Structural differences in the diaphragm of patients following controlled vs assisted and spontaneous mechanical ventilation.

PURPOSE: Ventilator-induced diaphragm dysfunction or damage (VIDD) is highly prevalent in patients under mechanical ventilation (MV), but its analysis is limited by the difficulty of obtaining histological samples. In this study we compared diaphragm histological characteristics in Maastricht III (MSIII) and brain-dead (BD) organ donors and in control subjects undergoing thoracic surgery (CTL) after a period of either controlled or spontaneous MV (CMV or SMV). METHODS: In this prospective study, biopsies were obtained from diaphragm and quadriceps. Demographic variables, comorbidities, severity on admission, treatment, and ventilatory variables were evaluated. Immunohistochemical analysis (fiber size and type percentages) and quantification of abnormal fibers (a surrogate of muscle damage) were performed. RESULTS: Muscle samples were obtained from 35 patients. MSIII (n = 16) had more hours on MV (either CMV or SMV) than BD (n = 14) and also spent more hours and a greater percentage of time with diaphragm stimuli (time in assisted and spontaneous modalities). Cross-sectional area (CSA) was significantly reduced in the diaphragm and quadriceps in both groups in comparison with CTL (n = 5). Quadriceps CSA was significantly decreased in MSIII compared to BD but there were no differences in the diaphragm CSA between the two groups. Those MSIII who spent 100 h or more without diaphragm stimuli presented reduced diaphragm CSA without changes in their quadriceps CSA. The proportion of internal nuclei in MSIII diaphragms tended to be higher than in BD diaphragms, and their proportion of lipofuscin deposits tended to be lower, though there were no differences in the quadriceps fiber evaluation. CONCLUSIONS: This study provides the first evidence in humans regarding the effects of different modes of MV (controlled, assisted, and spontaneous) on diaphragm myofiber damage, and shows that diaphragm inactivity during mechanical ventilation is associated with the development of VIDD.

Health-related quality of life in men with prostate cancer undergoing active surveillance versus radical prostatectomy, external-beam radiotherapy, prostate brachytherapy and reference population: a cross-sectional study.

BACKGROUND: The purpose of this study is to describe Health-Related Quality of Life (HRQoL) of localized prostate cancer patients in an Active Surveillance (AS) program, and to compare them with those undergoing radical prostatectomy (RP), external-beam radiotherapy (XRT) and brachytherapy (BT). METHODS: Multi-institutional pooled cross-sectional analysis on patients in an AS protocol: < 75 years old; pathologically confirmed LPC (maximum of three positive cylinders); Gleason score < 3 + 4; clinical stage T1a-T2b; and PSA < 15 ng/ml. Exclusion criteria for this study were: less than 6 months in AS, termination of AS protocol, or incomplete data. Patients in AS were matched with those treated with RP, XRT or BT from the 'Spanish Multicentric Study of Clinically Localized Prostate Cancer' cohort according to risk group, time from treatment selection to HRQoL survey, and age. Prostate-specific (EPIC) and generic (SF-36) HRQoL instruments were completed. Analysis was stratified by HRQoL survey moment (>or < 2.5 years from treatment selection), and age (>or < 70 years old). RESULTS: Median of time from treatment selection to HRQoL survey in the total 396 patients (99 per treatment group) was 2.4 years (range 0.5-8.3). Patients in AS presented higher (better) urinary incontinence scores than RP ones in both stratus of time from treatment selection to HRQoL survey (92.6 vs 67.0 and 81.4 vs 64.4, p <  0.01). Patients in AS for < 2.5 years presented greater sexual scores than any active treatment (p <  0.01), but only statistically higher than RP for those in AS for longer than 2.5 years. The magnitude of the differences between AS and RP groups in both EPIC domains ranged from moderate (0.7 SD) to large (1.0 SD). Regardless of treatment applied, patients presented similar and slightly increased SF-36 scores than US general population reference norms. Nonetheless, patients in AS for < 2.5 years reported worse outcomes than other treatment groups on physical health domains, especially in bodily pain (0.5-0.6 SD), and vitality (0.6-0.8 SD). CONCLUSIONS: Considering patients' well-being, AS can be a good therapeutic option due to the low impact caused on urinary continence and sexual function. However, longitudinal studies are required to take into account HRQoL evolution over time.

Correlation between the biopsies in marginal donor kidneys for transplantation: is it necessary to biopsy both kidneys?

OBJECTIVES: The objective of this study was to analyze the correlation between histological findings in both transplanted kidneys from marginal donors. METHODS: We retrospectively reviewed the histological information on 92 kidneys obtained between January 2001 and January 2004, corresponding to 46 marginal donors. Criteria for biopsy were age greater than 55 years, hypertension, diabetes, and proteinuria. Scores were established by the pathologist including glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis. The score for each lesion was classified as 0 if absent; 1 if <20%; 2 if >20% and <50%; and 3 if >50%. Finally, we defined an index of renal severity damage (RSD) in order to classify the kidneys for single transplantation (0), double transplantation (1), and unsuitable for transplantation (2). RESULTS: Of the kidneys studied, 82.6% of both kidneys showed similar degrees of glomerulosclerosis (<20% in 71.7% and >20% in 10.9%), while 17.4% showed discrepancies (> vs <20%; P=.008). On the other hand, RSD correlated in 82.6% of both kidneys (in 69.6% RSD=0; in 8.7% RSD=1; and in 4.3% RSD=2), while 17.4% showed discrepancies (P=.001). In one case (2.2%), a great discrepancy was observed; one kidney was valid for single transplantation, and the other one not valid for any transplantation, single or double. CONCLUSIONS: This study demonstrated a correlation between the biopsy findings in both kidneys in 82.6% of marginal organ donors. However, in 17.4% of cases we observed discrepancies. The degree of glomerulosclerosis seemed to be a powerful parameter to define renal severity damage. According to these results we would recommend biopsy of both kidneys.

Behavior of free testosterone in patients with prostate cancer on androgen deprivation therapy.

OBJECTIVES: Determination of free testosterone (FT) serum level is an efficient method to evaluate bioavailable testosterone. We analyzed the behavior of serum FT in patients with prostate cancer receiving androgen deprivation therapy (ADT) and correlated FT with total testosterone (TT). We also analyzed the efficiency of both isoforms in the evaluation of the ADT. METHODS: Serum levels of TT and FT were determined in 191 patients with prostate cancer in a cross-sectional study. A subset of 56 patients submitted only to radical prostatectomy served as control group. The remaining 135 patients with advanced prostate cancer on three-month LHRH agonist treatment comprised the study group. The median age of the population was 73 years (range, 53-86 years) and the median time on ADT was 42 months (6-198). RESULTS: A significant correlation and linear regression between TT and FT was observed (r2 0.948). The efficiency of TT and FT to discriminate patients with and without ADT was similar (AUC: 0.993 and 0.995, respectively, p > 0.05). A castration level of serum FT established at 1.7 pg/mL had a sensitivity of 85.9% and a specificity of 100%, which are similar to the sensitivity and specificity of 50 ng/dL of TT. All patients without ADT had levels of serum TT and FT above the castration level. In 19 of the 135 (14.1%) patients on ADT serum TT was above 50 ng/dL. In 12 of these 19 patients (63.2%) serum FT was below 1.7 pg/mL while in seven patients (5.2%) FT was also above the castration level. CONCLUSIONS: The castration level of FT was established at 1.7 pg/mL. Serum TT and TF correlated very well; however, they seemed to provide complementary information in the evaluation of ADT efficiency. 14.1% of the patients on ADT failed to reach the castration level of serum TT; determination of serum FT in these patients would reduce this rate to 5.2%.

Initial high-grade T1 urothelial cell carcinoma: feasibility and prognostic significance of lamina propria invasion microstaging (T1a/b/c) in BCG-treated and BCG-non-treated patients.

OBJECTIVES: This study aimed to determine the prognostic value of depth of lamina propria invasion in initial high-grade T1 bladder tumors. Secondary aims were to evaluate the prognostic significance of concomitant carcinoma in situ (CIS) and the impact of bacillus Calmette-Guérin (BCG) treatment as well as to assess the feasibility of microstaging by pathologists in a community setting. PATIENTS AND METHODS: Ninety-seven tumors were available for study and were substaged according to invasion superficial to, into or beyond the muscularis mucosae (MM) (T1a, T1b, T1c). Outcomes were compared by chi-square analysis. Recurrence-free and progression-free survival estimates were obtained by Kaplan-Meier analysis. BCG treatment impact and prognostic significance of CIS were also evaluated (Cox regression). RESULTS: T1 subclassification was possible in 87% (85/97) of cases: 38 (39.1%) T1a, 10 (10.3%) T1b, and 37 (38.1%) T1c; in 12 patients (12.4%) substaging was not possible. Mean age was 66.4 years and mean follow-up was 53 months. Recurrence rates were similar for all groups. By contrast, the progression rate for deep lamina propria-invasive tumors, i.e. T1b and T1c, was 34% (16/47) in comparison to 8% (3/38) for T1a (p=0.016). Progression-free intervals were significantly different in patients with (T1b, T1c) or without (T1a) deep lamina propria involvement (p=0.003), regardless of BCG treatment (p=0.02). BCG-treated patients (67 cases) showed a slight trend towards a better outcome, but differences were not significant. CIS was associated with more than 50% of cases that progressed. On multivariate analysis, depth of invasion and CIS remained two independent prognostic factors, increasing the hazards ratio of progression to 4.47 and 3.19 respectively. CONCLUSIONS: The depth of invasion in the TURB specimens is an independent prognostic factor for T1 bladder cancer even in BCG-treated patients. Associated CIS significantly increases the risk of progression in these patients. The percentage of cases that can be substaged according to the depth of lamina propria involvement increases over time with the collaboration between urologists and pathologists. Consequently, we support that routine pathological assessment of the level of MM invasion in patients with stage T1 bladder cancer should be included in the histopathological report.

Renal collecting (Bellini) duct carcinoma displays similar characteristics to upper tract urothelial cell carcinoma.

OBJECTIVES: To describe 3 cases of tumors located in the kidney that may relate collecting (Bellini) duct carcinoma (CDC) to urothelial cell carcinoma (UC). We hypothesized that these distinct tumor types may share a common origin. CDC is a subtype of renal cell carcinoma associated with a highly aggressive course, poor prognosis, and limited response to immunotherapy, behaving similarly to UC. METHODS: We present 2 cases of CDC and 1 case of UC of the renal papilla. We compared the clinical presentation and survival rate, together with the radiologic, histologic, and immunostaining (including p53) findings, with strong emphasis on the similarities. RESULTS: One patient with CDC had a previous history of grade 3, Stage Ta bladder UC. The urothelial carcinoma from the kidney papilla (case 3) presented carcinoma in situ of the adjacent urothelium and displayed mixed characteristics with CDC, namely location, positive staining for Ulex europaeus and pyelonephritic changes. p53 staining showed marked positivity in the tumor of patient 2. Disease progression was rapid, with a median survival of 5.6 months (range 5 to 7). CONCLUSIONS: The results of this study suggest that the broad category of renal cell carcinoma includes a spectrum of lesions. In this range of diseases, CDC might be distinct from conventional renal cell carcinoma but share biologic features with UC, with the consequent implications for management. This association between CDC and UC may reflect the common embryologic origin of collecting duct and urothelial cells, since they derive from progressive branching of the mesonephric (wolffian) duct. Furthermore, the differential cytogenetic expression profiles suggest that the molecular events underlying the development of distal nephron and proximal tubule renal cancers are distinct.

Usefulness of prostate-specific antigen nadir as predictor of androgen-independent progression of metastatic prostate cancer.

The objective of this study was to analyze the value of the nadir level of prostate-specific antigen (PSA) to predict androgen-independent progression (AIP) in metastatic prostate cancer patients after androgen deprivation therapy. In a group of 185 metastatic prostate cancer patients who received androgen deprivation therapy serum PSA was determined every three months until AIP occurred. Multiple regression analysis was performed to define independent clinical and PSA-related predictors of AIP. AIP was assumed to be present after two consecutive increases in serum PSA after the PSA nadir. Independent predictors of the duration of AIP-free survival (less than 12 months versus more than 12 months) were the extent of bone involvement (six or fewer hot spots versus more than six) with an odds ratio (O.R.) of 3.95, Gleason score (7 or less versus more than 7) with an O.R. of 3.47, and PSA nadir (2 microg/L or less versus more than 2 microg/L) with an O.R. of 14.63. AIP was independently predicted by the extent of bone involvement with an O.R. of 1.72, Gleason score with an O.R. of 1.74, PSA nadir with an O.R. of 3.22, and time to reach the PSA nadir (9 months or less versus more than 9 months) with an O.R. of 2.84. When patients were stratified according to these predictors, those with three good prognostic factors had a median AIP-free survival of 58 months while those with two, one or no good prognostic factors had a median AIP-free survival of 19 months, 12 months and 7 months, respectively. We conclude that the PSA nadir seems to be a good predictor of AIP in patients with metastatic prostate cancer after androgen deprivation therapy. Time to PSA nadir, extent of bone involvement and Gleason score are also independent predictors. The combination of these prognostic factors allows to stratify metastatic prostate cancer patients for the prediction of AIP.

Behavior of free testosterone in patients with prostate cancer on androgen deprivation therapy.

OBJECTIVES: Determination of free testosterone (FT) serum level is an efficient method to evaluate bioavailable testosterone. We analyzed the behavior of serum FT in patients with prostate cancer receiving androgen deprivation therapy (ADT) and correlated FT with total testosterone (TT). We also analyzed the efficiency of both isoforms in the evaluation of the ADT. METHODS: Serum levels of TT and FT were determined in 191 patients with prostate cancer in a cross-sectional study. A subset of 56 patients submitted only to radical prostatectomy served as control group. The remaining 135 patients with advanced prostate cancer on three-month LHRH agonist treatment comprised the study group. The median age of the population was 73 years (range, 53-86 years) and the median time on ADT was 42 months (6-198). RESULTS: A significant correlation and linear regression between TT and FT was observed (r2 0.948). The efficiency of TT and FT to discriminate patients with and without ADT was similar (AUC: 0.993 and 0.995, respectively, p>0.05). A castration level of serum FT established at 1.7 pg/mL had a sensitivity of 85.9% and a specificity of 100%, which are similar to the sensitivity and specificity of 50 ng/dL of TT. All patients without ADT had levels of serum TT and FT above the castration level. In 19 of the 135 (14.1%) patients on ADT serum TT was above 50 ng/dL. In 12 of these 19 patients (63.2%) serum FT was below 1.7 pg/mL while in seven patients (5.2%) FT was also above the castration level. CONCLUSIONS: The castration level of FT was established at 1.7 pg/mL. Serum TT and TF correlated very well; however, they seemed to provide complementary information in the evaluation of ADT efficiency. 14.1% of the patients on ADT failed to reach the castration level of serum TT; determination of serum FT in these patients would reduce this rate to 5.2%. (Int J Biol Markers 2005; 20: 119-22).

Gender-related differences in clinical and pathological characteristics and therapy of bladder cancer.

OBJECTIVE: To confirm the very high male:female ratios previously observed among Spanish bladder cancer patients and to assess gender differences in tumoral characteristics, diagnostic procedures, and treatment in a large series of consecutive bladder cancer patients. PATIENTS AND METHODS: All newly diagnosed bladder cancer patients (n=615) in 17 Spanish hospitals, between 1997-2000, were included. Information was collected both through personal interviews to patients and from medical records using a structured form. RESULTS: Seventy-six percent of tumours were superficial. The male:female ratio was 6.7 and it was similar for superficial and infiltrating tumours. Women were older than men at the diagnosis of bladder cancer (68.2+/-9.4 years versus 65.7+/-9.7 years, p=0.01). Ten percent of superficial tumours in women, versus 3% in men, were classified as "other histological types" (p=0.008). T1GIII tumours were more frequent among men (17% versus 7%, p=0.047). On the other hand, women were more likely to present with 0a-stage tumours (48.6% versus 35.5%, p=0.04), multiple tumours (50% versus 29%, trend test: 0.005), multi-centric tumours (54% versus 38%, p=0.019), and larger infiltrating masses (5.2 cm versus 3.8 cm, p=0.03) than men. Among 0a-stage tumours, only 23% of women compared to 54% of men received transurethral resection (TUR) alone (p=0.002). Women were almost five-fold more likely to receive additional therapies to TUR (p=0.004) after adjusting for age, geographical area, stage, tumoral size, nuclear grade, and multiplicity. CONCLUSION: The study confirms the very high male:female ratio of bladder cancer in Spain. We found substantial differences in the pathological characteristics of tumours from men and women. There was a tendency for women to receive more frequently non-standard, more aggressive, therapy than men.

Validation of the 13C-urea breath test for the diagnosis of Helicobacter pylori infection in children: a multicenter study.

OBJECTIVE: The 13C-urea breath test (13C-UBT) is a safe, noninvasive, and accurate test for the detection of Helicobacter pylori (H. pylori) infection in adults. The aim of this study was to evaluate sensitivity and specificity of 13C-UBT in children using different types of test meal, doses of 13C-urea and breath sampling intervals. As yet, a validated, standardized 13C-UBT protocol for children has not been formulated. METHODS: 13C-UBT was performed in 115 children and repeated within 3 days, modifying the test meal or the dose of 13C-urea. H. pylori status was assessed by histology and rapid urease test. 13C-UBT was performed using 100 mg or 50 mg of 13C-urea and a fatty test meal (100 FA; 50 FA), 50 mg of 13C-urea, and a carbohydrate test meal (50 CA). Breath samples were collected every 10 min for 60 min. RESULTS: The 13C-UBT in children was highly sensitive and specific with all three protocols used. The best combination of sensitivity (97.92%) and specificity (97.96%) was obtained with Protocol 50 FA at 30 min with a cut-off of 3.5 per mil. CONCLUSIONS: The 13C-UBT is an accurate test for the detection of H. pylori infection also in children. Administration of 50 mg of 13C-urea, a fatty test meal, and breath sampling at 30 min appears to be the most convenient protocol.

Plasmapheresis in the therapy of hyperthyroidism associated with leukopenia.

Surgery, the treatment of choice for hyperthyroidism due to nodular goiter, requires an euthyroid state, which is generally achieved with thionamides. Leukopenia is the most serious toxic effect of thionamides, and it causes controindication. We report a 50-year old woman with severe hyperthyroidism and leukopenia, in whom an euthyroid state before thyroidectomy was obtained with the use of therapeutic plasmapheresis. This procedure was carried out immediately before surgery using an intermittent flow separator; three sessions removed a total of 6,300 cc of plasma. Plasmapheresis caused a rapid reduction of both total and free thyroid hormone levels. Thyroidectomy was performed without any complications. Plasmapheresis can be considered a valid and safe method to prepare hyperthyroid patients for thyroidectomy when other therapies are ineffective or counterindicated.

Comparison of the side effects of therapeutic cytapheresis and those of other types of hemapheresis.

The side effects of a series of 2418 hemapheresis procedures performed in a total of 570 subjects (patients and donors) are described. Patients with various diseases were subjected to plasmapheresis (926 procedures in 181 patients) or cytapheresis (305 procedures in 89 patients). One hundred twelve plasmapheresis procedures and 1075 of cytaphereses were also performed in 300 blood donors. A total of 225 complications involving 107 patients (39.6%) occurred during 196 (15.9%) therapeutic procedures. Among the blood donors only 45 complications, involving 35 patients (11.6%) occurred during 45 procedures (4.2%). The complications seen with therapeutic plasmaphereses were circulatory disturbances (38% of all those observed), citrate reactions (27%), technical problems (20%), allergic reactions (9%) and miscellaneous complications (6%). Therapeutic cytaphereses were complicated by citrate reactions (44%), technical problems (25%), circulatory disturbances (14%), allergic reactions (11%) and miscellaneous complications (6%). Complications in the blood donor group included circulatory disturbances (51%), technical problems (36%) and various other problems (13%). No infectious complications or deaths were observed. The probability that adverse reactions will occur depends on the condition of the patient, the frequency of the sessions and the volume of fluid exchanged. Evaluation of the main risk factors, use of less intensive protocols and interruption of the session at the first sign of disturbances will help improve patient tolerance of these procedures.

Autoimmune polyglandular syndrome, primary empty sella, and acute lymphocytic leukaemia.

A young man is reported with an autoimmune polyglandular syndrome (APS) characterized by Addison's disease, primary hypothyroidism, primary hypogonadism, vitiligo, associated with primary empty sella and partial impairment of pituitary hormone secretion. Two years later the patient showed a null cell type acute lymphocytic leukaemia, immediately after surgery for an inguinal hernia. Pathogenetic mechanisms are postulated on the basis of HLA studies and lymphocytic typing.

A clinical study of Addison's disease.

Fifty-four patients affected by primary adrenocortical insufficiency have been retrospectively studied. Eighteen were affected by a tuberculous Addison's disease, 24 by an idiopathic Addison's disease and 12 by an unclassifiable form. Modality of arise, clinical presentation and association with other diseases are reviewed. The most useful laboratory and instrumental tests for the diagnosis are discussed and a diagnostic flow-chart is proposed.