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La patología ha ido evolucionando conjuntamente con los avances científicos y tecnológicos, siendo quizá ladisciplina oncológica donde estos avances se han incorporado más rápidamente a la práctica diaria. La patología molecular nace de los avances en la comprensión del genoma humano y la subsecuente descripción de los genomas del cáncer, así como de la rápida simplificación y abaratamiento de las técnicas moleculares. La patología molecular ofrece no solo una descripción más comprehensiva de las características del cáncer, sino que también le otorga al médico encargado del tratamiento, un abanico de debilidades del cáncer que son blancos terapéuticos.

El análisis de la proporción y cantidad de células sanguíneas es una forma muy confiable de evaluar el estado de salud en humanos y otras especies. El objetivo fue estandarizar una metodología para la cuantificación rápida de poblaciones de leucocitos sanguíneos de Oncorhynchus mykiss (trucha arcoíris). Se procesaron muestras de leucocitos obtenidos de la sangre de un grupo de truchas juveniles saludables mantenidas en el laboratorio. Las muestras fueron analizadas empleando el minicitómetro Scepter™ y los resultados fueron contrastados con los obtenidos por citometría de flujo. Los histogramas generados por ambos métodos mostraron un máximo correspondiente a la población de linfocitos/trombocitos y otro a la de monocitos/neutrófilos. No se encontraron diferencias significativas entre los resultados de ambos métodos (P > 0,05). El método con el minicitómetro se utilizó para evaluar muestras de truchas procedentes de una piscigranja, el perfil obtenido mostró la disminución significativa de neutrófilos compatible con los signos clínicos de enfermedad observados en los especímenes evaluados. Estos resultados indican que la metodología aplicada es válida y útil para determinar las concentraciones y proporciones celulares en muestras de sangre en trucha arcoíris y permiten el análisis rápido de su estado de salud. The analysis of the ratio and number of blood cells is a very reliable way to assess the health status in humans and other species. The aim was to standardize a methodology for rapid quantification of blood leukocytes in rainbow trout Oncorhynchus mykiss. Samples of blood leukocytes obtained from a group of healthy juvenile trout maintained in the laboratory were processed. The samples were analyzed using a Scepter™ minicytometer, the results were compared with those obtained by flow cytometry. Histograms generated by both methods showed a peak corresponding to the population of lymphocytes/thrombocytes and one of monocyte/neutrophil. Non-significant differences were found between the results of both methods (P > 0.05). The method employing minicytometer was used to evaluate samples of trout from a fish farm, the profile obtained showed a significant decrease in the neutrophils consistent with clinical signs of disease observed in the tested specimens. These results indicate that the methodology is valid and useful in determining the concentrations and cell proportions in blood samples of rainbow trout and allow rapid analysis of its health status.

Summary Background We previously reported the 5-year results of the phase 3 IBCSG 23-01 trial comparing disease-free survival in patients with breast cancer with one or more micrometastatic (≤2 mm) sentinel nodes randomly assigned to either axillary dissection or no axillary dissection. The results showed no difference in disease-free survival between the groups and showed non-inferiority of no axillary dissection relative to axillary dissection. The current analysis presents the results of the study after a median follow-up of 9·7 years (IQR 7·8–12·7). Methods In this multicentre, randomised, controlled, open-label, non-inferiority, phase 3 trial, participants were recruited from 27 hospitals and cancer centres in nine countries. Eligible women could be of any age with clinical, mammographic, ultrasonographic, or pathological diagnosis of breast cancer with largest lesion diameter of 5 cm or smaller, and one or more metastatic sentinel nodes, all of which were 2 mm or smaller and with no extracapsular extension. Patients were randomly assigned (1:1) before surgery (mastectomy or breast-conserving surgery) to no axillary dissection or axillary dissection using permuted blocks generated by a web-based congruence algorithm, with stratification by centre and menopausal status. The protocol-specified primary endpoint was disease-free survival, analysed in the intention-to-treat population (as randomly assigned). Safety was assessed in all randomly assigned patients who received their allocated treatment (as treated). We did a one-sided test for non-inferiority of no axillary dissection by comparing the observed hazard ratios (HRs) for disease-free survival with a margin of 1·25. This 10-year follow-up analysis was not prespecified in the trial's protocol and thus was not adjusted for multiple, sequential testing. This trial is registered with ClinicalTrials.gov, number NCT00072293. Findings Between April 1, 2001, and Feb 8, 2010, 6681 patients were screened and 934 randomly assigned to no axillary dissection (n=469) or axillary dissection (n=465). Three patients were ineligible and were excluded from the trial after randomisation. Disease-free survival at 10 years was 76·8% (95% CI 72·5–81·0) in the no axillary dissection group, compared with 74·9% (70·5–79·3) in the axillary dissection group (HR 0·85, 95% CI 0·65–1·11; log-rank p=0·24; p=0·0024 for non-inferiority). Long-term surgical complications included lymphoedema of any grade in 16 (4%) of 453 patients in the no axillary dissection group and 60 (13%) of 447 in the axillary dissection group, sensory neuropathy of any grade in 57 (13%) in the no axillary dissection group versus 85 (19%) in the axillary dissection group, and motor neuropathy of any grade (14 [3%] in the no axillary dissection group vs 40 [9%] in the axillary dissection group). One serious adverse event (postoperative infection and inflamed axilla requiring hospital admission) was attributed to axillary dissection; the event resolved without sequelae. Interpretation The findings of the IBCSG 23-01 trial after a median follow-up of 9·7 years (IQR 7·8–12·7) corroborate those obtained at 5 years and are consistent with those of the 10-year follow-up analysis of the Z0011 trial. Together, these findings support the current practice of not doing an axillary dissection when the tumour burden in the sentinel nodes is minimal or moderate in patients with early breast cancer. Funding International Breast Cancer Study Group.

Jurassic World (Colin Trevorrow, 2015) is progressive about some things (capitalism, managerialism) and reactionary about others (gender, race, animals). It is also fun entertainment. What underpins all this is anxiety about proper procreation. This fuels the film's perceptions of economic enterprise and the natural order and also provides the source or reassurance so necessary for having fun. But perhaps there is just a hint that the reassurance itself is insecure.

Background: Cisplatin cures over 80% of testicular germ cell tumours (TGCTs), and nucleotide-excision repair (NER) modifies the sensitivity to cisplatin. We explored the association between NER proteins and their polymorphisms with cisplatin sensitivity (CPS) and overall survival (OS) of patients with non-seminomatous (ns)-TGCTs. Methods: The expression of ERCC1 and XPA and the presence of γH2AX were evaluated in cancer cell lines and in fresh ns-TGCTs. The ERCC1 protein was also determined in ns-TGCTs. The differences between CPS and non-CPS cell lines and patients were analysed by Student's t- or χ2-tests. The differences in OS were analysed using the log-rank test, and the hazard ratios (HRs) were calculated using the Cox model. Results: High ERCC1 expression was observed in the non-CPS cells, and both ERCC1 and γH2AX expressions were augmented after cisplatin treatment. Increased ERCC1 expression was also identified in non-CPS patients. Neither polymorphism was associated with either CPS or OS. The presence of ERCC1 was associated with non-CPS (P=0.05) and adjusted in the prognosis groups. The HR in ERCC1-negative and non-CPS patients was >14.43, and in ERCC1-positive and non-CPS patients the HR was >11.86 (P

Breast cancer is the most common malignant tumor in women worldwide. In recent years, there has been an increasing use of immunohistochemistry (the process of detecting the expression of certain proteins in cytological images) to obtain useful information for diagnosis. This paper presents an efficient algorithm that automatically detects breast cancer cell nuclei and divides them into two groups: those that express the ER marker and those that do not. First, the areas that belong to the carcinoma are automatically identified. Then, the algorithm evaluates features such as size and shape to correctly segment the nuclei in these fields. Finally, the Fuzzy C-Means algorithm is used to classify the detected nuclei. The method proposed was evaluated with a set of 10 images which contained 4093 cell nuclei. The algorithm correctly identified 93.1% of the nuclei, and sensitivity and specificity of the classification were 95.7% and 93.2% respectively.

Six hundred thirty-nine patients with CIN on referral Pap were evaluated cytocolposcopically at the first visit and decided whether to be treated the same day or not. One hundred ninety-two patients (30%) were considered negative. Follow-up evidenced later appearance of CIN in five of them. One hundred fifty-three (24%) were candidates for delayed treatment due to conditions contraindicating same-day treatment. Two hundred ninety-four patients (46%) were randomly allocated in LEEP (149) or excisional laser (145) arms, and treated the same day under local anesthesia. Both arms were comparable. There were three microinvasive carcinomas diagnosed in the surgical specimen. LEEP was faster and produced less bleeding than laser, although required a mean of four slices to remove the lesion. Arterial hypertension after anesthetic infiltration was detected in 26% of cases. Two intraoperative and two delayed bleeders required surgery. The size of lesion and surgical defect were larger than those reported in the literature. Margins were involved in 8 patients (2.7%). Only 4.7% (7/149) of patients randomized to LEEP and 3.4% (5/145) with excisional laser had persistent or recurrent CIN on follow-up. Factors predisposing to failure included depth of surgical defect, grade of lesion, and operator's expertise. With this approach, 69% of patients referred for cytology of CIN were adequately managed in the first visit, which contrasts to classical management that reaches the state of treatment in 30% of patients. LEEP appears to be faster, less costly, and requires less expertise. Its use in conjunction with adequate screening is recommended for developing countries.

Molecular classification is an excellent prognostic and predictive method in breast cancer (BC). In this study. we evaluated differences in clinicopathologic features and overall survival (OS) in four BC molecular subtypes: luminal A, luminal B, basal cell-like, and HER2/neu.Immunohistochemical evaluation of estrogen receptor (ER), progesterone receptor (PgR), and HER2 was performed using a Peruvian hospital database of 1198 BC patients who were diagnosed between 2000 and 2002. Overall survival was calculated.Out of 1198 patients with invasive BC, 49.3% were luminal A; 13.2%, luminal B; 21.3%, basal-like; and 16.2%, HER2. The mean of age at diagnosis was 51.5 years for luminal A; 49.6 for luminal B; 49.5 for basal-like; and 49.4 for HER2. The HER2 subtype showed 63.7% positive lymph nodes, 42.3% stage III and 9.7% stage IV cases. Basal subtypes showed the highest prevalence of a poorly differentiated phenotype (70.3%). Average follow-up was 60 months. Five-year OS was significantly different between all 4 groups (P.0001); luminal A had the highest OS, followed by luminal B, basal-like; and HER2. Results are compared with other population studies.This study shows significant differences between the distribution of molecular subtypes and clinicopathologic features. Immunohistochemistry is useful in the clinical management of BC patients.

11066 Background: TLR4 is typically activated by gram (-) bacterial lipopolysaccharide; however, recent reports describe that paclitaxel could trigger the TLR4 signaling pathway leading to chemothe...

4555 Background: Cisplatin-based chemotherapy cures over 80% of testicular germ cell tumors (TGCTs); nucleotide-excision repair (NER) modifies the sensitivity to cisplatin. In this work we explored the association between NER-proteins and their polymorphisms (SNPs) with cisplatin-sensitivity (CPS) and overall survival (OS) of patients with advanced non-seminomatous (ns)-TGCTs treated with bleomycin-etoposide-cisplatin (BEP). Methods: ERCC1, XPA-expression and gammaH2AX-presence, were tested in cisplatin-treated cancer cell lines. ERCC1 and XPA-expression were also analyzed in ns-TGCTs by qPCR. Immunohistochemistry was performed to detect ERCC1 protein in ns-TGCTs specimens. The SNPs were genotyped by PCR-RFLPs technique. Results: High basal ERCC1-expression was observed in non-CPS cancer cell lines; ERCC1-expression augmented further, as well as gammaH2AX, after cisplatin-treatment. Basal ERCC1 expression increases in the non-CPS patients in Mexican and Peruvian populations compared to CPS patients (p14.43 and in patients ERCC1-positive and non-CPS the HR was >11.86 (p

Objectives To evaluate the safety and efficacy of low-power slow-heating diode laser-induced photocoagulation of prostatic tissue for treatment of benign prostatic hyperplasia, we conducted a series of acute and chronic studies using a diode laser (810 nm) to irradiate human prostate. Methods The study included 6 patients undergoing radical prostatectomy because of malignancy. Laser radiation to the prostate was given transurethrally, in a noncontact mode, at the time of the procedure in 2 patients (acute group): 10 W for 300 seconds on the right side of the prostate and 15 W for 180 seconds on the left. In the remaining 4 patients (chronic group), laser radiation was given at 1, 7, 10, and 12 weeks prior to the prostatectomy. Results In the acute group the average depth of coagulation was 8.5 and 9.0 mm for the laser regimens of 15 W for 180 seconds and the 10 W for 300 seconds, respectively. In the chronic group, the average depth of coagulation was 8.9 mm for both laser regimens studied. In the acute group, there was an ill-defined hemorrhagic ring at the periphery of the lesion. At 1 week, an intact necrotic coagulum was present. At 7 weeks, some of the coagulated tissue had already sloughed off. Longer follow-up at 10 and 12 weeks demonstrated formation of a well-defined cavity with mostly re-epithelialized surface. Conclusions Our findings suggest that noncontact diode laser (810 nm) irradiation can induce in the human prostate significant coagulation necrosis followed by sloughing of tissue and cavitation of the prostatic urethra.

e11066 Background: PI3K signaling pathway is responsible for balancing cell survival and apoptosis, and plays an important role in the pathogenesis and progression of human breast cancers. Alterations in this pathway could influence the response to targeted therapy. Our aim is to know the frequency of mutations in the PIK3CA gene in HER2+, operable breast tumors in an Andean population. Methods: We include a cohort of 59 patients with HER2+ surgically resected breast cancer that received adjuvant anti-HER2 targeted therapy at the Instituto Nacional de Enfermedades Neoplásicas. Genomic DNA was extracted from Paraffin embedded-formalin fixed tumor samples and mutational status of PIK3CA gene was using PCR-based DNA sequencing Results: At the current date, the median of follow-up in our cohort is 2.4 years and two recurrences have been registered. Four samples were not evaluable for molecular analysis. Mutation in PIK3CA gene was detected in 12 cases (20.3%). In cases where PIK3CA mutation was detected, eight cases (66.7%) had mutations in exon 9 (A1634C/E545A in 6 cases; G1624A/E542K in 1 case and G1633A/E545K in 1 case). Four cases (33.3%) had exon 20 mutated (A3140G/H1047R in all cases). There was not coexistence of mutations in both exons. One case of tumor recurrence had mutation in exon 9. Conclusions: We found similar rates of PIK3CA mutations as described previously to HER2+, breast tumors. A longest follow upwill show the prognostic value of PIK3CA status in our cohort treated with targeted anti-HER2 therapy. [Table: see text]

Prediction of high probability of survival from standard cancer treatments is fundamental for individualized cancer treatment strategies.To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer.Prospective multicenter study conducted from June 2000 to March 2010 at the M. D. Anderson Cancer Center to develop and test genomic predictors for neoadjuvant chemotherapy. Patients were those with newly diagnosed ERBB2 (HER2 or HER2/neu)-negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline-based regimens (then endocrine therapy if estrogen receptor [ER]-positive). Different predictive signatures for resistance and response to preoperative (neoadjuvant) chemotherapy (stratified according to ER status) were developed from gene expression microarrays of newly diagnosed breast cancer (310 patients). Breast cancer treatment sensitivity was then predicted using the combination of signatures for (1) sensitivity to endocrine therapy, (2) chemoresistance, and (3) chemosensitivity, with independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response.Distant relapse-free survival (DRFS) if predicted treatment sensitive and absolute risk reduction ([ARR], difference in DRFS between 2 predicted groups) at median follow-up (3 years).Patients in the independent validation cohort (99% clinical stage II-III) who were predicted to be treatment sensitive (28%) had 56% (95% CI, 31%-78%) probability of excellent pathologic response and DRFS of 92% (95% CI, 85%-100%), with an ARR of 18% (95% CI, 6%-28%). Survival was predicted in ER-positive (30% predicted sensitive; DRFS, 97% [95% CI, 91%-100%]; ARR, 11% [95% CI, 0.1%-21%]) and ER-negative (26% predicted sensitive; DRFS, 83% [95% CI, 68%-100%]; ARR, 26% [95% CI, 4%-48%]) subsets and was significant in multivariate analysis. Other genomic predictors showed paradoxically worse survival for patients predicted to be responsive to chemotherapy.A genomic predictor combining ER status, predicted chemoresistance, predicted chemosensitivity, and predicted endocrine sensitivity identified patients with high probability of survival following taxane and anthracycline chemotherapy.

Hruska et al. (1980) reported that hypophysectomy prevented the onset of dopamine receptor supersensitivity. We have repeated this investigation administering haloperidol (0.75 mg/day) or sulpiride (2 X 15 mg/day) or saline for 17 days, followed by a 3 day drug washout period, to sham-operated or hypophysectomised rats. Haloperidol or sulpiride pretreatment caused an enhancement of apomorphine-induced stereotyped behaviour and increased the number of specific striatal [3H]spiperone binding sites (Bmax) in both hypophysectomised and sham-operated animals compared to their respective saline controls. We conclude that hypophysectomy does not prevent the onset of striatal dopamine receptor supersensitivity induced by repeated neuroleptic treatment in the rat.

1 Luteinizing hormone releasing hormone (50 ng/100 g body weight) was injected into male and female rats which had been anaesthetized with either urethane (1.2 g/kg) or pentobarbitone (45 g/kg) for 15, 100 or 240 min and serial blood samples were taken for estimation of plasma luteinizing hormone concentrations. 2 The rats anaesthetized with urethane tended to show a greater response to the releasing hormone than those given pentobarbitone. 3 The magnitude of the responses observed in male rats and in female rats anaesthetized with pentobarbitone did not change as the period of anaesthesia prior to injection of releasing hormone was lengthened from 15 min to 4 h. By contrast, in the groups of female rats anaesthetized with urethane the magnitude of the response to luteinizing hormone releasing hormone was related to the length of pretreatment anaesthesia. Thus both dioestrous and pro-oestrous rats given releasing hormone only 15 min after the onset of urethane anaesthesia had significantly (P less than 0.001 and less than 0.05 respectively) higher concentrations of luteinizing hormone (LH) in the plasma than rats treated with the releasing hormone after 240 min of anaesthesia. 4 These effects were not due to a differential action of the anaesthetics on the mechanism for clearing LH from the plasma.

Neuroleptic drugs, on repeated administration, increase plasma prolactin levels and induce behavioural and biochemical changes suggesting supersensitivity of striatal dopamine receptors. It has been suggested that the increase in plasma prolactin is responsible for the change in striatal dopamine receptors. We now find that repeated administration of haloperidol (5 mg/kg i.p.) for 21 days, followed by a 3 day drug-washout period, caused a 12-fold increase in circulating prolactin concentration in samples taken 1 h after the last injection. Haloperidol treated animals also exhibited an exaggerated stereotyped response to apomorphine 0.0625–0.5 mg/kg s.c.) and an increase in striatal dopamine receptor numbers labelled by [ 3 H]spiperone. Administration of the same dose of domperidone or sulpiride (5 mg/kg i.p., 21 days), compounds which penetrate poorly into brain, also elevated plasma prolactin levels, but failed to alter cerebral dopamine function. Our findings indicate that neuroleptic-induced elevations in plasma prolactin levels are not responsible for the induction of cerebral dopaminergic supersensitivity.