Correlation between response to neoadjuvant chemotherapy and survival in locally advanced breast cancer patients.

BACKGROUND: Measurement of residual disease following neoadjuvant chemotherapy that accurately predicts long-term survival in locally advanced breast cancer (LABC) is an essential requirement for clinical trials development. Several methods to assess tumor response have been described. However, the agreement between methods and correlation with survival in independent cohorts has not been reported. PATIENTS AND METHODS: We report survival and tumor response according to the measurement of residual breast cancer burden (RCB), the Miller and Payne classification and the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, in 151 LABC patients. Kappa Cohen's coefficient (К) was used to test the agreement between methods. We assessed the correlation between the treatment outcome and overall survival (OS) and relapse-free survival (RFS) by calculating Harrell's C-statistic (c). RESULTS: The agreement between Miller and Payne classification and RCB classes was very high (К = 0.82). In contrast, we found a moderate-to-fair agreement between the Miller and Payne classification and RECIST criteria (К = 0.52) and RCB classes and RECIST criteria (К = 0.38). The adjusted C-statistic to predict OS for RCB index (0.77) and RCB classes (0.75) was superior to that of RECIST criteria (0.69) (P = 0.007 and P = 0.035, respectively). Also, RCB index (c = 0.71), RCB classes (c = 0.71) and Miller and Payne classification (c = 0.67) predicted better RFS than RECIST criteria (c = 0.61) (P = 0.005, P = 0.006 and P = 0.028, respectively). CONCLUSIONS: The pathological assessment of tumor response might provide stronger prognostic information in LABC patients.

Chemotherapy (CT) and hormonotherapy (HT) as neoadjuvant treatment in luminal breast cancer patients: results from the GEICAM/2006-03, a multicenter, randomized, phase-II study.

BACKGROUND: Luminal breast cancer is a highly endocrine responsive disease. However, the therapeutic benefit of chemotherapy (CT) in this population is not fully characterized. This study investigates the value of CT and hormone therapy (HT) in luminal breast cancer patients in the neoadjuvant setting. PATIENTS AND METHODS: Patients with operable breast cancer and immunophenotypically defined luminal disease (ER+/PR+/HER2-/cytokeratin 8/18+) were recruited. Patients were randomized to CT (epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) 4 cycles followed by docetaxel 100 mg/m(2 )4 cycles [EC-T]) or HT (exemestane 25 mg daily 24 weeks [combined with goserelin in premenopausal patients]). The primary end point was the clinical response measured by magnetic resonance imaging. RESULTS: Ninety-five patients were randomized (47 CT, 48 HT). The clinical response rate was 66% for CT and 48% for HT (P = 0.075). We performed an unplanned analysis based on Ki67 levels (cut-off of 10%). Similar clinical response was seen between arms in patients with low Ki67 (CT: 63%, HT: 58%; P = 0.74); patients with high Ki67 had a better response with CT (67 versus 42%; P = 0.075). Grade 3/4 toxicity was more frequent with CT. CONCLUSIONS: Luminal immunophenotype is not enough to identify patients who do not benefit from neoadjuvant CT. Luminal patients with low proliferation index could potentially avoid CT.

Genomic predictors of response to doxorubicin versus docetaxel in primary breast cancer.

UNLABELLED: Taxanes and anthracyclines improve the outcome of early breast cancer, although the benefit is limited to a small proportion of patients and are toxic. We prospectively looked for predictors of response to these drugs. EXPERIMENTAL DESIGN: Four cycles of doxorubicin (75 mg/m²) or docetaxel (100 mg/m²) were compared as presurgical chemotherapy for breast cancer. Biomarkers were determined by immunohistochemistry and fluorescent in situ hybridization using prechemotherapy core biopsies. Tumors were also classified into one of the molecular intrinsic subtypes using an immunohistochemical panel of five biomarkers and genomic profiles. Single genes and intrinsic subtypes were correlated with response to doxorubicin versus docetaxel. Among the 204 evaluable patients, significant predictors of sensitivity in multivariate analysis were low topo2a expression and ER-negative status for doxorubicin and small tumor size and ER-negative status for docetaxel. Predictors of resistance in multivariate analysis were triple-negative status (ER/PgR/HER2 negative by IHC/FISH) for doxorubicin, and high TNM stage for docetaxel. Triple-negative tumors were associated with topo2a overexpression more than the other subtypes. In 94 patients with gene expression profiles, docetaxel was superior to doxorubicin in the basal-like subtype (good pathological response rate - PCR + class I of 56 vs. 0%; P = 0.034); no significant differences were observed in the other subtypes when comparing these two drugs. Low topo2a expression and ER-negative status were predictors of response to doxorubicin, while small tumor size and ER-negative status predicted response to docetaxel. Docetaxel was superior to doxorubicin in triple-negative/basal-like tumors, while no significant differences were seen in the remaining intrinsic subtypes.

C4D immunostaining in surveillance endomyocardial biopsies from well-functioning heart allografts.

OBJECTIVE: The meaning of biopsy C4d detection in heart allografts without dysfunction or morphologic changes suggesting antibody-mediated rejection (AMR) is not clear. The aim of this study was to search for an association between C4d detection in allograft biopsies of well-functioning hearts without changes suggestive of AMR, and clinical outcomes. METHODS: Endomyocardial protocol biopsies from 44 heart transplant patients with well-functioning grafts and without changes suggesting AMR were performed at 1 month and 1 year after transplantation and analyze the presence of C4d deposition using immunohistochemistry. Two-year follow-up was based on clinical parameters and echocardiographic information. Heart graft function was categorized as good vs. poor. The presence of C4d, using diverse schemes to graduate the extension of the deposition, was correlated with clinical graft outcomes. RESULTS: C4d deposition was observed in the capillary walls of 33 biopsies (37.5%; n = 25 patients; 56.8%). No biopsy had diffuse (>50%) immunostaining. Six patients presented with multifocal capillary C4d immunostaining in at least 1 biopsy. Capillary positivity for C4d (if focal or multifocal) showed no statistical association with cellular rejection or graft function. Perimyocytic C4d detection was neither associated with rejection nor graft outcome. CONCLUSION: Our work failed to demonstrate an association between C4d detection in protocol biopsies of heart grafts and clinical outcomes. The clinical utility of C4d staining in solid organ transplantation may vary by organ. Our results suggest that C4d did not have clinical utility in surveillance biopsies of well-functioning heart grafts without morphological changes suggesting AMR.

Prostatectomía radical asistida por ROBOT (Da Vinci®). Un año de experiencia en el Hospital Clínico San Carlos / Da Vinci® robot assisted radical prostatectomy: one year experience at the Hospital Clínico San Carlos

Objetivo: El Hospital Clínico San Carlos de Madrid, es el primer centro público español en disfrutar de la última tecnología en cuanto a cirugía se refiere: el robot Da Vinci®. La primera intervención fue llevada a cabo en nuestro servicio el nueve de octubre de 2006. Desde entonces, se han producido numerosos cambios que nos han permitido ir superando dificultades, hasta superar la curva de aprendizaje. Métodos: Durante el período comprendido entre el 9 de octubre de 2006 y el 30 de noviembre de 2007 hemos realizado 30 prostatectomías radicales con el robot Da Vinci®. La edad media de los pacientes es de 63 años (47-70 años) con riesgo quirúrgico según la Asociación Americana de Anestesia siempre inferior a III, un grado de Gleason entre 2 y 8 y PSA≤15 (3,5-15). El volumen prostático medio valorado por ecografía transrectal fue de 36cc (16-90cc). Resultados/Conclusiones: Se utilizaron 6 trócares y un neuoperitoneo de 15mmHg. La duración media del tiempo de ocupación de quirófano fue de 5,9 horas (4-14horas). Dos casos fueron reconvertidos a cirugía abierta y uno a laparoscopia. No se han producido complicaciones intraoperatorias severas. En el postoperatorio inmediato 2 pacientes presentaron plexopatía y artralgia, 1 infección de uno de los trócares y 2 hematomas por colocación del trócar. 16 pacientes requirieron transfusión (media 1 concentrado (0-4)). La sonda se retiró entre el 5º y 21º días (media 11 días). En lo referente a incontinencia: 10 presentan una continencia completa o incontinencia leve (0-1 absorbentes) y 5 incontinenciamoderada (2-5 absorbentes). La potencia sexual se mantiene en 3 pacientes y en el resto existen diferentes grados de disfunción (AU)

Objectives: Hospital Clínico San Carlos in Madrid is the first Spanish public centre using the latest surgical technology: the Da Vinci® robot. First operation was carried out in our department in October 9th 2006. Since then, numerous changes have happened which enabled us to overcome difficulties, to complete the learning curve. Methods: Between October 9th 2006 and November30th 2007 we performed 30 radical prostatectomies with the Da Vinci® robot. Mean patient age was 63 years (47-70 years) with an ASA (American society of anesthesia) risk below III in all cases, a Gleason score between 2 and 8 and a PSA ≤ 15 (3.5-15). Mean prostatic volume measured by transrectal ultrasound was 36 cc (16-90 cc). Results/Conclusions: Six trocars and a 15 mm Hg pneumoperitoneum were employed. Mean operative room occupation time was 5.9 hours (4-14 hours). Two cases were converted to open surgery and one to laparoscopy. No major intraoperative complications have happened. In the immediate post-operative period,2 patients presented plexopathy and arthralgia, 1 infection at the site of one trocar, and 2 haematomas at the site of trocar insertion. Sixteen patients required transfusion (mean 1 red blood cells unit (0-4)). Bladder catheter was retrieved between 5th and 21st post-operative days (mean 11 days). Regarding continence: 10 patients were completely continent or present mild incontinence (0-1 pad) and 5 had moderate incontinence (2-5 pads). Three patients preserve sexual potency, the rest show different grades of dysfunction (AU)

Cuirasse skin metastases secondary to gastric adenocarcinoma.

Skin metastases are infrequent manifestations of solid tumours. However, it is important to recognize them since they may be the first evidence of a neoplasia, or a sign of tumour progression or recurrence. Skin metastases from gastric adenocarcinomas are particularly rare, and represent 6% of the total in males and 1% in females. We report, here, the case of a patient diagnosed with gastric adenocarcinoma with extensive subcutaneous infiltration of the abdominal wall, resulting in an abdominal cuirass.

Cuirasse skin metastases secondary to gastric adenocarcinoma

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Pinning of tumoral growth by enhancement of the immune response.

Tumor growth is a surface phenomenon of the molecular beam epitaxy universality class in which diffusion at the surface is the determining factor. This Letter reports experiments performed in mice showing that these dynamics can, however, be changed. By stimulating the immune response, we induced strong neutrophilia around the tumor. The neutrophils hindered cell surface diffusion so much that they induced new dynamics compatible with the slower quenched-disorder Edwards-Wilkinson universality class. Important clinical effects were also seen, including remarkably high tumor necrosis (around 80%-90% of the tumor), a general increase in survival time [the death ratio in the control group is 15.76 times higher than in the treated group (equivalent to a Cox's model hazard ratio of 0.85; 95% confidence interval 0.76-0.95, p=0.004)], and even the total elimination of some tumors.

Correlación clínico-citohistológica de los quistes congénitos cervicales. Discusión / Clinical-cytohistological correlation of cervicofacial congenital cysts. Discussion

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Hematuria masiva en una paciente con artritis reumatoide / Massive hematuria in a patient with rheumatoid arthritis

Describimos el caso de una paciente de 61 años diagnosticada de artritis reumatoide. Desarrolló hematuria masiva con expulsión de coágulos sanguíneos; una biopsia de la mucosa vesical reveló amiloidosis secundaria. La amiloidosis secundaria sintomática de la vejiga es muy rara. Solamente se han descrito 22 casos en la bibliografía. La mayoría de estos casos tenía enfermedades reumáticas, más frecuentemente artritis reumatoide (AR) y espondilitis anquilosante (EA). Creemos que es necesario tener en cuenta la posibilidad de amiloidosis secundaria de la vejiga cuando el reumatólogo se enfrente a un paciente con artritis reumatoide y hematuria macroscópica (AU)

We describe the case of a 61-year-old woman with a diagnosis of rheumatoid arthritis. She developed massive hematuria with expulsion of blood clots. Biopsy of the vesical mucosa revealed secondary amyloidosis. Symptomatic amyloidosis of the bladder is highly infrequent and only 22 cases have been reported in the literature. Most reported patients had rheumatic disease, especially rheumatoid arthritis and ankylosing spondylitis. The possibility of secondary amyloidosis of the bladder should be suspected in patients with rheumatoid arthritis and gross hematuria (AU)

Diagnóstico por PET de una recidiva única en un paciente con carcinoma epidermoide de pulmón estadio I previamente resecado / PET diagnosis of an isolated relapse in a patient with a previously resected stage I epidermoid carcinoma of the lung

Propósito: Descripción de un caso de recidiva única mediastínica adenopática diagnosticada por PET de carcinoma epidermoide de pulmón estadio I. Material y métodos: Varón de 70 años, intervenido quirúrgicamente de carcinoma epidermoide de pulmón estadio I, presentando tras 28 meses, recidiva ganglionar única subcarinal, confirmada por PET y tratada con quimioterapia con reducción del 50 por ciento tras 2 ciclos de quimioterapia. Resultados: Se realiza una revisión de la literatura orientada a determinar los factores pronósticos moleculares en cáncer de pulmón no de células pequeñas en estadios precoces y a valorar la utilidad de la tomografía por emisión de positrones (PET-FDG) en el diagnóstico de enfermedad recurrente. Conclusiones: Aunque el PET-FDG puede ayudar en el diagnóstico de las recaídas locales asintomáticas, no se conocen aún las consecuencias del tratamiento precoz de las mismas ni la repercusión en la supervivencia o el pronóstico final. La determinación del grado de proliferación celular con Ki 67 y c-erb2 realizados inicialmente podrían aportar información acerca de las posibilidades de respuesta a la quimioterapia (AU)

[Usefulness of PSA-complex in the diagnosis of prostatic carcinoma]. / Utilidad del PSA-complex en el diagnóstico del carcinoma de próstata.

OBJECTIVE: Since its discovery as a marker for prostate cancer, there have been many attempts to enhance the diagnostic efficacy of the prostate specific antigen (PSA). Among these are the studies that analyze the behavior of different forms of serum PSA bound to different antiproteases, such as alpha-1-antichymotrypsin, which forms the complexed PSA (PSA-c). This study analyzed the utility of PSA-c to enhance specificity without altering sensitivity in comparison to total PSA (PSA-t). METHODS: From September 1998 to March 1999, blood samples were obtained from 96 patients that had undergone a prostate biopsy due to a suspicion of prostate cancer. PSA-c, PSA-t (Technicon Immunol system, Bayer) and PSA-c/PSA-t ratio were analyzed in these patients. RESULTS: ROC curves were plotted and the optimal cutoffs were found for which the specificity was higher for PSA-c (44.6% [CI 95%, 32-57]) versus PSA-t (35.4% [CI 95%, 25-49]) and the PSA-c/PSA-t ratio (38.5% [CI 95%, 27-51]) while maintaining a similar sensitivity index (90%). PSA-c showed similar results for other values of sensitivity. CONCLUSIONS: PSA-c was found to improve specificity in comparison to PSA-t and PSA-c/PSA-t ratio. PSA-c determination could avoid unnecessary biopsies without altering sensitivity; i.e., the same number of prostate cancers will be detected.

[Usefulness of p53 oncoprotein immunohistochemistry in the follow-up of bladder carcinoma: a 5-year study]. / Utilidad de la oncoproteína p53-IHQ en el seguimiento del carcinoma vesical: estudio a 5 años.

OBJECTIVE: Mutations in the TP53 gene are frequently detected in some types of malignant tumors (bladder, prostate, kidney, lungs, breast, colon and rectum). This study analyzed the utility of semi-quantitative determination of p53 in transitional cell carcinoma of the bladder by an immunohistochemical technique and evaluated the results at 5 years. METHODS/RESULTS: A prospective clinical cohort study was conducted on 81 patients. The study comprised two groups: nontumoral bladder tissue specimens from 20 patients (group I) and tissue specimens from 61 patients with bladder carcinoma (group II). In both groups the tissue specimens were obtained between November 1992 and November 1993, and during the follow-up period until July 1998. p53 expression was determined by a semi-quantitative method based on an immunohistochemical technique (NCL-p53-DO7, Novocastra). CONCLUSIONS: p53 oncoprotein was not found to be useful in the characterization of carcinoma of the urinary bladder.

[Usefulness of P53 oncoprotein in urinary wash cytology: experience in patients with superficial bladder carcinoma]. / Utilidad de la oncoproteína p53 en citología urinaria de arrastre: experiencia en pacientes con carcinoma vesical superficial de vejiga.

OBJECTIVES: 1) To determine p53 expression in urinary wash cytology by immunohistochemistry in patients with superficial transitional cell carcinoma of the bladder and controls; 2) to correlate p53 in urinary wash cytology and anatomopathological characteristics of the bladder tumors analyzed; 3) to determine the utility of p53 expression in urinary wash cytology as a prognostic factor; and 4) to identify a subgroup of patients with superficial tumors of worse prognosis in order to improve control of the evolution of the tumor and treatment. METHODS: From 1993 to 1998, 141 cases were studied; 32 controls comprised group I and 109 (38 primary and 71 recurrence) patients with transitional cell carcinoma of the urinary bladder comprised group II. RESULTS: In group II, 29.5% were positive for p53 in urinary wash cytology, while no positive cases were found in group I. A total of 104 valid data were analyzed, which showed a higher percentage of p53-positive cases in grade III tumors (44.4%). Statistical analysis showed the percentage of p53-positive cases increased with tumor grade in a linear trend (p = 0.17). The recurrence rate in the p53-positive was 20% greater than in the p53-negative cases. Tumor progression was three times higher in the p53-positive than in the p53-negative patients. CONCLUSIONS: The application of biomolecular knowledge to cytology is a useful complement in follow-up of patients with superficial transitional cell carcinoma of the bladder and offers additional parameters to distinguish benign and malignant cells. Immunohistochemical determination of p53 in urinary wash cytology identifies patients with superficial tumors with a worse prognosis.

[The molecular biology of bladder carcinoma]. / Biología molecular del carcinoma vesical.

OBJECTIVE: The clinical course of transitional cell carcinoma of the bladder can be difficult to predict due to its potential to invade the muscle layer and/or develop to a high grade lesion. Bladder carcinoma can arise from genetic changes that may activate the oncogenes (-c-erbB2, c-erbB1, c-myc, ras, etc.) and/or inactivate the suppressor genes (p53, Rb). The aim of the present study is to continue a study protocol on the molecular biology of bladder tumors. METHODS/RESULTS: From January, 1993 to January, 1995, 85 patients were studied. These patients were divided into two groups: the first group comprised 14 controls of urothelial tissue and the second comprised 65 cases of transitional cell carcinoma of the bladder. p53 expression was determined by an immunohistochemical method (NCL-p53-DO7 monoclonal antibody). Quantification of the p8 oncoprotein in cytosol and EGFR (epidermal growth factor receptor) in membrane was performed by ELISA (Oncogene Science) and RIA (Vienna Lab), respectively. A statistically significant relationship between the expression of p53 and EGFR with tumor stage and grade was found. Quantification of p185 and EGFR showed higher values in the tumor tissue than in the control samples, but a worse survival could not be determined. CONCLUSIONS: The present study shows that p53 expression can be considered to be a prognostic factor. It provides useful information on the aggressive behaviour of the tumor and has a direct relation with the survival rates.

Primary malignant lymphoma of the bladder. Report of three cases.

Primary malignant lymphoma of the bladder is a rare tumour. In a recent literature search only 70 cases have been found since 1885. Most of these tumours were low grade B-cell non Hodgkin's lymphomas and only 20% were high grade neoplasms. This tumour usually appears in women between 20 and 85 years (median 64 yr.) of age. 20% of them have antecedents of chronic cystitic. Some authors have considered that some of the primary malignant lymphomas of the bladder arise from the mucosa-associated lymphoid tissue (MALT), therefore acting like MALT lymphomas which affect the gastrointestinal tract, the salivary glands or the thyroid. We report three additional cases of primary malignant lymphoma of the bladder, two of high grade, and discuss the histological criteria that support their MALT nature.