Concomitant intraductal carcinoma of the prostate and response to hormonal therapy in metastatic prostate carcinoma.

INTRODUCTION AND OBJECTIVE: Most prostate cancers are classified as acinar adenocarcinoma. Intraductal carcinoma of the prostate (IDC-P) is a distinct histologic entity that is believed to represent retrograde spread of invasive acinar adenocarcinoma into prostatic ducts and acini. We have analyzed the impact of IDC-P in hormonal naïve and castration resistant metastatic prostate cancer patients. PATIENTS AND METHODS: We retrospectively evaluated 118 metastatic castration resistant prostate cancer (mCRPC) patients who were initially diagnosed with distant metastases from May 2010 to September 2018. Group 1 patients included 81 metastatic PCa patients with acinar adenocarcinoma and Group 2 included 37 metastatic PCa patients with IDC-P. RESULTS: Mean age at presentation was 76 years (IQR 73.4-78.7) in group 1 and 74 years (68.5-80.6) in group 2. Mean PSA at diagnosis was 619 ng/mL (IQR 85-1113) and 868 ng/mL (IQR 186-1922), respectively. Time to castration resistance was 24.7 months (IQR 16.7-32.7) in group 1 and 10.2 months (IQR 4.2-16.2) in group 2 (P = .007). Time to progression in CPRC patients was: 10.6 months (IQR 5.6-15.6) and at 6.2 months (3.2-9.2), respectively (P = .05). Overall survival was 57.9 months in group 1(CI 95% 56.4-59.5) and 38 months (CI 95% 19.9-48.06) in group 2 (P = .001). In the multivariate analysis, adenocarcinoma subtype was statistically significant P .014, CI 95% (HR 0.058, 0.006-0.56) CONCLUSIONS: IDC-P seems to be a subtype of prostate cancer that is associated with a shorter response to hormonal treatment when compared to acinar adenocarcinoma in metastatic patients. New drugs in CRPC scenario as abiraterone and enzalutamide also obtained less response in IDC-P patients. Once IDC-P is identified, clinicians could extrapolate the relative poor response to hormonal therapy. Consequently, follow-up of these patients in this scenario should be more strict.

[Value of nasal nitric oxide in the diagnosis of primary ciliary dyskinesia]. / Valor del óxido nítrico nasal en el diagnóstico de la discinesia ciliar primaria.

OBJECTIVE: The aim of this study is to report nasal nitric oxide (nNO) values in children with primary ciliary dyskinesia (PCD) and to compare them with nNO values in healthy children, asthmatic children, children with cystic fibrosis and children with post infectious bronchiectasis. PATIENTS AND METHODS: We determined nNO values in 9 children with PCD, 36 asthmatic children, 31 children with cystic fibrosis, 8 children with post infectious bronchiectasis and 37 healthy children. We compared nNO values between these different conditions and calculated sensitivity and specificity of nNO to diagnose PCD. RESULTS: All children with PCD - except one (nNO 348 ppb) - had nNO values below 112 ppb, mean 88 ppb (95%CI 9.6-166). The nNO mean was 898 ppb (95%CI 801-995) in healthy children, 1023 ppb (95%CI 911-1137) in asthmatic children, 438 ppb (95%CI 367-508) in cystic fibrosis children and 361 ppb (95%CI 252-470) in children with post infectious bronchiectasis. The mean concentration of nNO was lower (P<0.05) in PCD patients, compared to the other groups. The measurement of nasal NO in our study population showed, at a cut-off level of < or =112 ppb, a sensitivity of 88.9% and a specificity of 99.1% in the diagnosis of PCD [ROC 0.98 (95%CI 0.94-0.99); P<0.0001; probability ratio 95.1]. CONCLUSIONS: The measurement of nasal NO appears to be a useful tool for screening children for PCD, in which a cut-off level of < or =112 ppb suggests the disease, although nNO above 112 ppb does not exclude PCD.

[Immunohistochemical expression of p53, p21, p16, and cyclin D1 in superficial bladder cancer. A tissue microarray study]. / Expresión inmunohistoquímica de p53, p21, p16 y ciclina D1 en el cáncer de vejiga superficial. Estudio en un soporte de tissue microarray.

INTRODUCTION AND OBJECTIVES: To retrospectively assess the relationship between immunohistochemical expression of p53, p21, p16, and cyclin D1, with recurrence, progression and survival in superficial bladder cancer. METHODS: 163 patients undergoing transurethral resection for superficial bladder cancer between February 1995 and March 2004. Tumor samples were included in a tissue microarray support that was serially sectioned for immunohistochemical staining. Grade and stage associations for each marker were evaluated by the Chi-square test. Assessment of the relationship with recurrence, progression, and survival Kaplan-Meier curves and log-rank test were used. RESULTS: There were no statistically significant differences in marker expression depending on tumor grade and stage, with the exception of Cyclin D1, that was significantly different depending on tumor stage (p=0.030). p21 expression was related to tumor recurrence (p=0.035), progression (p=0.008) and survival (p=0.034). p16 expression was also related to recurrence (p=0.048) and survival (p=0.047), but not to tumor progression (p=0.116). p53 and Cyclin D1 were not statistically associated with tumor recurrence, progression or survival. CONCLUSIONS: In our experience, only p16 and p21 may be useful in the management of superficial bladder tumors, as they are predictors of recurrence and survival in Ta and T1 patients.

[Development of tissue microarray technology (TMA) for immunohistochemical study of molecular expression profiling in prostate cancer (part 1)]. / Desarrollo de un microarray tisular (TMA) para el estudio inmunohistoquímico del patrón de expresión molecular en el cáncer de próstata (parte 1).

Tissue microarray technology (TMA) is nowadays considered as a powerful tool for the high-throughput analysis of molecular expression pattern of cancer. In this manuscript we show the experience of both groups in the design and building of a TMA for the study of protein expression pattern of prostatecancer as well as a summary of the technical points to analyze the results obtained with this technology. Today, different data generated by the immunostained tissues are studied to achieve a molecular profile in different clinical scenarios.

[Histopathologic validation of the tissue-microarray technology of urothelial cancer. Our experience]. / Validación histopatológica de la tecnología tissue-microarray de cáncer de urotelio. Nuestra experiencia.

INTRODUCTION: The array technology offers: a big advance to clinic and basic investigator, it provides a variety of technics (immunohistochemistry, FISH, proteomics) to understand the molecular mechanisms of cancer. It offers scale economy in reagents versus the conventional methods. Array most be ratified because the sample is so reduced. MATERIAL AND METHODS: 52 consecutive cases have been chosen from paraffin blocks of bladder and ureteral cancer which are 5-7 years old, a tissue array has been made; disks have been arranged in lines and columns, in an aleatory way, in order to guide it's reading. It has been evaluated by a pathologist with any relation to specimen selection. RESULTS: 87 sheets ha been obtained. Number 1 has been dyed with HE. Has been discrepancy in 27% of sample's stage. Has not been a discrepancy in histopathologic diagnostic. There is no sample's representation in 11 points (17%). DISCUSSION: Our results offer good results in sample's validation. The sample's antigenicity of tissue is conserved. Array sample's represent a 97%, similarly to all unit of conventional sections of the specimen.

[Oculopharyngeal muscular dystrophy: study of patients from seven Spanish families with different GCG expansions in PABP2 gene]. / Distrofia muscular oculofaríngea: estudio de pacientes pertenecientes a siete familias españolas con diferentes expansiones GCG en el gen PABP2.

INTRODUCTION: Autosomal dominant oculopharyngeal muscular dystrophy (OPMD), with late onset due to ptosis and/or dysphagia, is caused by short (GCG)8-13 triplet-repeat expansions in the polyadenylation binding protein 2 (PABP2) gene, which is localized in chromosome 14q11. The severity of the dominant OPMD as well as the number of expansions that cause the disease are variable. (GCG)9 is mentioned as the most frequent and the genotype/phenotype has still not been well-determined. OBJECTIVE: To describe the type of expansions (GCG)n found in Spanish families with OPMD, establishing if there is variability of them and the possible geno-phenotypical correlations. METHODS: Clinicopathological and molecular studies have been performed in 15 consecutive patients, belonging to seven Spanish families with OPMD. The muscular biopsy study under electronmicroscopy shows intranuclear inclusions (INIs) in all the examined patients (one patient per family). The genetic findings confirm the cause of the disease in all the affected members and in one clinically asymptomatic member of one recently examined family: three families (six, one and one studied members, respectively) present the (GCG)9 expansion, two families (one studied member each one) present the (GCG)10 expansion and two families (one and four studied members respectively) present the (GCG)11 expansion. In these 15 patients with a short GCG expansion causing OPMD, clinical tests for OPMD and a follow-up study of their clinical course have been carefully assessed: in patients with the (GCG)9 expansion major abnormalities appeared in extrinsic ocular mobility and more precocious presentation of limb girld (lumbopelvic preferentially) weakness leading to a great disability before the seventh decade of life under the seventies in some patients and sometimes leading to death. In patients with (GCG)10 and (GCG)11 expansions, eye movements are always preserved and the limb girld muscles weakness did not appear before the seventh decade. No correlation seems to exist between age of onset of the ptosis or dysphagia and the different (GCG)n expansions and the surgical treatment of ptosis, performed in eight patients, showed good results independently of the (GCG)n mutation. CONCLUSIONS: Although further clinical and genetic studies are necessary to establish a strict genotype/phenotype correlation in OPMD, we concluded that the (GCG)9 expansion involve more severe phenotypes than those related to the (GCG)10 or (GCG)11 expansions. Therefore, genetic testing could benefit prognosis in asymptomatic individuals.

[Comparative study of the effect of complete prolonged neoadjuvant hormonal blockade versus standard hormonal blockade]. / Estudio comparativo del efecto del bloqueo hormonal completo neoadyuvante prolongado frente al estándar.

INTRODUCTION: Radical prostatectomy is considered as a curative treatment option in clinically localised prostate cancer patients. Therapy failure is related to positive surgical margins and/or extracapsular extension. The use of neoadjuvant combined androgen blockade (CAB) withdrawal therapy, mainly in cT2 disease, has been shown to decrease positive margin rates. However, CAB therapy remains controversial since there is no proof that this approach confers any benefit in relation to biochemical and clinical disease-free survival. Increasing negatives surgical margins and lower tumour volume (TV) with prolonged CAB therapy has been recently reported. AIM: To analyse the effect of 6 months neoadjuvant CAB therapy in front of 3 months in clinically localised prostate cancer patients submitted to radical prostatectomy. PATIENTS AND METHODS: The pathological stage and TV in forty-two patients treated by 6 months in front of thirty-four patients treated by 3 months were studied. The relationship of clinical stage and initial PSA concentration were analysed. RESULTS: TV was significantly lower in 6 months treated patients (0.97 cc vs. 0.48 cc, p = 0.05). The lowest TV was observed in cT1 patients, but significant differences only were observed in cT2 (1.5 cc vs. 0.86 cc, p = 0.04). No relationship between TV and PSA was obtained. No differences in the incidence of organ-confined disease were seen depending of the CAB length (47% vs. 43%, p = NS). However, increasing incidence of specimen-confined disease was observed in 6 months treated patients (56% vs. 74%, p = 0.05). CONCLUSION: The duration of neoadjuvant CAB can affect both TV and surgical margin status. Lower TV and increasing incidence of specimen-confined disease with 6 months CAB treatment were observed. Patients with palpable disease may be more benefited by this treatment option.

[The role of the electron microscope in the study of muscular diseases]. / Papel de la microscopía electrónica en el estudio de las enfermedades musculares.

AIMS: Our study examines the most significant aspects of electron microscopy in primary and secondary myopathies from the point of view of the day-to-day activity of a general ultrastructural diagnosis laboratory. DEVELOPMENT: We review cases of neuromuscular pathologies in which electron microscopy has contributed to greater accuracy in diagnosis or the understanding of the pathogenic process, and our own data were tested against the existing literature. CONCLUSIONS: As stated in several recent papers, our experience shows that electron microscopy is still a very important tool in the field of muscular diseases and can provide crucial diagnostic data, confirm the results obtained by other techniques or help settle the physiopathological foundations of many of these disorders.

A longer duration of neo-adjuvant combined androgen blockade prior to radical prostatectomy may lead to lower tumour volume of localised prostate cancer.

OBJECTIVES: To analyse tumour volume (TV) in clinically localised prostate cancer patients treated with neo-adjuvant combined androgen blockade (CAB) therapy prior to radical prostatectomy. PATIENTS AND METHODS: Two hundred consecutive patients treated between 1996 and 2000 were retrospectively analysed. Fifty patients underwent radical prostatectomy alone and 45 were treated with CAB for 1-3 months, 83 for 4-6 months and 22 for more than 6 months before surgery. Logistic regression analysis was performed to identify the strongest independent prognosticator of organ-confined disease. RESULTS: No evidence of residual cancer was found in 11 specimens (5.6%). Regarding TV, 20 specimens showed less than 0.1cc, 33 between 0.1 and 0.49cc and 86 more than 0.5cc. Smaller TV was found in CAB-treated patients. Significant correlation was observed between treatment duration and TV. In logistic regression analysis, only CAB duration and TV were significantly correlated with organ-confined disease. CONCLUSIONS: Prominent regressive features and lower TV were found after neo-adjuvant CAB. It seems that more prolonged treatment may lead to greater tumoural regression. Only tumour burden and length of CAB therapy were independent variables significantly correlated with pathologically localised prostate cancer.

[Nephrectomy of a giant hypernephroma (5,150 g)]. / Nefrectomía de un hipernefroma gigante (5.150 g).

We report a giant renal adenocarcinoma (5150 g weight) excised in a 52 years old male. He presented a severe clinical symptoms: serious haematuria, fever (40 degrees C), left flank pain, abdominal discomfort and weight loss (10 kg). The patient underwent left renal artery embolization because of severe anemia (blood transfusion: 4 uu) but haematuria didn't decrease; that's why radical surgery was advised. Until our knowledge this case is the largest removed kidney adenocarcinoma published in the world literature (Medline 1966-2001).

Intercellular junctions, apical differentiation, and infiltrative features in colon cancer: an ultrastructural study. The Colon Cancer Team at IMAS.

Changes in the structure and number of cell junctions have been related to the infiltrative and metastatic potential of tumor cells. Apparently, the loss of cell adhesion should be coordinated with significant changes in the apical and basal cell domains. The authors have performed a sequential ultrastructural study of cells in the superficial, middle, and deep regions of well- and moderately differentiated colon adenocarcinomas. This was to investigate the differences in the organization of different membrane domains among tumor cells in the in situ areas, the advancing, infiltrative edge of the tumors, and the infiltrating zones between these two extreme zones. The results of the study suggest that the organization of these domains is not strictly coordinated, and that, for each infiltration level, both a settling and an infiltrating cell population can be found. These findings could explain the fact that apparently well-differentiated tumors are able to seed distant tissues with individual cells, rather than with well-differentiated glandular aggregates that would hardly be able to reach the vessel lumina without significantly modifying their organization.

[Association between heroin consumption in pregnancy and structural abnormalities of the respiratory cilia in newborn infants]. / Asociación entre el consumo de heroína durante la gestación y anomalías estructurales de los cilios respiratorios en el período neonatal.

OBJECTIVE: To describe structural abnormalities of the respiratory cilia in newborn infants whose mothers consumed heroin during pregnancy. PATIENTS AND METHODS: The medical records of 295 newborn infants whose mothers consumed heroin either throughout or at some time during pregnancy and who were cared for in Hospital del Mar in Barcelona (Spain) between January 1982 and December 1997 were reviewed. Seven infants with neonatal respiratory distress after the withdrawal syndrome period were selected. Diagnoses were established by electron microscopy of nasal mucosa samples. RESULTS: All seven newborns with prolonged neonatal respiratory distress had ultrastructural abnormalities of the ciliary axoneme similar to those of primary ciliary dyskinesia or immotile cilia syndrome. The incidence of this alteration in this series was higher than that in the general population. CONCLUSIONS: These data suggest a possible association between ultrastructural abnormalities of the ciliary axoneme and prolonged neonatal respiratory distress in the infants of heroin-consuming mothers.

Ultrastructural morphometry of nucleoli: potential usefulness for objective grading of clear cell renal cell carcinoma.

The authors attempted to determine the potential prognostic value of several ultrastructural morphometric parameters, including nuclear, nucleolar, and cytoplasmic features, that could be used in the objective and reproducible histological grading of clear cell renal cell carcinoma. Several nuclear and cytoplasmic parameters were assessed by ultrastructural morphometry in 26 consecutive cases of clear cell renal cell carcinoma. The nuclear and nucleolar sizes, the number of nucleoli per nuclear section and the number of marginated nucleoli, Fuhrman's nuclear grade, and Robson's stage were recorded. In addition, the proportion of cytoplasmic components was semiquantitatively estimated and compared to light microscopic appearance. Follow-up ranged from 5 to 15 years (mean = 10 years). Statistical evaluations were performed by means of the Pearson or Spearman correlation coefficient tests, and differences in survival were estimated, using the Mantel-Cox proportional risk method. Differences in survival among patients with a mean nuclear area over and under 160 microm2, and among those with a mean nucleolar area over and under 10 microm2, were statistically significant. (Cutoff points were selected at the median value for both parameters; Mantel-Cox test: chi2 = 7.102, p < .01; and chi2 = 11.096, p < .001, respectively). Fuhrman's nuclear grade (p < .01) and tumor stage at diagnosis (p < .001) were also related to survival. These data suggest that, out of all the ultrastructural morphometric features, nucleolar area is the most useful in the reproducible and accurate grading of clear cell renal cell carcinoma.

[Familial myopathy with desmin storage seen as a granulo-filamentar, electron-dense material without mutation of the alphabeta-crystallin gene]. / Miopatía familiar con sobrecarga de desmina, bajo forma de material granulofilamentoso denso en microscopia electrónica, sin mutación en el gen de la alphabeta-cristalina.

BACKGROUND: Desmin-related myopathy is a familial myopathy and cardiomyopathy. Three subgroups have been outlined, an autosomal dominant (AD) granulofilamentous type with cardiomyopathy, an AD cytoplasmic/spheroid inclusion body type and an autosomic recessive Mallory body-like inclusion type. Recently, in one family belonging to the first group it has been identified a mutation within a gene coding for a chaperone protein, alphabeta-crystallin (CRYAB gene). OBJECTIVE: To describe a Spanish family with a desmin-related myopathy, an AD granulofilamentous type with cardiomyopathy, with a molecular study that does not express any point mutation in the CRYAB gene. PATIENTS, METHODS AND RESULTS: This report concerns a family from southern Spain in which 2 sisters (37 and 44 and 36 years old respectively) present an involvement of skeletal (distal more than proximal) and velo-pharyngeal muscles with onset at the third decade of life and with a rather severe progression, leading soon to bilateral foot drops. The mode of transmission is autosomal dominant. Two other members, the mother and one brother _the latter with hypertrophic cardiomyopathy, atrioventricular block and severe heart failure_, have already died. The electrophysiological study carried out in the sisters shows myogenic patterns with abundant spontaneous activity but not genuine myotonic discharges. Muscle biopsy, also purchased in both sisters, shows myopathic changes, a few rimmed vacuoles in one of them, and several "rubbed-out" fibers or fibers "effacées" visible within the intramyofibrilary network on the enzymatic stainings. The ultrastructural findings in both biopsies reveal a similar pattern of structural damage: an intrasarcoplasmic (specially subsarcolemmal) accumulation of an electro-dense filamentous material arising from the Z-bands and a focal disruption of the myofibrils. Immunohistochemically the subsarcolemmal material stained positively for the intermediate filament protein desmin but other proteins as ubiquitin, tropomyosine and actin were found overexpressed. Genetic studies have excluded myotonic dystrophy, any point mutation in the CRYAB gene, and different markers failled to express linkage to any loci on chromosome 12. The possible mutations in desmin gene are to be studied. CONCLUSION: The distinct intrafamilial phenotype observed in this family confirms the multisystemic character of the desmin-related myopathyies. The genetic results also support the genetic heterogeneity of these myopathies and reinforce the concept that mutations in the desmin gene must be investigated as a cause of the disease.

[Primary ciliary dyskinesia. report of three cases]. / Discinesia ciliar primaria: tres nuevos casos.

Primary ciliary dyskinesia is an autosomal recessive disorder, characterized by total or partial dysfunction of the ciliary or flagellated cells. It is clinically expressed by sinusitis and/or bronchiectasis occasionally associated with sterility in males. We report three cases of immotile cilia syndrome with chronic respiratory symptoms (sinusitis, bronchitis, otitis). The syndrome was associated with bronchiectasis in two cases and by half lobe atelectasis in the third. Diagnosis was established by ultrastructural study of samples from the nasal mucosa, in which the absence of the dynein arms and/or the anomalous disposition of the microtubules was observed. In all three patients great clinical improvement and symptom control were achieved, thereby improving the prognosis of these children. Although the syndrome cannot be cured, as in other chronic pneumopathies, early diagnosis and appropriate treatment can considerably reduce morbidity.

Electron microscopy in pathology articles: a retrospective appraisal.

Electron microscopy (EM) is a valuable standard tool in basic research and teaching. However, its use in diagnosis is limited, either for strategic reasons or budgetary constraints. This means that its many potential applications are more often neglected, either as an ancillary tool, quality control method, or gold standard, to complement, support, or confirm results of pathological studies. To evaluate the use of EM in this setting, the authors analyzed all articles (n = 2,531) in the three top indexed diagnostic pathology journals for a period of 60 months from July 1993 to June 1998. A total of 448 articles in which the use of EM was indicated, according to standard surgical pathology textbooks, were selected. Both the actual and the potential EM content of each article were scored, as follows: zero, illustrative, supportive, gold standard (for confirmation of research results), extensive, and predominant. Of the total number of articles in which EM was indicated, 77% made use of the technique. EM support was lacking most frequently in articles on serosal neoplasms and on new diagnostic strategies (p < .00005). There was no definite trend toward an increase or decrease in the use of EM during the period analyzed. The authors conclude that EM is used in most reports on diagnostic pathology, when it is indicated. However, a small but non-negligible percentage of articles (23%) could benefit from including EM as an ancillary, control, or gold standard method to complement, support, or confirm their results.

Pigmented carcinoma of the breast: an ultrastructural study.

A pigmented skin lesion on a breast removed for carcinoma resembled melanoma by routine light microscopy, but correlation with immunohistochemistry and electron microscopy established that carcinoma cells within the upper dermis were intermingled with a proliferation of non-neoplastic melanocytic cells. Ultrastructurally, the tumor cells possessed desmosomes and intracytoplasmic lumina and mature melanosomes were present in their cytoplasm. The melanocytic cells were identified as melanocytes or melanophages, and it was concluded that the tumor in the skin was a passively pigmented carcinoma and not a melanoma or metaplastic breast carcinoma.

Biology and pathology of the mitochondrion.

The mitochondrion is a highly efficient organelle that is essential for the function of cells. It is currently accepted that mitochondria originated from primitive nonphotosynthetic bacteria that were engulfed by early eucharyotic cells. Most of the normal and pathologic interactions between mitochondria and the cells that contain them can be viewed as symbiotic processes. The main features of mitochondrial structure and function and some of the pathological disorders that involve this organelle are reviewed.

Tumor volume and prostate specific antigen: implications for early detection and defining a window of curability.

PURPOSE: We attempted to determine the relationship between tumor volume and extent of localized prostate cancer, as well as the interrelationships of tumor volume with prostate specific antigen (PSA) level, grade and stage. MATERIALS AND METHODS: Serial whole mount sections from 128 patients who underwent radical prostatectomy were analyzed using a computer assisted volumetric program. Statistical evaluations were performed using logistic and simple regression analyses. RESULTS: The median tumor volume for patients with organ confined disease was significantly lower than for those with extraprostatic extension (1.25 versus 2.94 cc, p < 0.001). A significant incidence (32%) of small volume cancers (0.51 to 1.5 cc) exhibited extraprostatic extension while that of extraprostatic disease increased to 66% for patients with tumor volumes greater than 1.5 cc (p < 0.001). Of men with clinically significant (greater than 0.5 cc, or Gleason score 7 or more) pathological stage B disease 31% had a serum PSA value of 4 ng./ml. or less. Multivariate regression analysis of tumor volume as a function of PSA, grade and stage demonstrated that log PSA had the strongest association with tumor volume. Goodness-of-fit analysis (coefficient of determination) revealed that only 40 to 50% of the PSA levels are explained by tumor volume. CONCLUSIONS: These data suggest that the window of curability for prostate cancer decreases significantly once the tumor grows to a volume greater than 1.5 cc, and that grade and tumor volume are more significantly related to stage than PSA.