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.

A randomized phase II trial of platinum salts in basal-like breast cancer patients in the neoadjuvant setting. Results from the GEICAM/2006-03, multicenter study.

Chemotherapy remains as the only systemic treatment option available for basal-like breast cancer (BC) patients. Preclinical models and several phase II studies suggested that platinum salts are active drugs in this BC subtype though there is no randomized study supporting this hypothesis. This study investigates if the addition of carboplatin to a combination of an alkylating agent together with anthracyclines and taxanes is able to increase the efficacy in the neoadjuvant treatment context. Patients with operable breast cancer and immunophenotypically defined basal-like disease (ER-/PR-/HER2- and cytokeratin 5/6+ or EGFR+) were recruited. Patients were randomized to receive EC (epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) for 4 cycles) followed either by D (docetaxel 100 mg/m(2) × 4 cycles; EC-D) or DCb (docetaxel 75 mg/m(2) plus carboplatin AUC 6 × 4 cycles; EC-DCb). The primary end point was pathological complete response (pCR) in the breast following the Miller and Payne criteria. Ninety-four patients were randomized (46 EC-D, 48 EC-DCb). pCR rate in the breast was seen in 16 patients (35 %) with EC-D and 14 patients (30 %) with EC-DCb (P value = 0.61). pCR in the breast and axilla was seen in 30 % of patients in both arms. The overall clinical response rate was 70 % (95 % CI 56-83) in the EC-D arm and 77 % (95 % CI 65-87) in the EC-DCb arm. Grade 3/4 toxicity was similar in both arms. The addition of carboplatin to conventional chemotherapy with EC-D in basal-like breast cancer patients did not improve the efficacy probably because they had already received an alkylating agent. These findings should be taken into consideration when developing new agents for this disease.

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.

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.

Cerebral mucormycosis in two cases of acquired immunodeficiency syndrome.

We describe two patients with isolated cerebral mucormycosis and acquired immunodeficiency syndrome (AIDS). Their clinical course was rapid and fatal; early diagnosis and treatment with amphotericin B did not prevent a fatal outcome in both cases. Isolated cerebral mucormycosis has not (to our knowledge) been reported previously in patients with AIDS. Mucormycosis should be included in the differential diagnosis of central nervous system infections in intravenous drug abusers with AIDS. A brain biopsy is needed for the diagnosis of mucormycosis.

Prognostic value of DNA quantification in early epithelial ovarian carcinoma.

OBJECTIVE: To evaluate the prognostic value of flow cytometric DNA quantification and immunohistochemical expression of c-erbB-2 and p53, and traditional clinicopathologic variables in stages I-II invasive epithelial ovarian cancer. METHODS: We retrospectively reviewed 77 cases of stages I-II ovarian cancer after comprehensive surgical staging. We recorded anthropometric data (age, menopausal status, weight loss, Karnofsky index) and pathologic variables (tumor size, bilaterality, capsular status, ascites, peritoneal cytology, histologic type, and grade). In 72 cases representative paraffin-embedded samples were available for DNA quantification and immunohistochemical evaluation of c-erbB-2 and p53 overexpression. Most women (87%) had received cisplatin-based adjuvant chemotherapy. RESULTS: The median follow-up was 90 months (range 50-148 months). The 6-year overall disease-free survival rate was 70% (95% confidence interval [CI] 60%, 81%), and overall global survival was 77% (95% CI 67%, 87%). Multivariable analysis using Cox stepwise regression identified DNA content (odds ratio [OR] 12.3; P <.001) and stage (OR 1.4, P =.09) as independent poor prognosis factors for relapse, and DNA content (OR 9.8, P <.001) as the main independent factor for survival. In stepwise discriminant analysis the combination of DNA content and stage provided a correct prediction of relapse in 78% of women. CONCLUSION: Flow cytometric DNA quantification was the main independent prognostic factor of relapse and survival in these women with stages I-II epithelial ovarian cancer.

[Epidermal growth factor receptor in non-small cell cancer of the lung]. / Receptor para el factor de crecimiento epidérmico en el cáncer de pulmón no microcítico.

In this study we determined the concentration of epidermic growth factor receptors (EGFr) in non-small cell carcinoma of the lung (NSCCL) and analyzed its relation to the anatomical, pathological and clinical factors of these neoplasms. The concentration of EGFr in 62 tumor tissue samples was 9.9 +/- 14 fmol/mg, higher than that found in 14 tissue samples from cases of spontaneous pneumothorax (3.9 +/- 3.6 fmol/mg) (p = 0.005). EGFr concentration in lung tissue with no signs of neoplasm was 6.5 +/- 10 fmol/mg. In 21 (33%) cases of NSCCL the concentration exceeded the normal threshold of 10 fmol/mg. EGFr concentration was higher in cases of epidermoid carcinoma than in other tissue samples (p = 0.042). No significant association was found between EGFr levels and status of tumor node metastasis, degree of differentiation and mitotic index. The probability of remaining free of tumor recurrence and of survival after 24 months among patients whose tumoral EGFr concentration was below 10 fmol/mg was 34 and 40%, respectively. The rates for patients with concentrations that exceeded the threshold were 20% (p = 0.32) and 25% (p = 0.26), respectively. The results seem to indicate that the study of EGFr concentration alone does not yield practically important information for the management of patients with NSCCL who have undergone surgery. The concentration of EGFr marks degree of differentiation in NSCCL and has prognostic implications derived from its association with other factors.

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.

Early lymphocyte activation in the synovial microenvironment in patients with osteoarthritis: comparison with rheumatoid arthritis patients and healthy controls.

Osteoarthritis (OA) is largely considered to be a non-inflammatory disease, although there is compelling evidence that subclinical inflammation is a common event, even in the absence of acute inflammatory flares. In this study we analyze, by means of CD5 and CD69 expression, the infiltration and early activation of CD5+cells, mostly lymphocytes, in both synovial membrane and synovial fluid from advanced OA patients and compare them with samples from patients with rheumatoid arthritis and healthy controls. The number of infiltrating CD5+ cells in both synovial membrane and synovial fluid from patients with advanced OA was significantly reduced as compared with rheumatoid arthritis patients. However, synovial membrane and synovial fluid CD5+ cells on OA exhibited a phenotype with evidence of recent activation comparable to that observed in RA.

Human parvovirus B19, varicella zoster virus, and human herpes virus 6 in temporal artery biopsy specimens of patients with giant cell arteritis: analysis with quantitative real time polymerase chain reaction.

OBJECTIVE: To evaluate the role of parvovirus B19 (B19), varicella zoster virus (VZV), and human herpes virus 6 (HHV-6) in the aetiopathology of giant cell arteritis (GCA). METHODS: Temporal artery biopsy specimens from 57 patients with GCA and 56 controls were investigated. DNA was obtained by biopsy, and quantitative real time polymerase chain reaction assay performed to establish the prevalence and viral load of B19, VZV, and HHV-6. Amplification of the human beta-globin gene was used as internal positive control. RESULTS: (a) B19 was detected in 31/57 (54%) patients (median viral load 45.2 (25th-75th centiles 0-180.2) copies/microg DNA) v 21/56 (38%) controls (median viral load 0 (0-66.7) copies/microg of DNA; p = 0.07 for DNA prevalence, p = 0.007 for viral load. Among 31 B19 positive samples, 21 (68%) patients with biopsy proven GCA had >10(2) B19 copies/microg of DNA v 5/21 (24%) controls; p = 0.001. (b) No significant difference was found for VZV (p = 0.94 for DNA prevalence; p = 0.76 for viral load) and HHV-6 (p = 0.89 for DNA prevalence; p = 0.64 for viral load) in the GCA group compared with controls. CONCLUSION: B19 may have a role in the aetiopathology of GCA, particularly in those patients with high viral load; no evidence was found for VZV and HHV-6.

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.

Mechanisms of CD23 hyperexpression on B cells from patients with rheumatoid arthritis.

OBJECTIVE: To analyze the mechanisms involved in the characteristic hyperexpression of CD23 on peripheral blood B cells from patients with rheumatoid arthritis (RA). METHODS: Peripheral blood mononuclear cells (PBMC) were obtained from patients with active disease and activated during 18 h with an anti-CD3 monoclonal antibody in the presence or absence of blocking antibodies to CD154 or CD40. PBMC were further purified by rosetting and CD23 expression was assessed on B cells by flow cytometry after double staining (CD19/CD23). Lymphocytes were also isolated from synovial fluid (SF). CD154 expression was analyzed on PB or SF CD4+ T cells after double staining (CD4/CD154) by flow cytometry at basal conditions and after different stimuli [anti-CD3 or phorbol myristic acetate (PMA) plus ionomycin]. Co-culture experiments between SF and PB cells were performed to analyze the involvement of the CD40-CD154 interaction on CD23 expression. CD154 and CD23 expression was also analyzed on synovial membrane by immunohistochemical techniques. RESULTS: A high proportion of activated CD23 B cells was detected in patients with RA. Blocking experiments with both anti-CD40 and anti-CD154 Mab showed a significant reduction in the proportion of PB B cells expressing CD23. Following activation with anti-CD3 Mab or PMA plus ionomycin, CD154 expression was mainly induced on PB CD4+ T cells. In co-culture experiments, SF T cells were more efficient than PB T cells in inducing CD40 dependent CD23 expression on PB B cells. In addition, CD4+ T cells from synovial membrane clearly expressed CD154. CONCLUSION: Our results establish a link between CD154-CD40 pathway and CD23 expression on PB B cells from patients with RA. T cells from the synovial microenvironment were active participants in this CD23 expression, presumably in the context of cell recirculation.

Quantitative analysis of carcinoembryonic antigen, squamous cell carcinoma antigen, CA 125, and CA 50 cytosolic content in non-small cell lung cancer.

BACKGROUND: The cytosolic content of carcinoembryonic antigen (CEA), squamous cell carcinoma (SCC), CA 125, and CA 50 antigens in non-small cell lung cancer (NSCLC) is analyzed in this study. The aim was to ascertain the relationship between tumor marker content and the clinicopathologic aspects of this neoplasm. METHODS: Lung tissue samples were obtained at the time of surgery from 75 patients with NSCLC patients (samples of tumor and unaffected tissue) and 29 subjects with idiopathic pneumothorax. All determinations were performed on cytosols obtained from lung specimens. CEA and CA 125 were determined by enzyme immunoassay, SCC antigen by radioimmunoassay, and CA 50 by fluoroimmunoassay. Tumor marker content was analyzed by TNM stage, histologic type, tumor grade, and number of atypias. RESULTS: The concentration of the four markers was significantly higher in cytosol obtained from neoplastic tissue. Frequency of elevated levels of CEA was higher in adenocarcinoma (87% cases expressing high levels of the marker), SCC antigen in epidermoid carcinoma (65% expressing high levels), and CA 125 in large cell carcinomas (100% expressing high levels). No association was found between TNM stage and cytosol concentration for any of the four markers. CEA exhibited significantly greater concentration in well differentiated tumors, whereas this was true of CA 125 in poorly differentiated tumors. CA 125 content was higher in tumors with more atypia. CONCLUSIONS: Cytosolic quantification of tumor markers may be an adjuvant mechanism to evaluate histologic subtypes of non-small cell lung cancer and identification of tumors with poorly differentiated features.

Survival to oral cancer. A study of clinical risk markers with independent prognostic value.

BACKGROUND: The aims of this study have been to describe survival to oral cancer and to identify clinical variables with independent influence on its prognosis before treatment. METHODS: 94 oral cancer patients treated during 1991-99 entered the study. The variables considered were: age, sex, location of the lesion, clinical presentation, symptoms, TNM classification, months elapsed since treatment and ploidy pattern. A descriptive study of the data was performed, along with a survival analysis using Kaplan-Meier curves (log rank test for comparison among curves) and single and multivariate Cox regression. RESULTS: Multivariate analysis recognized a prognostic value for the age of the patient (OR = 1.06; CI95%: 1.02-1.09) and also for tumour size. Tumour stage resulted also selected, but its predictive value was lower than size's, so it was excluded from the predictive model. No statistically significant differences in terms of survival were identified on the rest of variables considered in the study. CONCLUSIONS: This study suggests the need for considering age and tumour size as the most relevant clinical variables for predicting survival to oral cancer at the time of diagnosis.

[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.