Molecular alterations in prostate cancer and association with MRI features.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) has been increasingly used for prostate cancer (PCa). Recent studies identified distinct molecular subclasses of PCa with recurrent genomic alterations. However, the associations between molecular alterations in PCa and characteristics on mpMRI are unknown. Therefore, the objective of this study was to investigate recurrent molecular alterations in PCa and their associations with mpMRI features. METHODS: Sixty-two PCa nodules >0.5 cm had a preoperative mpMRI. Nodules were evaluated for ERG rearrangement, PTEN deletion, SPINK1 overexpression, SPOP mutation and CHD1 deletion. Each PCa focus was matched to the corresponding location on mpMRI. Lesions were scored by single observer according to the PI-RADSv2 scale. RESULTS: Of the 62 nodules, 22 (35.5%) were ERG positive, 6 (9.7%) had SPINK1 overexpression, 6 (9.7%) had SPOP mutations, 4 (6.5%) had CHD1 deletions and 1 (1.6%) had PTEN deletion. All of the nodules with CHD1 deletions were not visible on mpMRI (P=0.037). All of the nodules with SPINK1 overexpression were visible on mpMRI, although the association was not statistically significant (P=0.06). There were no significant associations between any molecular alteration with the severity of the PI-RADS scores (all P>0.05). CONCLUSIONS: This investigation represents the first description of an association between recurrent molecular alterations and the characterization of PCa nodules on mpMRI. This study can be considered hypothesis-generating for future studies to rigorously evaluate the association of specific PCa molecular subclasses with imaging features and potentially define specific subsets of PCa for which the utility of MRI is higher or lower.

Distinct ERG rearrangement prevalence in prostate cancer: higher frequency in young age and in low PSA prostate cancer.

BACKGROUND: The TMPRSS2-ERG gene fusion resulting in ERG overexpression has been found in around 50% of prostate cancers (PCa) and is a very early event in tumorigenesis. Most studies have reported on selected surgical cohorts with inconsistent results. We hypothesized that ERG gene rearrangements impact tumor development and investigated the frequency of ERG overexpression in the context of clinicopathological tumor characteristics. METHODS: ERG overexpression (ERG+ or ERG-) was determined by immunohistochemistry (IHC) in 1039 radical prostatectomy (RP) tumors and association with PSA, D'Amico risk score, histopathology, biochemical recurrence, body mass index and age of PCa cases was analyzed. RESULTS: ERG+ was associated with younger age at diagnosis (P<0.0001), lower serum PSA (P=0.002) and lower prostate volume (PV) (P=0.001). It was most frequent in the youngest age quartile (≤55 years, 63.9% ERG+) and decreased constantly with increasing age to 40.8% in the oldest age quartile (≥67 years, P<0.0001). In the PSA range <4 ng ml(-1) the frequency of ERG positivity was 60.2% compared with 47.5 and 49.1% in the PSA ranges 4-10 and ≥10 ng ml(-1), respectively. In the first age quartile, ERG+ patients had lower median serum PSA and fPSA% and smaller PV. In the highest age quartile tumor volume (TV) was increased. Similar differences were observed in the low PSA range. Multivariate analysis identified the first age quartile as a predictor for ERG status (odds ratios (OR) 2.05, P=0.007). No association was found with the D'Amico progression risk score and with biochemical tumor recurrence. CONCLUSIONS: ERG+ tumors manifest clinically at lower PSA levels and their prevalence is age dependent. This suggests acceleration of tumor development by ERG overexpression that results in earlier tumor detection in young patients. Long-term results are warranted to determine the impact of ERG overexpression on disease outcome.

Morphological features of TMPRSS2-ERG gene fusion prostate cancer.

The TMPRSS2-ETS fusion prostate cancers comprise 50-70% of the prostate-specific antigen (PSA)-screened hospital-based prostate cancers examined to date, making it perhaps the most common genetic rearrangement in human cancer. The most common variant involves androgen-regulated TMPRSS2 and ERG, both located on chromosome 21. Emerging data from our group and others suggests that TMPRSS2-ERG fusion prostate cancer is associated with higher tumour stage and prostate cancer-specific death. The goal of this study was to determine if this common somatic alteration is associated with a morphological phenotype. We assessed 253 prostate cancer cases for TMPRSS2-ERG fusion status using an ERG break-apart FISH assay. Blinded to gene fusion status, two reviewers assessed each tumour for presence or absence of eight morphological features. Statistical analysis was performed to look for significant associations between morphological features and TMPRSS2-ERG fusion status. Five morphological features were associated with TMPRSS2-ERG fusion prostate cancer: blue-tinged mucin, cribriform growth pattern, macronucleoli, intraductal tumour spread, and signet-ring cell features, all with p-values < 0.05. Only 24% (n=30/125) of tumours without any of these features displayed the TMPRSS2-ERG fusion. By comparison, 55% (n=38/69) of cases with one feature (RR=3.88), 86% (n=38/44) of cases with two features (RR=20.06), and 93% (n=14/15) of cases with three or more features (RR=44.33) were fusion positive (p<0.001). To our knowledge, this is the first study that demonstrates a significant link between a molecular alteration in prostate cancer and distinct phenotypic features. The strength of these findings is similar to microsatellite unstable colon cancer and breast cancer involving BRCA1 and BRCA2 mutations. The biological effect of TMPRSS2-ERG overexpression may drive pathways that favour these common morphological features that pathologists observe daily. These features may also be helpful in diagnosing TMPRSS2-ERG fusion prostate cancer, which may have both prognostic and therapeutic implications.

TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort.

The identification of the TMPRSS2:ERG fusion in prostate cancer suggests that distinct molecular subtypes may define risk for disease progression. In surgical series, TMPRSS2:ERG fusion was identified in 50% of the tumors. Here, we report on a population-based cohort of men with localized prostate cancers followed by expectant (watchful waiting) therapy with 15% (17/111) TMPRSS2:ERG fusion. We identified a statistically significant association between TMPRSS2:ERG fusion and prostate cancer specific death (cumulative incidence ratio=2.7, P<0.01, 95% confidence interval=1.3-5.8). Quantitative reverse-transcription-polymerase chain reaction demonstrated high ets-related [corrected] gene (ERG) expression to be associated with TMPRSS2:ERG fusion (P<0.005). These data suggest that TMPRSS2:ERG fusion prostate cancers may have a more aggressive phenotype, possibly mediated through increased ERG expression.

[Two HHV8-related illnesses in a HIV-negative patient: Kaposi's sarcoma and multicentric Castleman's disease. Response to treatment with Rituximab and CHOP]. / Dos enfermedades relacionadas con el VHH-8 en un paciente VIH-negativo: sarcoma de Kaposi y enfermedad de Castleman multicéntrica. Respuesta a tratamiento con rituximab y CHOP.

Human herpes virus 8 (HHV8) was discovered in 1994 in the biopsy of a Kaposi's sarcoma in a patient with AIDS. Since then it has been identified in all variants of Kaposi's sarcoma and in another two rare disorders: multicentric Castleman's disease and primary body-cavity based lymphomas. The case discusses a 68 year old, HIV-negative male patient, presenting Kaposi's sarcoma for one year and being monitored by dermatology, who presented for weakness, anorexia and fever. On examination, he was found to have adenitis of the lymph nodes in his neck, underarm and groin. A biopsy on one of the swellings led to findings characteristic of multicentric plasma cell variant Castleman's disease. Blood tests for HHV8 and HIV were carried out, resulting positive and negative respectively (IgG anti-HHV8 positive, title 1/640, indirect immunofluorescence). PCR amplification showed HHV8 in peripheral blood. Patient received 8 cycles of CHOP and rituximab, leading to complete disappearance of the adenitis and general symptoms, with no worsening of his Kaposi's sarcoma. Patient remained in complete remission for 10 months after treatment. This paper discusses the case of a HIV-, HHV8+ patient, diagnosed with classic Kaposi's sarcoma, who developed multicentric plasma cell variant Castleman's disease. The coincidence of two or more HHV8-related illnesses in a HIV-negative patient has rarely been described in medical literature. Treatment with rituximab combined with CHOP chemotherapy was effective in this case, and no worsening of the patient's KS was observed.

Histological features with clinical impact in chronic allograft nephropathy: review of 66 cases.

UNLABELLED: The histological features of chronic allograft nephropathy (CAN) are variable, since it is related to multiple donor and recipient factors. The main histological parameters in CAN are interstitial fibrosis, tubular atrophy, chronic vasculopathy and glomerulosclerosis. There have been many attempts to relate chronic deterioration of renal function with histologic features. MATERIALS AND METHODS: We reviewed 66 kidney transplant patients (43 men/23 women) with renal failure 6 months after transplant. The clinical data included donor and recipient age, cold ischemia time, delayed graft function (DGF), creatinine clearance, proteinuria, HLA compatibility, CMV infection, cholesterol levels, diastolic and systolic blood pressure. Banff criteria were used to grade histological parameters. The relation between clinical and histological data were analyzed using chi square, Student t, Mann Whitney and Kruskal-Wallis tests as appropriate. The cumulative graft and patient survival rates were calculated by the Kaplan-Meier method. RESULTS: The survival rate of patients with creatinine clearances >3 mg/dL at the time of the biopsy was worse than that of patients with creatinine <3 mg/dL (P =.001; log rank 20.1). We found an association between the grade of arteriosclerosis and the diastolic blood pressure (P =.017). The creatinine level was greater among patients with tabulitis than those without tubulitis (P =.06). In addition to our results we review the literature especially related to the histological feature of CAN in an attempt to detect histological findings predictive of the long term outcome of kidney allografts.

Sequential epidemic outbreaks of septicaemias by Serratia and Klebsiella species on a medical intensive care unit.

The high rate of septicaemias (20%, 19% and 14%) observed in our Intensive Care Unit (ICU) during the first 3 years was due to an epidemic incidence of Serratia sp. (S) (26% during the first year) and Klebsiella sp. (K) (25% during the third) and decreased significantly in the following 6 years (mean incidence of 11%) (p less than 0.01). During this epidemic phase these organisms were isolated quite frequently (between a 14% and a 6%) from all patients admitted. The K was more regularly present, for the mean time intervals free of its bacteriological presence were shorter (11 days) than those of S (27 days) (p less than 0.01). The K was isolated in more patients (160) than S (79) (p less than 0.01) and in more samples (360) than S (235) (p less than 0.01), but caused less secondary septicaemias per colonized patient (7% versus 29%) (p less than 0.01). In 59% of all S septicaemias the organism was previously isolated in other culture, while this was observed in only 34% of K septicaemias (x2 = 3.78, p = 0.052). The large variations in the incidence of septicaemias within our ICU, the appearance of sequential epidemic outbreaks, with a different behaviour of S and K and the individual risk of septicaemia of patients colonized by these organisms are noted.

Early evaluation of coagulase negative staphylococcus in blood samples of intensive care unit patients. A clinically uncertain judgement.

Of 2160 intensive care unit patients, 36 patients with positive blood cultures had coagulase-negative staphylococcus in one blood bottle, whereas the organism was present in two or more bottles in 38 cases. The groups were not significantly different in 27 clinical variables, obtained at the time of their first positive blood culture. There was also no significant difference in the antimicrobial sensitivities. No initial clinical data supported the classification of coagulase-negative staphylococcus as either pathogen or contaminant. When the 74 patients with blood culture positive coagulase-negative staphylococcus were compared with three "control groups" ("absent septicemia," "probable septicemia" and "proven septicemia") they were not different from those with "probable septicemia." A discriminant analysis was performed comparing patients with "absent septicemia" and with "proven septicemia" in an attempt to classify patients with isolates of coagulase-negative staphylococcus in one of these groups at an early stage. Patients with two or more positive blood cultures were not statistically classified more frequently as septicemic than patients with one blood bottle positive for this organism. However, patients categorized as septicemic had a significantly higher mortality (59%) than those classified as non-septicemic (35%) (p less than 0.05).

Simple and accurate monitoring of end-tidal carbon dioxide tensions during high-frequency jet ventilation.

To determine whether end-tidal carbon dioxide tension (PETCO2) accurately reflects PaCO2 during high-frequency jet ventilation (HFJV), 43 studies were performed on eight mongrel dogs with normal lungs. During HFJV, minute volume was modified to obtain a range of PaCO2 values from 15.5 to 74.5 torr. When PETCO2 was measured with an infrared gas analyzer, there was a poor correlation between PaCO2 and PETCO2 values. However, when the high-frequency ventilator was adjusted to deliver large tidal-volume (sigh) breaths, PETCO2 values were significantly (r = 0.94, p less than .001) correlated with PaCO2. Our data suggest that the PETCO2 of alveolar gas is an accurate indicator of the PaCO2 during HFJV in nondiseased lungs.

Prolonged high-frequency jet ventilation in a patient with bronchopleural fistula. An alternative mode of ventilation.

We report a case of bronchopleural fistula (BPF) in a patient submitted to conventional mechanical ventilation in which high frequency jet ventilation (HFJV) was applied during five consecutive days. Gas exchange was adequate, the bronchial secretions could easily be cleared and the patient adapted comfortably to HFJV. In spite of PEEP levels between 4 and 8 mm Hg, the leak through the BPF ceased completely.

Septicaemia in a medical intensive care unit. Clinical, biochemical and microbiological data of 109 cases.

Blood cultures were obtained from 39% of all 574 admissions to our Medical Intensive Care Unit. (ICU); in 109 (19%) a pathogenic organism was demonstrated. 45% of the septicaemias were detected within the first 48 h of ICU stay have been considered as "non ICU-acquired". Septicaemic patients were significantly older, had longer ICU stays and a higher mortality rate (62%) than non septicaemic patients (28%) (p less than 0.05). Gram negative organisms (69%) predominated over gram positive (29%) and Serratia marcescens and coagulase positive Staphylococcus were the most frequently isolated. Shock appeared in 32% and had an extremely high mortality (91%) and was associated with the presence of "multiple species septicaemia". Prior to the septicaemia the survivors differed from the fatalities only in the level of serum albumin; this was significantly lower in patients with gram negative in comparison with gram positive septicaemias and in patients who developed shock. Arterial, pulmonary artery and urinary catheters, and endotracheal devices were used frequently in these patients and were statistically associated with the presence of septicaemia. The airway was the most frequent possible source for the septicaemia.

Abnormal temperature control after intoxication with short-acting barbiturates.

Changes in rectal and toe temperatures were measured in 16 patients who had been intoxicated with short-acting barbiturates. The lowest temperatures observed in the group of 16 patients averaged 35.5 +/- 2.0 degrees C. In 11 patients, the interval between intoxication and admission was documented. There was a significant correlation (r = 0.83) between the time of estimated intoxication and hypothermia. Patients who were admitted soon after the ingestion of the barbiturates had the lowest rectal temperatures. These observations indicate that hypothermia is a usual clinical sign in the initial period after intoxication with a short-acting barbiturate. Except for 2 patients, rectal temperature exceeded 38 degrees C during the interval of recovery with the maximum rectal temperature averaging 39.0 +/- 0.8 degrees C. Hyperthermia was not related to infection of the airways, lungs, urinary tract, or bloodstream. In 11 patients, pathogenic organisms were recovered from the airway and/or urine, but there was no difference in the highest rectal temperature in these patients (39.0 +/- 0.9 degrees C) when compared with 5 patients from whom no pathogenic organisms were recovered (39.2 +/- 0.7 degrees C). Accordingly, there was no evidence that hyperthermia was due to infection. The skin temperatures of the ventrum of the first toe were not typically decreased during hypothermia. To the contrary, increases in skin temperatures were often observed during hypothermia. These observations provide evidence of altered thermoregulation with increased surface heat loss accounting for the hypothermia in the early course and heat conservation with hyperthermia during the later course of intoxication by short-acting barbiturates.

Amikacin treatment of Serratia septicemia in critically ill patients.

Serratia marcescens septicemia represents a serious problem in high risk critical care patients. Treatment is difficult because Serratia is usually resistant to most antibiotics. Amikacin is at present the most effective antibiotic in vitro against gentamycin-resistant Serratia, although significant loss of activity may occur in vivo in the group of compromised patients, whose ultimate prognosis may depend eventually upon other associated conditions. In this Medical ICU, 15 patients with Serratia septicemia who were treated with in vitro effective antibiotics (14 were given amikacin) had a mortality of 60%, while 5 patients who received ineffective in vitro antibiotics had a mortality of 100%. In this ICU, 80% of the Serratia isolates were resistant to gentamycin, while only 2.8% were resistant to amikacin. Because amikacin-resistant strains of Serratia have already emerged, appropriate use of this antibiotic is essential in order not to promote the selection of amikacin-resistant strains.

Association of a low serum albumin with infection and increased mortality in critically ill patients.

214 patients among 282 consecutive admissions had at least one measurement of serum albumin (SA) during their stay on the ICU and were classified according to their lowest value of SA. Mean SA was 2.88 /+- 0.74 g/100 mg. Survivors had a mean SA (3.18 /+- 0.60) higher than non-survivors (2.35 /+- 0.68 g/100 ml) (p < 0.05). 64% of patients were admitted with an abnormally low SA (less than 3.5 g/100 ml) and in 56% of these the initial value was higher than the last. Mortality increased in the groups with lower SA and the level of SA was associated with infection (x2 = 73.9) and mortality (x2 = 69.7) (p < 0.05). The percentage of infected patients who died increased in groups with lower SA.