Circulating levels of HER-2/neu oncoprotein in breast cancer.

HER-2/neu, also known as c-erbB-2/neu, is an oncogene located in chromosome 17 which encodes HER-2/neu, a transmembrane protein belonging to the EGFR family. The external domain of this protein is released by the cell and can be studied in serum by immunoassay. HER-2/neu in serum is a specific tumor marker and only slight elevations may be found in the absence of malignancy, mainly in association with liver diseases. Likewise, the highest concentrations of this oncoprotein are found in patients with breast cancer, but lower concentrations may be found in other malignancies, particularly ovarian, prostate and lung cancer (mainly adenocarcinomas). HER-2/neu assay sensitivity in patients with untreated primary loco-regional breast cancer is <10% and seems to be related to overexpression in tissue as well as to the most important prognostic factors: tumor size and nodal involvement. Serial HER-2/neu determinations after surgery seem to be useful in the early diagnosis of recurrence, mainly in patients with HER-2/neu overexpression in tissue, but additional studies are necessary to confirm these results. HER-2/neu sensitivity (proportion of patients with abnormal values) in patients with metastasis is around 40%-45%, with a clear relationship to tissue overexpression and to site (higher in visceral metastases) and number of metastases. The clinical utility of HER-2/neu in patients with advanced disease is mainly for therapeutic monitoring. Likewise, in most of the studies published, a relationship has been found between serum HER-2/neu levels (either pretreatment or at follow-up) with tumor response.

CA 19-9 in pancreatic cancer: retrospective evaluation of patients with suspicion of pancreatic cancer.

CA 19.9 serum levels were prospectively determined in 573 patients admitted to hospital for suspicion of pancreatic cancer. The final diagnosis was 77 patients with no malignancy, 389 patients with pancreatic cancer, 37 neuroendocrine pancreatic cancer, 28 cholangiocarcinomas, 4 gallbladder cancer, 27 ampullary carcinomas, and 11 periampullary carcinomas. CA 19.9 was determined using a commercial assay from Roche Diagnostics, and 37 U/ml was considered as the upper limit of normality. Abnormal CA 19.9 serum levels were found in 27%, 81.5%, 85.7%, 59.3%, 63.6%, and 18.9% of patients with benign diseases, pancreatic cancer, cholangiocarcinomas, and ampullary, periampullary, or neuroendocrine tumors. Significantly higher concentrations of CA 19.9 were found in patients with than in those without malignancy or with neuroendocrine tumors. CA 19.9 serum levels were higher in pancreatic cancer or cholangiocarcinoma than in other malignancies (p < 0.0001). CA 19.9 serum levels were also correlated with tumor stage, treatment (significantly lower concentrations in resectable tumors), and tumor location (the highest in those located in the body, the lowest in those in the tail or uncinate) and site of metastases (highest in liver metastases). A trend to higher CA 19.9 serum concentrations was found in patients with jaundice, but only with statistical significance in the early stages. Using 50 or 100 U/ml in patients with jaundice, CA 19.9 was useful as an aid in the diagnosis of pancreatic cancer (sensitivity 77.9%, specificity 95.9%) as well as tumor resectability in pancreatic cancer with different cutoffs according to tumor location and bilirubin serum levels with specificities ranging from 90% to 100%. CA 19.9 is the tumor marker of choice in pancreatic adenocarcinomas, with a clear relationship with tumor location, stage, and resectability.

Comparison of serum human epididymis protein 4 with cancer antigen 125 as a tumor marker in patients with malignant and nonmalignant diseases.

BACKGROUND: Human epididymis protein 4 (HE4), a precursor of human epididymis protein, has been proposed as a tumor marker for ovarian cancer. We evaluated HE4 in comparison with cancer antigen 125 (CA 125) in healthy individuals and in patients with benign and malignant diseases. METHODS: CA 125 and HE4 serum concentrations were determined in 101 healthy individuals, 535 patients with benign pathologies (292 with benign gynecologic diseases) and 423 patients with malignant diseases (127 with ovarian cancers). CA 125 and HE4 cutoffs were 35 kU/L and 140 pmol/L, respectively. RESULTS: HE4 and CA 125 results were abnormal in 1.1% and 9.9% of healthy individuals and in 12.3% and 37% of patients with benign diseases, respectively. Renal failure was the most common cause of increased HE4 in patients with benign disease, who had significantly higher HE4 concentrations (P = 0.001) than patients with other benign diseases. HE4 showed a higher specificity than CA 125 in patients with benign gynecologic diseases, with abnormal concentrations in 1.3% and 33.2% of the patients, respectively. HE-4 concentrations were abnormal primarily in gynecologic cancer and lung cancer. By contrast, CA 125 was increased in many different nonovarian malignancies, including nonepithelial tumors. A significantly higher area under the ROC curve was obtained with HE4 than with CA 125 for differentiating benign from malignant diseases (0.755 vs 0.643) and in the differential diagnosis of gynecologic diseases (0.874 vs 0.722). CONCLUSIONS: HE4 has significantly higher diagnostic specificity than CA 125, and the combination of CA 125 and HE4 improved the detection of ovarian cancer in all stages and histological types.

HE4 a novel tumour marker for ovarian cancer: comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases.

The aim of this study is to evaluate a new tumour marker, HE4, in comparison with CA 125 and the Risk of Ovarian Malignancy Algorithm (ROMA) in healthy women and in patients with benign and malignant gynaecological diseases. CA 125 and HE4 serum levels were determined in 66 healthy women, 285 patients with benign gynaecological diseases (68 endometriosis, 56 myomas, 137 ovarian cysts and 24 with other diseases), 33 patients with non-active gynaecological cancer and 143 with active gynaecological cancer (111 ovarian cancers). CA 125 and HE4 cut-offs were 35 U/mL and 150 pmol/L, respectively. ROMA algorithm cut-off was 13.1 and 27.7 for premenopausal or postmenopausal women, respectively. HE4, CA 125 and ROMA results were abnormal in 1.5%, 13.6% and 25.8% of healthy women and in 1.1%, 30.2% and 12.3% of patients with benign diseases, respectively. Among patients with cancer, HE4 (in contrast to CA 125) had significantly higher concentrations in ovarian cancer than in other malignancies (p < 0.001). Tumour marker sensitivity in ovarian cancer was 79.3% for HE4, 82.9% for CA 125 and 90.1% for ROMA. Both tumour markers, HE4 and CA 125 were related to tumour stage and histological type, with the lowest concentrations in mucinous tumours. A significantly higher area under the ROC curve was obtained with ROMA and HE4 than with CA 125 in the differential diagnosis of benign gynaecological diseases versus malignant ovarian cancer (0.952, 0.936 and 0.853, respectively). Data from our population indicate that ROMA algorithm might be further improved if it is used only in patients with normal HE4 and abnormal CA 125 serum levels (cancer risk for this profile is 44.4%). ROMA algorithm in HE4 positive had a similar sensitivity and only increases the specificity by 3.2% compared to HE4 alone.

Prospective evaluation of carcinoembryonic antigen (CEA) and carbohydrate antigen 15.3 (CA 15.3) in patients with primary locoregional breast cancer.

BACKGROUND: The utility of carcinoembryonic antigen (CEA) and carbohydrate antigen 15.3 (CA 15.3) as prognostic factors in primary breast cancer is unclear. METHODS: We prospectively studied CEA and CA 15.3 in the sera of 2062 patients with untreated primary breast cancer diagnosed between 1984 and 2008. RESULTS: Increased CEA (>5 microg/L) and CA 15.3 (>30 kU/L) concentrations were found in 12.7% and 19.6% of the patients, respectively, and 1 or both tumor markers were increased in 28% (570 of 2062). Increases in each tumor marker correlated with larger tumor sizes and nodal involvement. Tumor size, estrogen receptor (ER), and CEA were independent prognostic factors by multivariate analysis in the total group [disease free survival (DFS) and overall survival (OS)] as well as in node-positive (NP) and node-negative (NN) patients. Nodal involvement and histological grade were independent prognostic factors in the total group as well as in NP patients. By contrast, adjuvant treatment and CA 15.3 were independent prognostic factors only in NN patients (DFS and OS). All patients with CEA >7.5 microg/L had recurrence during follow-up. Use of both tumor markers allowed discrimination of the groups of risk in T1 NN patients: 56.3% of recurrences were seen when 1 or both tumor markers were increased, whereas only 9.4% of recurrences were seen in T1 NN patients without increases of either marker. CONCLUSIONS: CEA and CA 15.3 are useful prognostic factors in NP and NN breast cancer patients. CEA >7.5 microg/L is associated with a high probability of subclinical metastases.

Evaluation of tumor markers (HER-2/neu oncoprotein, CEA, and CA 15.3) in patients with locoregional breast cancer: prognostic value.

Tumor markers were studied in the sera of 883 untreated patients with primary breast cancer diagnosed between 1989 and 2007. Abnormal human epidermal growth factor receptor 2 (HER-2)/neu levels (>15 ng/mL) were found in 9.5%, carcinoembryonic antigen (CEA) in 15.9%, and cancer antigen (CA) 15.3 in 19.7% of the patients. One or more tumor markers were abnormal in 305 (34.5%) of the 883 studied patients. Significantly higher serum HER-2/neu levels were found in patients with tissue overexpression of this oncoprotein (p < 0.0001). CEA, CA 15.3, and HER-2/neu (only in those patients with tissue overexpression) serum levels were related with tumor stage (tumor size and nodal involvement) and steroid receptors (higher values in estrogen receptor-negative (ER-) tumors). Univariate analysis showed that HER-2/neu serum levels were prognostic factors in disease-free survival (DFS) and overall survival (OS) only in patients with tissue overexpression. Multivariate analysis in 834 patients show that nodal involvement, tumor size, ER, CEA, and adjuvant treatment were independent prognostic factors in DFS and OS. When only patients with HER-2/neu overexpression in tissue were studied, tumor size, nodal involvement, and tumor markers (one or another positive) were independent prognostic factors for both DFS and OS. HER-2/neu serum levels were also an independent prognostic factor, with CEA, ER, and nodes in 106 patients treated with neoadjuvant treatment. In summary, serum HER-2/neu, CEA, and CA 15.3 are useful tools in the prognostic evaluation of patients with primary breast cancer.

Long-term results (three to five years) of the Restenosis Intrastent: Balloon angioplasty versus elective Stenting (RIBS) randomized study.

OBJECTIVES: We sought to analyze the very late outcomes of patients treated for in-stent restenosis (ISR) according to treatment allocation and 10 prespecified variables. BACKGROUND: Long-term results (>2 years) of patients with ISR undergoing repeat coronary interventions are not well established. METHODS: The Restenosis Intrastent: Balloon angioplasty versus elective Stenting (RIBS) randomized study compared these two strategies in 450 patients with ISR. A detailed systematic protocol was used for late clinical follow-up. RESULTS: At one-year follow-up (100% of patients), the event-free survival was similar in the two groups (77% stent implantation [ST] arm, 71% balloon angioplasty [BA] arm, log-rank p = 0.19). Additional long-term clinical follow-up (median 4.3 years, range 3 to 5 years) was obtained in 98.6% of patients. During this time 22 additional patients died (9 ST arm, 13 BA arm), 7 suffered a myocardial infarction (3 ST arm, 4 BA arm), 23 required coronary surgery (11 ST arm, 12 BA arm), and 9 underwent repeat coronary interventions (4 ST arm, 5 BA arm) (nonexclusive events). At four years the event-free survival was 69% in the ST arm and 64% in the BA arm (log-rank p = 0.21). Among the 10 prespecified variables, vessel size > or = 3 mm had a major influence on the clinical outcome at four years, with better results in the ST group (hazard ratio 0.51, 95% confidence interval 0.3 to 0.89, p = 0.016). CONCLUSIONS: Patients with ISR undergoing repeat interventions have a significant event rate at late follow-up. Continued medical surveillance should be continued after one year. Patients with large vessels have a better outcome after repeat stenting.

Pro-gastrin-releasing peptide (proGRP) in patients with benign and malignant diseases: comparison with CEA, SCC, CYFRA 21-1 and NSE in patients with lung cancer.

We studied the specificity and sensitivity of progastrin releasing peptide (ProGRP) in 37 healthy subjects and 195 patients with benign and 149 with malignant diseases other than lung cancer. Likewise, we compared the ProGRP with other tumor markers used in lung cancer (CEA, SCC, CYFRA and NSE) in 187 patients with NSCLC and in 66 SCLC patients. We considered 50 pg/ml, 5 ng/ml, 2 ng/ml, 3.3 ng/ml and 20 ng/ml as the upper limits of normality for ProGRP, CEA, SCC, CYFRA 21-1 and NSE, respectively. Abnormal ProGRP serum levels were found in 10% of patients with benign diseases and in 13% of patients with malignancies other than lung. Renal failure was the main source of false-positive results (51.6%). Slightly raised ProGRP serum levels, excluding renal failure, were found in 4.1% of patients with benign diseases (<80 pg/ml) and in 5% of patients with malignancies other than lung cancer or neuroendocrine tumors (<120 pg/ml). Abnormal levels of ProGRP, NSE, CEA, CYFRA and SCC were found in 30%, 22.5%, 55.6%, 65.2% and 26.7% of NSCLC and in 73%, 64%, 53%, 46% and 4.5% of SCLC, respectively. Tumor marker serum levels were related to histological type and tumor extension, with ProGRP being the most sensitive marker in SCLC, CEA in adenocarcinomas and CYFRA 21-1 in squamous tumors. The most sensitive combinations of tumor markers were ProGRP and NSE in SCLC (88%), and CEA plus CYFRA in NSCLC (82%). In summary, ProGRP is the tumor marker of choice in SCLC and NSE is a complementary tumor marker in this histological type.

CYFRA 21.1 in patients with cervical cancer: comparison with SCC and CEA.

The serum levels of CYFRA 21.1, CEA and SCC were prospectively determined in 156 patients diagnosed with carcinoma of the uterine cervix from 1995 to 2003. Histology revealed squamous cancer in 119 patients, adenocarcinoma in 25 patients and adenosquamous carcinoma in the remaining 12 patients. We considered 3.3 ng/ml, 5 ng/ml and 2 ng/ml as the upper limits of normality for CYFRA 21.1, CEA and SCC, respectively. The sensitivity of CYFRA 21.1, CEA and SCC was 26%, 25% and 43%, respectively, at diagnosis. SCC was clearly related to tumor histology, with significantly higher levels in squamous tumors than in other histological types (p<0.0001). The relationship of CEA with the histological type was poor, but the highest concentrations were found in adenocarcinomas (p=0.034). All the tumor markers were related to well known prognostic factors such as tumor size, tumor stage, parametrial invasion and nodal involvement. Abnormal pretreatment serum levels indicated a high probability (>83%) of parametrial invasion in squamous tumors. Likewise, pretreatment SCC and CYFRA 21.1 serum levels were of prognostic value, with a shorter DFS and OS in patients with abnormal levels. Multivariate analysis indicated that stage, histological grade and parametrial invasion were independent prognostic factors, but not tumor markers. In conclusion, SCC is the tumor marker of choice in squamous tumors and the addition of CEA or CYFRA 21.1 does not significantly increase the sensitivity obtained by using SCC alone.

Pro-gastrin-releasing peptide in patients with benign and malignant diseases.

The specificity and sensitivity of pro-gastrin-releasing peptide (ProGRP) was evaluated in 37 healthy subjects, 197 patients with benign diseases and 310 patients with malignant diseases of different origins. Abnormal ProGRP serum levels (>50 pg/ml) were found in 10% of the patients with benign diseases and in 26.1% of the patients with active cancer. None of the healthy subjects had abnormal ProGRP levels. The benign disease with the highest ProGRP concentration was renal failure, with abnormal values in 51.6% of the patients studied. Excluding patients with renal failure or patients with creatinine levels greater than 1.5 mg/dl, raised ProGRP values (<80 ng/ml) were found in 2.5% (4/160) of patients with benign diseases and in 4.9% of patients with active malignancies other than lung cancer or neuroendocrine tumors (<110 ng/ml). Abnormal ProGRP serum levels were found in 26.2% of patients with non-small cell lung cancer (NSCLC) (mean 40.5 +/- 35.4 pg/ml) and in 76.8% of patients with small cell lung cancer (SCLC) (mean 694 +/- 1,776 pg/ml) (p < 0.001). ProGRP serum levels >300 pg/ml were only found in SCLC patients (41.4%). ProGRP results were related to tumor extension in SCLC (sensitivity in limited disease 58.3%, in extensive disease 95.5%) but not in NSCLC. In summary, renal failure is the most frequent source of false-positive results with ProGRP, and this marker is useful in the histological differential diagnosis of lung cancer.

[Spanish Registry on Cardiac Catheterization and Coronary Interventions. Twelfth official report of the Working Group on Cardiac Catheterization and Interventional Cardiology of the Spanish Society of Cardiology (1990-2002)]. / Registro Español de Hemodinámica y Cardiología Intervencionista. XII informe oficial de la Sección de Hemodinámica y Cardiología Intervencionista de la Sociedad Española de Cardiología (1990-2002).

The results of the Registry of the Working Group on Cardiac Catheterization and Interventional Cardiology of the Spanish Society of Cardiology for 2002 are presented. Data were obtained from 101 centers representing all cardiac catheterization laboratories in Spain; 95 centers performed mainly adult catheterization and 6 carried out only pediatric procedures. In 2002, 97,609 diagnostic catheterization procedures were performed, including 83,667 coronary angiograms, representing a total increase of 5.1% in comparison to 2001. The population-adjusted rate was 2,053 coronary angiograms per 106 inhabitants. Coronary interventions increased by 11% in comparison to 2001, with a total of 34,723 procedures and a rate of coronary interventions of 850 per 106 inhabitants. Coronary stents were the devices used most frequently, with 47,249 implanted in 2002, for a total increase of 20% in comparison to 2001. Stenting accounted for 91.7% of all procedures. Direct stenting was done in 13 768 procedures (43.2%). IIb-IIIa glycoprotein inhibitors were used in 9966 procedures (28.7%). Multivessel percutaneous coronary interventions were performed in 9,830 patients (28%), and ad hoc interventions were done in the course of diagnostic coronary angiography in 26,341 patients (76%).A total of 4,766 percutaneous coronary interventions were done in patients with acute myocardial infarction, representing an increase of 23.9% in comparison to 2001, and accounting for 13.7% of all interventional procedures. Of the noncoronary interventions recorded, we note the decrease in percutaneous mitral valvuloplasties (21.2%) and atrial septal defect closures (11.1%), and the slight increase in pediatric interventions (3.7%). In conclusion, we emphasize the high rate of reporting by laboratories, which allows the Registry to compile data that are highly representative of the activity at cardiac catheterization laboratories in Spain

Registro Español de Hemodinámica y Cardiología Intervencionista. XII Informe Oficial de la Sección de Hemodinámica y Cardiología Intervencionista de la Sociedad Española de Cardiología (1990-2002) / Spanish Registry on Cardiac Catheterization and Coronary Interventions. Twelfth Official Report of the Working Group on Cardiac Catheterization and Interventional Cardiology of the Spanish Society of Cardiology (1990-2002)

Se presentan los resultados del Registro de actividad de la Sección de Hemodinámica y Cardiología Intervencionista de la Sociedad Española de Cardiología del año 2002. Se han recogido datos de 101 centros, la práctica totalidad de los laboratorios del país, de los que 95 realizaron su actividad sobre todo en pacientes adultos y 6 exclusivamente en pacientes pediátricos. Se realizaron 97.609 estudios diagnósticos, con una cifra de 83.667 coronariografías, con un incremento de éstas del 5,1 por ciento respecto al año 2001 y una tasa de 2.053 coronariografías por millón de habitantes. Se efectuaron 34.723 procedimientos de intervencionismo coronario, con un incremento del 11 por ciento respecto al año anterior y una tasa de 850 intervenciones por millón de habitantes. El stent intracoronario fue el dispositivo más empleado, en el 91,7 por ciento de los procedimientos, con 47.249 unidades utilizadas (incremento del 20 por ciento). El stent con carácter directo, sin predilatación, fue utilizado en 13.768 procedimientos, el 43,2 por ciento de los casos. Los inhibidores de la glucoproteína IIb/IIIa fueron utilizados en 9.966 procedimientos (28,7 por ciento). En 9.830 casos (28 por ciento) se efectuó un procedimiento en multivaso, y en 26.341 casos (76 por ciento) la intervención coronaria percutánea se realizó en la misma sesión que la coronariografía diagnóstica. Se llevaron a cabo 4.766 procedimientos de intervencionismo en el infarto agudo de miocardio, lo que supone un 23,9 por ciento más respecto al año 2001 y el 13,7 por ciento del total de las intervenciones coronarias percutáneas. En el intervencionismo no coronario destaca el descenso del número de valvuloplastias mitrales (21,2 por ciento), un descenso en los cierres percutáneos de comunicación interauricular en pacientes adultos (11,1 por ciento), y un ligero incremento de los procedimientos intervencionistas en pacientes en edad pediátrica (3,7 por ciento). Finalmente, destacamos el alto grado de participación de centros en el registro, lo que hace que los datos aquí presentados sean representativos de la actividad hemodinámica en nuestro país (AU)

A randomized comparison of repeat stenting with balloon angioplasty in patients with in-stent restenosis.

OBJECTIVES: This randomized trial compared repeat stenting with balloon angioplasty (BA) in patients with in-stent restenosis (ISR). BACKGROUND: Stent restenosis constitutes a therapeutic challenge. Repeat coronary interventions are currently used in this setting, but the recurrence risk remains high. METHODS: We randomly assigned 450 patients with ISR to elective stent implantation (224 patients) or conventional BA (226 patients). Primary end point was recurrent restenosis rate at six months. Secondary end points included minimal lumen diameter (MLD), prespecified subgroup analyses, and a composite of major adverse events. RESULTS: Procedural success was similar in both groups, but in-hospital complications were more frequent in the balloon group. After the procedure MLD was larger in the stent group (2.77 +/- 0.4 vs. 2.25 +/- 0.5 mm, p < 0.001). At follow-up, MLD was larger after stenting when the in-lesion site was considered (1.69 +/- 0.8 vs. 1.54 +/- 0.7 mm, p = 0.046). However, the binary restenosis rate (38% stent group, 39% balloon group) was similar with the two strategies. One-year event-free survival (follow-up 100%) was also similar in both groups (77% stent vs. 71% balloon, p = 0.19). Nevertheless, in the prespecified subgroup of patients with large vessels (> or =3 mm) the restenosis rate (27% vs. 49%, p = 0.007) and the event-free survival (84% vs. 62%, p = 0.002) were better after repeat stenting. CONCLUSIONS: In patients with ISR, repeat coronary stenting provided better initial angiographic results but failed to improve restenosis rate and clinical outcome when compared with BA. However, in patients with large vessels coronary stenting improved the long-term clinical and angiographic outcome.

[Spanish Registry on Cardiac Catheterization Interventions. 11th official report of the Working Group on Cardiac Catheterization and Interventional Cardiology of the Spanish Society of Cardiology (years 1990-2001)]. / Registro Español de Hemodinámica and Cardiología Intervencionista. XI informe oficial de la sección de hemodinámica y cardiología intervendionista de la Sociedad Española de Cardiología (años 1990-2001).

The results of the Spanish Registry of the Working Group on cardiac catheterization and Interventional Cardiology of the Spanish Society of Cardiology (years 1990-2001) are presented. One-hundred-and-three centers contributed data, all the cardiac catheterization laboratories in Spain; 97 centers performed mainly adult catheterization and 6 carried out only pediatric procedures. In 2001, 95,430 diagnostic catheterization procedures were performed, with 79,607 coronary angiograms, representing a total increase of 8.4% over 2000. The population-adjusted incidence was 1947 coronary angiograms per 106 inhabitants. Coronary interventions increased by 15.4% compared with 2000, with a total of 31,290 procedures and an incidence of coronary interventions of 761 per 106 inhabitants. Coronary stents were the most frequently used devices with 39,356 implanted in 2001, and increase of 33.4% over 2000. Stenting accounted for 88.2% of procedures. Direct stenting was done in 11,280 procedures (40.9%). IIb-IIIa glycoprotein inhibitors were given in 7,012 procedures (22.4%). Multivessel percutaneous coronary interventions were performed in 8,445 cases (27%) and interventions were performed ad hoc during diagnostic study in 23,144 cases (74 %).A total of 3,845 percutaneous coronary interventions were carried out in patients with acute myocardial infarction, an increase of 22.9% over 2000 and 12.3% of all interventional procedures. Among non-coronary interventions, atrial septal defect closure was performed more often (161 cases, a 60% increase over 2000). Pediatric interventions increased by 15.4% (from 817 to 943 cases).Lastly, we would like to underline the high rate of reporting by laboratories, which allowed the Registry to compile data that are highly representative of hemodynamic interventions in Spain.