciones y manejo analgésico antes descritas.

Bandas amnióticas constrictivas y derivación oportuna: a propósito de 2 casos clínicos / Constriction band syndrome and the right time for intervention: two clinical cases

Introducción: El síndrome de bridas amnióticas (SBA) es una afección infrecuente de etiología controversial con manifestaciones muy heterogéneas. Las extremidades son las más frecuentemente afectadas, y puede asociarse a otras malformaciones. El recién nacido con SBA rara vez va a requerir de cirugía inmediata, sin embargo, la evaluación por el especialista y la indicación quirúrgica debe ser oportuna y no postergada innecesariamente, lo cual podría significar la pérdida de la extremidad. Objetivo: Comunicar 2 casos de SBA que afectan la extremidad superior, en los cuales la intervención oportuna providencial resultó en un favorable pronóstico. Caso clínico: Reportamos dos casos, donde hubo una derivación tardía de los pacientes por mitos preconcebidos tales como "que era necesario completar el crecimiento para realizar un tratamiento definitivo" (caso 2) o "que no había ningún tratamiento que ofrecerle frente a la severidad de la malformación del recién nacido" (caso 1). En ambos pacientes las bridas constrictivas fueron liberadas en forma exitosa con el uso de múltiples zetoplastias, sin complicaciones en la evolución postoperatoria. Conclusión: Se discute y enfatiza la importancia del diagnóstico, derivación y tratamiento precoz de ésta patología.

Introduction: The amniotic band syndrome is an infrequent affection, of controversial aetiology, with extreme heterogeneous manifestations. Extremities are most frequently compromised and may be associated to other malformations. These newborns rarely need immediate surgery nevertheless the surgical indication must be timely and not postponed, which could mean loss of the extremity. Objective: To report 2 patients with the amniotic band syndrome, in whom casual early interventions were associated to a favorable prognosis. Case reports: We present two patients with an important delay in the referral to the specialist because of the preconceived myths that either full growth was necessary for definitive surgery (case 2) or that no possible treatment could be offered due to the severity of the diagnosis (case 1). All constricting bands were successfully and effectively released with multiple Z plasties with uneventful post operative evolution. Conclusion: We discuss and emphasize the importance of early diagnosis and intervention.

Análisis crítico de guía clínica GES gran quemado versión 2007 / Critical appraisal of clinical guideline

Objective: Critical appraisal of the clinical practice guideline (CPG) "Gran Quemado-Extensive Burn Patients"(2007 issue) corresponding to "Garantías Explícitas en Salud- Explicit Health Guarantees" (GES). Material and Methods: The CPG was evaluated using the previously validated AGREE instrument. This instrument evaluates a series of items organized in 6 domains, that capture different dimensions of the guidelines quality comparing the scores obtained with a maximum theoretical score. The CPG was evaluated by three independent and masked authors applying the AGREE instrument. Results: Stratified by domain, in the "scope and purpose" domain there was an 88.9 percent of compliance; in "stakeholder involvement" 47.9 percent; in the "rigour of development" 47.6 percent; in "clarity and presentation" 79.2 percent; in "applicability" 30.6 percent and 75 percent in the "editorial independence" domain; reaching a 44.9 percent final score of compliance. Conclusions: The score obtained was below 50 percent of the optimum for a CPG. The detailed analysis by domain makes evident the areas that may be subject of improvement, so as to optimize the applicability of the CPG and therefore guarantee better health care and treatment results for all burn patients benefiting from the "Explicit Health Guarantees".

Objetivo: Evaluar críticamente la guía de práctica clínica (GPC) de Gran Quemado correspondiente a las Garantías Explícitas en Salud (GES) versión 2007. Material y Método: La evaluación se realizó con el instrumento AGREE el cual ha sido previamente validado. El instrumento AGREE evalúa una serie de ítems en 6 dominios entregando un puntaje específico que se compara con un máximo teórico. Tres autores en forma independiente y enmascarada evaluaron la GPC y puntuaron de acuerdo al instrumento utilizado. Resultados: Estratificando por dominio, en "alcance y objetivo" se obtuvo un 88,9 por ciento de cumplimiento; en participación de los implicados 47,9 por ciento; en rigor en la elaboración 47,6 por ciento; en claridad y presentación 79,2 por ciento; en aplicabilidad 30,6 por ciento y 75 por ciento en independencia editorial; entregando un puntaje final de 44,9 por ciento de cumplimiento. Conclusiones: El puntaje obtenido fue menor al 50 por ciento del óptimo para una GPC. El análisis detallado por dominio entrega en forma detallada las áreas susceptibles de perfeccionar para optimizar la aplicabilidad de la guía clínica y de tal forma garantizar la mejoría en el cuidado y los resultados del tratamiento de los pacientes quemados beneficiarios de las Garantías Explícitas en Salud.

N-(2-hydroxypropyl)methacrylamide copolymer-6-(3-aminopropyl)-ellipticine conjugates. Synthesis, in vitro, and preliminary in vivo evaluation.

Ellipticine derivatives have potential as anticancer drugs. Their clinical use has been limited, however, by poor solubility and host toxicity. As N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-anticancer conjugates are showing promise in early clinical trials, a series of novel HPMA copolymer conjugates have been prepared containing the 6-(3-aminopropyl)-ellipticine derivative (APE, NSC176328). Drug was linked to the polymer via GFLG or GG peptide side chains. To optimize biological behavior, HPMA copolymer-GFLG-APE conjugates with different drug loading (total APE: 2.3-7% w/w; free APE: <0.1% w/w) were synthesized. Conjugation of APE to HPMA copolymers considerably increased its aqueous solubility (>10-fold). HPMA copolymer-GG-APE did not liberate drug in the presence of isolated lysosomal enzymes (tritosomes), but HPMA copolymer-GFLG-APE released APE to a maximum of 60% after 5 h. The rate of drug release was influenced by drug loading; lower loading led to greater release. Whereas free APE (35 microg/mL) caused significant hemolysis (50% after 1 h), HPMA copolymer-APE conjugates were not hemolytic up to 300 microg/mL (APE-equiv). As would be expected from its cellular pharmacokinetics, HPMA copolymer-GFLG-APE was >75 times less cytotoxic than free drug (IC(50) approximately 0.4 microg/mL) against B16F10 melanoma in vitro. However, in vivo when tested in mice bearing s.c. B16F10 melanoma, HPMA copolymer-GFLG-APE (1-10 mg/kg single dose, APE-equiv) given i.p. was somewhat more active (highest T/C value of 143%) than free APE (1 mg/kg) (T/C =127%). HPMA copolymer-APE conjugates warrant further evaluation as potential anticancer agents.

Polymer-drug conjugates, PDEPT and PELT: basic principles for design and transfer from the laboratory to clinic.

There are now at least seven polymer-drug conjugates that have entered phase I/II clinical trial as anticancer agents. These include N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1, FCE28068), HPMA copolymer-paclitaxel (PNU 166945), HPMA copolymer-camptothecin, PEG-camptothecin, polyglutamic acid-paclitaxel, an HPMA copolymer-platinate (AP5280) and also an HPMA copolymer-doxorubicin conjugate bearing additionally galactosamine (PK2, FCE28069). The galactosamine is used as a means to target the conjugate to liver for the treatment of primary and secondary liver cancer. Promising early clinical results with lysosomotropic conjugates has stimulated significant interest in this field. Ongoing research is developing (1) conjugates containing drugs that could otherwise not progress due to poor solubility or uncontrollable toxicity; (2) conjugates of agents directed against novel targets; and (3) two-step combinations such as polymer-directed enzyme prodrug therapy (PDEPT) and polymer-enzyme liposome therapy (PELT) that can cause explosive liberation of drug from either polymeric prodrugs or liposomes within the tumour interstitium. Moreover, bioresponsive polymer-based constructs able to promote endosomal escape and thus intracytoplasmic delivery of macromolecular drugs (peptides, proteins and oligonucleotides) are also under study.

Novel inhibitors of carboxypeptidase G2 (CPG2): potential use in antibody-directed enzyme prodrug therapy.

The design and synthesis of potent thiocarbamate inhibitors for carboxypeptidase G2 are described. The best thiocarbamate inhibitor N-(p-methoxybenzenethiocarbonyl)amino-L-glutamic acid 6d, chosen for preliminary investigations of in vitro antibody-directed enzyme prodrug therapy (ADEPT), abrogated the cytotoxicity of a combination of A5B7-carboxypeptidase G2 conjugate and prodrug PGP (N-p-{N,N-bis (2-chloroethyl)amino}phenoxycarbonyl-L-glutamate) toward LS174T cells. This is the first report of a small-molecule enzyme inhibitor proposed for use in conjunction with the ADEPT approach.

Altered biodistribution of an antibody--enzyme conjugate modified with polyethylene glycol.

Polyethylene glycol modification of the antibody--enzyme conjugate, F(ab')2-A5B7-CPG2, extends its duration in the circulation of nude mice bearing human colonic cancer xenografts (LS174T). Increased concentration of modified conjugate is achieved in the tumour, but residual non-specific enzyme concentrations in normal tissue and blood demonstrate the fundamental requirement to remove or inactivate non-specifically held enzyme in this system.

The immune system in disease: gestational trophoblastic tumours.

Trophoblastic tumours form a spectrum of disease from the borderline malignancy of HM to highly aggressive choriocarcinoma. Their management requires the integration of the information derived from serial hCG estimations, the clinical history and pattern of spread of the disease, so that our understanding of the prognostic variables can be applied appropriately. This maximizes the patient's chances of complete remission from her disease with the minimum of toxicity. Given our knowledge of this group of diseases and an integrated approach to management, it should be uncommon for any woman to die from her trophoblastic tumour.

Ablation of human choriocarcinoma xenografts in nude mice by antibody-directed enzyme prodrug therapy (ADEPT) with three novel compounds.

Three novel prodrugs have been designed for use as anticancer agents. Each is a bifunctional alkylating agent which has been protected to form a relatively inactive prodrug. They are designed to be activated to their corresponding alkylating agents at a tumour site by prior administration of an antitumour antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2) in a two-phase system called antibody-directed enzyme prodrug therapy (ADEPT). The Km and Vmax values for three different antibody-CPG2 conjugates were determined in relation to each prodrug. The Km values ranged from 4.5-12 mumol/l and the Vmax from 0.5-1.6 mumol/U/min. Athymic Nu/Nu mice with palpable transplanted human choriocarcinoma xenografts, which are resistant to conventional chemotherapy, were treated with anti-human chorionic gonadotropin antibodies conjugated to CPG2. This was followed by each of the three novel prodrugs. Significant increase in survival was obtained in three of the regimens tested using only one course of treatment. This demonstrates the potential of a tumour-localised bacterial enzyme to activate protected alkylating agents in order to eradicate an established human xenograft.

Disposition of the prodrug 4-(bis (2-chloroethyl) amino) benzoyl-L-glutamic acid and its active parent drug in mice.

A novel therapy for improving selectivity in cancer chemotherapy aims to modify distribution of a cytotoxic drug by generating it selectively at tumour sites. In this approach an antibody-enzyme conjugate is allowed to localise at the tumour sites before injecting a prodrug which is converted to an active drug specifically by the targeted enzyme in the conjugate. We present here pharmacokinetic studies on the prodrug 4-(bis (2-chloroethyl) amino) benzoyl-L-glutamic acid and its activated derivative, benzoic acid mustard. The glutamic acid is cleaved from the prodrug to form the active drug by carboxypeptidase G2 (CPG2), an enzyme from Pseudomonas sp., which is not found in mammalian cells. The prodrug and its parent active drug were rapidly distributed in plasma and tissues after administration of prodrug or active drug (41 mumol kg-1 intraperitoneally) to mice bearing human choriocarcinoma xenografts. Prodrug and active drug both followed a two-compartment kinetic model. Prodrug was eliminated more rapidly (t1/2 alpha = 0.12 h, t1/2 beta = 0.70 h) than active drug (t1/2 alpha = 0.37 h, t1/2 beta = 1.61 h). Conversion of the prodrug to the activated parent drug was detected within 5 min of administration to mice which had previously received a F(ab')2-anti-human chorionic gonadotrophin antibody (W14A) conjugated to the enzyme, CPG2 (1,000 U kg-1). Tumour was the only tissue that activated all the prodrug reaching the site. It contained the highest concentration of targeted enzyme conjugate capable of catalysing the reaction of prodrug to drug. Plasma and other tissues were also capable of activating the prodrug but active drug production was limited by the amount of enzyme present. The active drug measured in plasma and tissues other than tumour was attributable to residual antibody-enzyme conjugate at non-tumour sites. Low levels of conjugate in tissues and plasma militate against the advantage of tumour localised enzyme therefore necessitating removal of non-localised enzyme.

Carboxypeptidase G2 and trimetrexate cause growth delay of human colonic cancer cells in vitro.

MAWI colonic cancer cells respond to sequential treatment in vitro with carboxypeptidase G2 and trimetrexate by a delay in cell growth as measured by cell numbers, but an increase in incorporation of 75-Se-selenomethionine per cell. The cells are not methionine auxotrophs.

The potential of carboxypeptidase G2: antibody conjugates as anti-tumour agents. II. In vivo localising and clearance properties in a choriocarcinoma model.

The in vivo localising and clearance properties of conjugates of the folate-degrading enzyme carboxypeptidase G2 (CPG2) with anti-human chorionic gonadotrophin (W14A) were measured in nude mice bearing CC3 choriocarcinoma xenografts. Conjugates of W14A-F (ab')2 fragment coupled to CPG2 localised in tumour as effectively as native antibody alone but showed lower uptake in other major tissues. The clearance rates of conjugates prepared with intact antibody or F (ab')2 fragment were shown to be up to five-fold faster than for native antibody and two-fold compared to F (ab')2 fragment. Molecular weight analysis of residual conjugate in the blood showed that no degradation of conjugate to its component molecules occurred during circulation. It was concluded that F (ab')2: CPG2 conjugates offered the greatest potential for targeting applications.

Novel prodrugs which are activated to cytotoxic alkylating agents by carboxypeptidase G2.

The synthesis of three novel prodrugs, 4-[bis[2-(mesyloxy)ethyl]amino]benzoyl-L-glutamic acid (7), 4-[(2-chloroethyl)[2-(mesyloxy)ethyl]amino]benzoyl-L-glutamic acid (8), and 4-[bis(2-chloroethyl)amino]benzoyl-L-glutamic acid (9), for use as anticancer agents, is described here. Each is a bifunctional alkylating agent in which the activating effect of the ionized carboxyl function is masked through an amide bond to the glutamic acid residue. These relatively inactive prodrugs are designed to be activated to their corresponding nitrogen alkylating agents (10, 11, and 12, respectively) at a tumor site by prior administration of a monoclonal antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2). The viability of two different tumor cell lines was monitored with each prodrug in the presence of CPG2. All three compounds showed substantial prodrug activity--with conversion to the corresponding active drug leading to greatly increased cytotoxicity.

Preliminary observations on the microdistribution of labelled antibodies in human colonic adenocarcinoma xenografts: relevance to microdosimetry.

Autoradiography with 125I-labelled antibodies 17-1-A and 11-285-14 (anti-carcinoembryonic antigen) injected singly or together into nude mice carrying two distinct human colorectal cancer xenografts delineates marked changes in distribution and retention of isotope over 72 h, which are relevant to microdosimetry. The antibodies localise independently at low concentrations. Slow accumulation and retention predominantly in membranes of glands and necrotic areas suggest that therapy will succeed best with isotopes whose range, half-life and/or mode of delivery can exploit optimally the greater selectivity of the late retention.

Serial measurements of Ca antigen in sera from patients with advanced malignant breast disease.

Ca antigen levels in serum samples from three groups of patients were assayed. From a survey of 173 patients with various malignancies, elevated levels were found most consistently in patients with metastatic breast cancer. Spearman rank correlation values of Ca and CEA values on individual serum samples, 0.3009, (n = 194), or individual and serial samples, 0.2406, (n = 264) from a total 194 patients with metastatic breast cancer showed that correlation between Ca and CEA values was poor. For a group of 20 patients within the 194, from whom fortnightly serial samples were available, serum levels for 10/20, measured retrospectively, corroborated clinical observations on the course of their disease, although only 4/20 showed marked elevations during active disease. No correlations between expression of the tumour marker and histological type of the primary tumour, age of the patient, site of recurrence nor aberrant elevation in response to cytotoxic drug could be found to explain the non-correspondence of marker behaviour and disease status in the remaining 10 patients. The indications from this small study are that serial Ca antigen serum measurement could be misleading in 50% of patients with metastatic breast cancer, and that the assay is unsuitable for follow-up of patients with breast cancer.