Supervised machine learning enables non-invasive lesion characterization in primary prostate cancer with [68Ga]Ga-PSMA-11 PET/MRI.

PURPOSE: Risk classification of primary prostate cancer in clinical routine is mainly based on prostate-specific antigen (PSA) levels, Gleason scores from biopsy samples, and tumor-nodes-metastasis (TNM) staging. This study aimed to investigate the diagnostic performance of positron emission tomography/magnetic resonance imaging (PET/MRI) in vivo models for predicting low-vs-high lesion risk (LH) as well as biochemical recurrence (BCR) and overall patient risk (OPR) with machine learning. METHODS: Fifty-two patients who underwent multi-parametric dual-tracer [18F]FMC and [68Ga]Ga-PSMA-11 PET/MRI as well as radical prostatectomy between 2014 and 2015 were included as part of a single-center pilot to a randomized prospective trial (NCT02659527). Radiomics in combination with ensemble machine learning was applied including the [68Ga]Ga-PSMA-11 PET, the apparent diffusion coefficient, and the transverse relaxation time-weighted MRI scans of each patient to establish a low-vs-high risk lesion prediction model (MLH). Furthermore, MBCR and MOPR predictive model schemes were built by combining MLH, PSA, and clinical stage values of patients. Performance evaluation of the established models was performed with 1000-fold Monte Carlo (MC) cross-validation. Results were additionally compared to conventional [68Ga]Ga-PSMA-11 standardized uptake value (SUV) analyses. RESULTS: The area under the receiver operator characteristic curve (AUC) of the MLH model (0.86) was higher than the AUC of the [68Ga]Ga-PSMA-11 SUVmax analysis (0.80). MC cross-validation revealed 89% and 91% accuracies with 0.90 and 0.94 AUCs for the MBCR and MOPR models respectively, while standard routine analysis based on PSA, biopsy Gleason score, and TNM staging resulted in 69% and 70% accuracies to predict BCR and OPR respectively. CONCLUSION: Our results demonstrate the potential to enhance risk classification in primary prostate cancer patients built on PET/MRI radiomics and machine learning without biopsy sampling.

Can the addition of clinical information improve the accuracy of PI-RADS version 2 for the diagnosis of clinically significant prostate cancer in positive MRI?

AIM: To report prostate cancer (PCa) prevalence in Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) categories and investigate the potential to avoid unnecessary, magnetic resonance imaging (MRI)-guided in-bore biopsies by adding clinical and biochemical patient characteristics. MATERIALS AND METHODS: The present institutional review board-approved, prospective study on 137 consecutive men with 178 suspicious lesions on 3 T MRI was performed. Routine data collected for each patient included patient characteristics (age, prostate volume), clinical background information (prostate-specific antigen [PSA] levels, PSA density), and PI-RADS v2 scores assigned in a double-reading approach. RESULTS: Histopathological evaluation revealed a total of 93/178 PCa (52.2%). The mean age was 66.3 years and PSA density was 0.24 ng/ml2 (range, 0.04-0.89 ng/ml). Clinically significant PCa (csPCa, Gleason score >6) was confirmed in 50/93 (53.8%) lesions and was significantly associated with higher PI-RADS v2 scores (p=0.0044). On logistic regression analyses, age, PSA density, and PI-RADS v2 scores contributed independently to the diagnosis of csPCa (p=7.9×10-7, p=0.097, and p=0.024, respectively). The resulting area under the receiver operating characteristic curve (AUC) to predict csPCa was 0.76 for PI-RADS v2, 0.59 for age, and 0.67 for PSA density. The combined regression model yielded an AUC of 0.84 for the diagnosis of csPCa and was significantly superior to each single parameter (p≤0.0009, respectively). Unnecessary biopsies could have been avoided in 50% (64/128) while only 4% (2/50) of csPCa lesions would have been missed. CONCLUSIONS: Adding age and PSA density to PI-RADS v2 scores improves the diagnostic accuracy for csPCa. A combination of these variables with PI-RADS v2 can help to avoid unnecessary in-bore biopsies while still detecting the majority of csPCa.

68Ga-PSMA 11 ligand PET imaging in patients with biochemical recurrence after radical prostatectomy - diagnostic performance and impact on therapeutic decision-making.

OBJECTIVE: To evaluate the diagnostic performance of [68Ga]Ga-PSMAHBED-CC conjugate 11 positron emission tomography (PSMA-PET) in the early detection of metastases in patients with biochemical recurrence (BCR) after radical prostatectomy (RP) for clinically non-metastatic prostate cancer, to compare it to CT/MRI alone and to assess its impact on further therapeutic decisions. MATERIAL AND METHODS: We retrospectively assessed 117 consecutive hormone-naïve BCR patients who had 68Ga-PSMA 11 PET/CT (n = 46) or PET/MRI (n = 71) between May 2014 and January 2017. BCR was defined as two PSA rises above 0.2 ng/ml. Two dedicated uro-oncological imaging experts (radiology/nuclear medicine) reviewed separately all images. All results were presented in a blinded sequential fashion to a multidisciplinary tumorboard in order to assess the influence of PSMA-PET imaging on decision-making. RESULTS: The median time from RP to BCR was 36 months (IQR 16-72). Overall, 69 (59%) patients received postoperative radiotherapy. Median PSA level at the time of imaging was 1.04 ng/ml (IQR 0.58-1.87). PSMA-positive lesions were detected in 100 (85.5%) patients. Detection rates were 65% for a PSA value of 0.2 to <0.5 ng/ml, 85.7% for 0.5 to <1, 85.7% for 1 to <2 and 100% for ≥2. PSMA-positive lesions could be confirmed by either histology (16%), PSA decrease in metastasis-directed radiotherapy (45%) or additional information in diffusion-weighted imaging when PET/MRI was performed (18%) in 79% of patients. PSMA-PET detected lesions in 67 patients (57.3%) who had no suspicious correlates according to the RECIST 1.1 criteria on MRI or CT. PSMA-PET changed therapeutic decisions in 74.6% of these 67 patients (p < 0.001), with 86% of them being considered for metastases-directed therapies. CONCLUSIONS: We confirm the high performance of PSMA-PET imaging for the detection of disease recurrence sites in patients with BCR after RP, even at relatively low PSA levels. Moreover, it adds significant information to standard CT/MRI, changing treatment strategies in a significant number of patients.

Magnetic resonance imaging-guided prostate biopsy: institutional analysis and systematic review.

OBJECTIVES: To evaluate the detection rate of prostate cancer (PCa) after magnetic resonance-guided biopsy (MRGB); to monitor the patient cohort with negative MRGB results and to compare our own results with other reports in the current literature. MATERIALS AND METHODS: A group of 41 patients was included in this IRB-approved study and subjected to combined MRI and MRGB. MRGB was performed in a closed 1.5 T MR unit and the needle was inserted rectally. The follow-up period ranged between 12 and 62 months (mean 3.1 years). To compare the results with the literature, a systematic literature search was performed. Eighteen publications were evaluated. RESULTS: The cancer-suspicious regions were punctured successfully in all cases. PCa was detected in eleven patients (26.9 %) who were all clinically significant. MRGB showed a benign histology in the remaining 30 patients. In the follow-up (mean 3.1 years) of patients with benign histology, no new PCa was diagnosed. The missed cancer rate during follow-up was 0.0 % in our study. CONCLUSION: MRGB is effective for the detection of clinically significant cancer, and this is in accordance with the recent literature. In the follow-up of patients with benign histology, no new PCa was discovered. Although the probability of developing PCa after negative MRGB is very low, active surveillance is reasonable.

P16INK4A immunohistochemistry for detection of human papilloma virus-associated penile squamous cell carcinoma is superior to in-situ hybridization.

We evaluated p16INK4A as a reliable option to detect human papilloma virus (HPV) DNA in penile tumor specimens. Formalin-fixed paraffin embedded samples of 26 patients with penile cancer and another 18 cases with non-tumorigenic lesions were stained by three different widely used commercially available chromogenic in-situ hybridization assays high-risk HPV CISH Y1443 (Genpoint, DAKO), pan HPV CISH Y1404 (Genpoint, DAKO), INFORM HPV III (Ventana, Tucson, Arizona) and p16INK4A immunohistochemistry, then compared to the known gold standard polymerase chain reaction detecting HPV 16, 18, 31, and 33. Immunoreactivity for p16INK4A was evaluated by using a 4-tiered (0, 1, 2, and 3) pattern based system. 19 cases were positive for p16INK4A, 13 of which showed a continuous transepithelial staining (pattern 3). Pan HPV ISH showed positivity in 9 cases, high-risk HPV ISH in 7 cases and INFORM HPVIII ISH in 7 cases. p16INK4A IHC pattern 3 versus pattern 0, 1 and 2 exhibited a specificity and positive predictive value of 100 percent, with a sensitivity and negative predictive value of 72 and 62 percent, respectively, which was much better than all HPV in-situ hybridization methods referred to polymerase chain reaction. p16INK4A seems to be a superior marker for the detection of HPV-associated penile squamous cell carcinoma compared to CISH tests, but is not recommend for the detection of non-tumorigenic lesions, where PCR should be used for the initial assessment.

[Osteosarcoma of the prostate after radiotherapy]. / Osteosarkom der Prostata nach Strahlentherapie.

Osteosarcoma of the prostate is a rare finding. These tumours usually occur years after radiotherapy for prostate cancer. We report the case of a 74-year-old man with prostate cancer who had been treated with radiotherapy and androgen deprivation therapy. The man presented with urinary retention and his prostate was transurethrally resected. The histopathological investigation showed formations of a poorly differentiated osteosarcoma in the prostate. Because of serious comorbidities we decided to withhold chemotherapy considering its potential side effects. The man died a few months after the diagnosis of osteosarcoma in the prostate with the disease in a metastatic stage. In conclusion, osteosarcoma of the prostate is a rarely reported consequence of radiotherapy in patients with prostate cancer and is characterised by poor life expectancy.

Is penile atherosclerosis the link between erectile dysfunction and cardiovascular risk? An autopsy study.

Erectile dysfunction (ED) is increasingly linked to coronary heart disease risk. Aim of this study was to test the hypothesis whether this association is due to penile atherosclerosis. We evaluated the prevalence and severity of penile atherosclerosis in relation to coronary and peripheral atherosclerosis. Between January and June 2010, a consecutive series of 31 men underwent an autopsy at the Department of Pathology at the Medical University Vienna. Atherosclerosis at the following localizations were histologically classified: right coronary artery, left coronary artery, left circumflex artery, internal iliac artery, dorsal penile artery and deep penile artery (bilateral). Coronary and peripheral atherosclerosis was present in 87.1 and 77.4% of cases. Atherosclerosis of penile arteries was detectable in only 4 men (12.9%). The only factor linked to penile atherosclerosis was diabetes (P=0.03). All other parameters as assessed according to medical history, general finding from autopsy or histological results regarding arterial lesions in general were not correlated to penile arterial lesions. In contrast to the high prevalence of atherosclerosis in general, penile arterial lesions are rarely present.

[Diagnostic of prostate cancer: conventional and molecular or cell biological methods]. / Diagnostik des Prostatakarzinoms : Konventionelle und molekular- bzw. zellbiologische Methoden.

At present the diagnosis of prostate cancer is carried out by transrectally obtained biopsy samples. The histological findings, the value for prostate-specific antigen (PSA) in the serum, and the clinical stage are the objective criteria for all subsequent therapy decisions. In over 95% of cases an acinar "usual" form of prostate cancer is diagnosed but can be very different in characteristics and differentiation. In order to correctly assess prostate cancer and to be able to select the best possible therapeutic measures resulting from the diagnosis, all information obtained from the biopsy must be used to a maximum. The demands on the optimal biopsy findings have considerably expanded in recent years. It must be able to obtain all additional biological, molecular and genetic findings from the biopsy material.

CD98hc (SLC3A2), a novel marker in renal cell cancer.

BACKGROUND: In a variety of malignant diseases, molecular targeting represents a therapeutic option, whereby, when compared with chemotherapy, fewer side effects are thought to be expected. Especially in renal cell cancer (RCC), tyrosine kinase-inhibitors have been established as useful and highly effective therapy. However, tyrosine kinase-inhibitors currently approved for RCC treatment lack single molecule specificity and bear a variety of side effects of the gastro-intestinal tract, skin, heart and haematopoietic system. Therefore, the identification of novel cell surface markers is sought, which might lead to novel diagnostic and therapeutic strategies in cancer. MATERIAL AND METHODS: Paraffin-embedded RCCs from a well characterized tissue bank were immunohistochemically quantified for embryonic transmembrane antigen CD98hc (SLC3A2) expression and semi-quantitative analyses were correlated with subtype or grade of differentiation. RESULTS: We found increased CD98hc expression in different types of malign RCCs, among them clear cell (cc)RCC, papillary (p)RCC and chromophobe (ch)RCC, but lack of expression in the benign renal oncocytoma. Thereby, the extent of CD98hc expression directly complies with grade of malignancy. Furthermore, the more malignant type II pRCC significantly higher expressed CD98hc than the less malignant and more differentiated type I pRCC (type II 83.34%, type I 4.76% CD98hc positive, P < 0.00001; n = 51). The established marker for type I pRCC, Cytokreatin 7, showed 95.24% expression in type I and 26.67% expression in type II pRCC (P < 0.00001, n = 51). CONCLUSIONS: From these data, we conclude that CD98hc is expressed in RCCs, whereby the extent of expression is likely to correlate directly with grade of malignancy. In pRCCs, CD98hc might represent a novel and reliable marker for type II pRCC.

Molecular-cytogenetic characterisation of sex cord-stromal tumours: CGH analysis in sertoli cell tumours of the testis.

Sertoli cell tumours (SCT) are rare and poorly explored neoplasias, and the genetic features of these uncommon tumours are largely unknown. Data about chromosomal aberrations in human SCT of the testis are very rare. We present in this paper the first molecular-cytogenetic study of SCT of the testis. DNA was isolated from paraffin-embedded tumour material from 11 patients with unilateral SCT. We used comparative genomic hybridisation to investigate changes in DNA copy number. The detected DNA imbalances showed variation from case to case, indicating a high genetic heterogeneity. Chromosomal aberrations were detected in 9 of the 11 tumours evaluated, with 13 losses versus 14 gains. The most frequent aberrations detected were gain of chromosome X (5 of 11 cases) followed by losses of entire or part of chromosomes 2 and 19 in three cases. This study suggests a high variability in histomorphological and genetic patterns. Only gain of the entire chromosome X seems to be a frequent aberration in these tumours. Further studies of these tumour types are necessary to clarify the significance of chromosomal alterations in carcinogenesis of SCT.

Leydig cell tumors of the testis: a molecular-cytogenetic study based on a large series of patients.

The genetic features of the uncommon Leydig cell tumors (LCT) are largely unknown. Consequently, it is of great importance to elucidate the pathogenesis of testicular germ cell tumors by cytogenetic and molecular biological investigations. The purpose of the present study was the examination of cytogenetic features of these tumors in a large series of LCT. It comprised formalin-fixed, paraffin-embedded tissue samples from 25 LCT to analyze the chromosomal constitution using comparative genomic hybridization (CGH). In most of the studied cases, the aberrant cell population was additionally defined by interphase fluorescence in situ hybridization (I-FISH). Our molecular-cytogenetic study indicates chromosomal imbalances in the majority of our cases (21/25, 84%). The most frequent findings were gain of chromosome X, 19 or 19p and loss on chromosome 8 and 16.

Flexible cystoscopy assisted by hexaminolevulinate induced fluorescence: a new approach for bladder cancer detection and surveillance?

OBJECTIVE: The aim of this study was the assessment of flexible cystoscopy assisted by hexaminolevulinate (HAL) fluorescence. METHODS: This study was a prospective controlled, within-patient comparison of flexible HAL cystoscopy with standard flexible cystoscopy, HAL rigid and standard white light rigid cystoscopy. Eligible patients received an intravesical instillation of 50 ml hexylaminolevulinate 8 mM solution. First flexible than rigid cystoscopy was performed in each patient using a Combilight PDD system (Richard Wolf, Germany), which provided standard white light and blue light at 375 to 440 nm, with mapping of all lesions detected. All tumors and suspicious areas identified under white light and by red fluorescence with flexible or rigid cystoscopy were then resected by TUR or biopsied. The specimen was assessed by an independent blinded pathologist. RESULTS: In the 45 patients studied 41 (91%) patients had exophytic tumors, of which 39 (95.1%) were detected by HAL flexible cystoscopy and 40 (97.5%) by HAL rigid cystoscopy. 17 (37.8%) patients had concomitant or carcinoma in situ only, which was identified by HAL flexible cystoscopy in 14 (82.3%), by HAL rigid cystoscopy in 15 (88.2%), by flexible standard in 11 (64.7%) and by standard white light rigid cystoscopy in 13 (76.7%) patients. CONCLUSION: HAL fluorescence flexible cystoscopy compared to HAL rigid cystoscopy showed almost equivalent results in detecting papillary and flat lesions in bladder cancer patients. Both procedures were superior to standard white light flexible cystoscopy.

Cloning and molecular and immunological characterisation of two new food allergens, Cap a 2 and Lyc e 1, profilins from bell pepper (Capsicum annuum) and Tomato (Lycopersicon esculentum).

BACKGROUND: Profilins are recognised by IgE of about 20% of patients allergic to birch pollen and plant foods. They are ubiquitous intracellular proteins highly cross-reactive among plant species. Therefore, they were called panallergens and are made responsible for cross-sensitisation between plant pollen and food. OBJECTIVES: The aim of the present study was to clone the cDNAs encoding profilins from bell pepper and tomato, to produce and purify the recombinant proteins and to compare their IgE-binding capacities to those of the natural proteins. METHODS: cDNA clones coding for profilin were obtained by RT-PCR from total RNA of tomato and bell pepper fruits, sequenced and expressed as non-fusion proteins in ESCHERICHIA COLI. The recombinant profilins were subsequently purified and tested for IgE-binding and inhibition capacity with sera from 34 food-allergic patients. Possible oligomerisation of recombinant profilins was investigated by HPLC analysis and its influence on IgE binding assayed by ELISA. RESULTS: The open reading frame from both profilins encompasses 393 bp with a predicted molecular mass of 14,184 kD and a pI of 4.44 for bell pepper profilin (Cap a 2) and 14,257 kD and a pI of 4.46 for the profilin from tomato (Lyc e 1). The two protein sequences display 91% identity, whereas tomato profilin from pollen shares only 75% identity with tomato fruit profilin. Eleven out of 34 food-allergic patients (32%) display IgE binding to both purified profilins. Preincubation of a serum pool with either purified rCap a 2 or rLyc e 1 nearly abolished IgE binding to natural Cap a 2 and Lyc e 1, respectively. In addition, purified recombinant Cap a 2 was able to inhibit IgE-binding to rLyc e 1 by approximately 50%, whereas rLyc e 1 completely blocked IgE-binding to rCap a 2 in cross-inhibition assays. HPLC analysis showed that in solution Cap a 2 and Lyc e 1 can be found predominantly as dimers, which can be partially reduced to monomers by addition of dithiothreitol (DTT). In ELISA DTT-treated Lyc e 1 displayed a clearly lower IgE-binding capacity than untreated profilin. CONCLUSIONS: Purified rCap a 2 and rLyc e 1 proved to be valuable tools for studying cross-reactivity to profilins in patients allergic to pollen and food.

[Adenosquamous carcinoma of the palate]. / Adenosquamöses Karzinom des Gaumens.

A rare case of adenosquamous carcinoma in a 74 year-old man is reported. Presenting as a nodule on the soft palate, diagnosis was prolonged because of the benign macroscopic aspect. CT-scan and MR-tomography showed an encapsulated lesion but biopsy and histologic examination revealed the typical features of adenosquamous carcinoma. The tumour consisted of adenocarcinoma and squamous cell carcinoma in close proximity to minor salivary glands of which the tumour seemed to have its origin. This entity, although rare in the head and neck region has been documented to be very aggressive with early regional and hematogenic metastasis. Therefore it has to be distinguished from other tumours, especially from mucoepidermoid carcinomas of the salivary glands, which have a better prognosis. Adenosquamous carcinoma is considered to have poor radiosensitivity and chemotherapeutic approaches have also not been successful in the literature. In our case radical surgical therapy was performed by excision of the whole soft palate and bilateral neck dissection. This resulted in total removal of the tumour but revealed bilateral lymph node metastases. Vital functions were saved by reconstruction of the palate with a free vascularized tensor-fasciae-latae-perforator-flap. For the first time in a case of adenosquamous carcinoma carcinoembryonic antigen in serum was monitored. A pretherapeutical 29-fold elevation resulted in a marked decrease after surgery, but supranormal values indicated remaining tumour burden which was found in metastases in the lung. Because of the limitations in therapy, early histologic diagnosis is most important in this highly malignant tumour.

Morbidity of transrectal ultrasound-guided prostate needle biopsy in patients receiving immunosuppression.

OBJECTIVES: To prospectively evaluate the safety and early and delayed morbidity of transrectal ultrasound-guided needle biopsies in patients receiving immunosuppressive therapy. METHODS: A total of 59 men receiving immunosuppressive agents after kidney transplantation, with a total prostate-specific antigen level between 4 and 10 ng/mL, were prospectively studied. All patients underwent transrectal ultrasound (TRUS)-guided sextant biopsy plus two additional transition zone biopsies. Biopsy samples were also obtained from suspicious areas identified during TRUS and digital rectal examination. The immediate and delayed morbidity, patient satisfaction, and complication rates were recorded and compared with the morbidity data recorded in the same period from 1051 men in the European Prostate Cancer Detection study. RESULTS: Of the 59 subjects, prostate cancer was detected in 17; 231 men were found to have cancer in the European Prostate Cancer Detection Study. Minor or no discomfort was observed in 88% and 92% of the transplant recipients and controls, respectively (P = 0.31). Twelve percent versus 8% experienced pain. Early morbidity included rectal bleeding (2.6% versus 2.1%, P = 0.19), severe hematuria (0.8% versus 0.7%, P = 0.08), and moderate to severe vasovagal episodes (1.9% versus 2.8%, P = 0.04). Late morbidity included fever (3.5% versus 2.9%, P = 0.1), hematospermia (11.0% versus 9.8%, P = 0.1), recurrent mild hematuria (17.4% versus 16.8%, P = 0.08), persistent dysuria (6.4% versus 7.2%, P = 0.2), and urinary tract infections (12.0% versus 10.9%, P = 0.08). Major complications were rare: urosepsis (0% versus 0.1%). CONCLUSIONS: The results of our study demonstrate that TRUS-guided biopsy of the prostate is generally well tolerated, with minor morbidity, in patients receiving immunosuppression. No differences were noted in pain apprehension or early and delayed morbidity, suggesting that TRUS-guided biopsies can be performed safely in these patients.

Prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: when should we stop?

PURPOSE: We evaluated biochemical parameters and pathological features, as well as biopsy related morbidity of prostate cancer detected on biopsies 2, 3 and 4 in men with total serum prostate specific antigen (PSA) between 4 and 10 ng./ml. These features were compared to those detected on prostate biopsy 1. MATERIALS AND METHODS: In this prospective European Prostate Cancer Detection study 1,051 men with total PSA between 4 and 10 ng./ml. underwent transrectal ultrasound guided sextant biopsy and 2 additional transition zone biopsies. All patients in whom biopsy samples were negative for prostate cancer underwent biopsy 2 after 6 weeks. If also negative, biopsies 3 and even 4 were performed at 8-week intervals. Those patients with clinically localized cancer underwent radical prostatectomy. Pathological and clinical features of patients diagnosed with cancer on either biopsy 1 or 2 and clinically organ confined disease who agreed to undergo radical prostatectomy were compared. RESULTS: Cancer detection rates on biopsies 1, 2, 3 and 4 were 22% (231 of 1,051), 10% (83 of 820), 5% (36 of 737) and 4% (4 of 94), respectively. Overall, of the patients with clinically localized disease, which was 67% of cancers detected, 86% underwent radical prostatectomy and 14% opted for watchful waiting or radiation therapy. Overall, 58.0%, 60.9%, 86.3% and 100% of patients had organ confined disease on biopsies 1, 2, 3 and 4, respectively. Despite statistically significant differences in regard to multifocality (p = 0.009) and cancer location (p = 0.001), including cancer on biopsy 2 showing a lower rate of multifocality and a more apico-dorsal location, there were no differences in regard to stage (p = 0.2), Gleason score (p = 0.3), percent Gleason grade 4/5 (p = 0.2), serum PSA and patient age between biopsies 1 and 2. However, cancer detected on biopsies 3 and 4 had a significantly lower Gleason score (p = 0.001 and 0.001), lower rate of grade 4/5 (p = 0.02), and lower volume (p = 0.001 and 0.001) and stage (p = 0.001), respectively. CONCLUSIONS: Despite differences in location and multifocality, pathological and biochemical features of cancer detected on biopsies 1 and 2 were similar, suggesting comparable biological behaviors. Cancer detected on biopsies 3 and 4 had a lower grade, stage and volume compared with that on biopsies 1 and 2. Morbidity on biopsies 1 and 2 was similar, whereas biopsies 3 and 4 had a slightly higher complication rate. Therefore, biopsy 2 in all cases of a negative finding on biopsy 1 appears justified. However, biopsies 3 and 4 should only be obtained in select patients with a high suspicion of cancer and/or poor prognostic factors on biopsy 1 or 2.

Expression of the cell cycle proteins p21, p27, and pRb in clear cell renal cell carcinoma and their prognostic significance.

OBJECTIVES: To determine whether p21, p27, and pRb can predict disease progression in clear cell renal cell carcinoma. METHODS: The expression of three negative regulators of the cell cycle, the retinoblastoma gene product (pRb), the WAF1/Cip1 gene product (p21), and the Kip1 gene product (p27), was investigated by immunohistochemistry on paraffin sections from 104 formalin-fixed clear cell carcinoma specimens and related to p53 overexpression, the clinicopathologic parameters, and survival. RESULTS: pRb expression was not associated with tumor stage, but the correlation with p27 and p21 positivity was statistically significant (r = 0.26, P = 0.008 and r = 0.3, P = 0.002, respectively). Tumors representing p53 overexpression showed a higher pRb labeling index compared with p53-negative tumors (P = 0.0004). p21 protein expression correlated significantly with p27 positivity (r = 0.2, P = 0.04) and was associated with p53 overexpression (P = 0.0005), but did not correlate with tumor stage or grade. No association could be found between p27 positivity and tumor grade, tumor stage, or p53 overexpression. In univariate survival analysis, an increased pRb positivity (P = 0.002) and a low p27 expression (P = 0.0001) predicted a poor outcome, especially if combined with p53 overexpression (P = 0.004 and P = 0.0002, respectively). p21 did not give any prognostic information. Moreover, in multivariate analysis, pRb and p27 were revealed to be statistically significant. CONCLUSIONS: The results of our study indicate that in clear cell renal cell carcinoma, the cell cycle proteins p27 and pRb are powerful and independent prognostic factors and that p21 has no predictive value.

Genetic engineering of a hypoallergenic trimer of the major birch pollen allergen Bet v 1.

An estimated 100 million individuals suffer from birch pollen allergy. Specific immunotherapy, the only curative allergy treatment, can cause life-threatening anaphylactic side effects. Here, we report the genetic engineering of a recombinant trimer consisting of three covalently linked copies of the major birch pollen allergen, Bet v 1. The trimer exhibited profoundly reduced allergenic activity but contained similar secondary structures such as Bet v 1 wild type, Bet v 1-specific B cell and T-cell epitopes, and induced Th1 cytokine release. As immunogen, rBet v 1 trimer induced IgG antibodies, which blocked patients' IgE binding to Bet v 1 and related allergens. Thus, rBet v 1 trimer represents a novel hypoallergenic vaccine prototype for treatment of one of the most frequent allergy forms.

Spatial distribution of prostate cancers undetected on initial needle biopsies.

OBJECTIVES: The spatial distribution of cancer foci of prostate carcinomas with negative initial biopsies was compared to that of prostate carcinomas with positive initial biopsies to detect areas in which carcinomas were more frequently located when the initial biopsy was negative. METHODS: Twenty patients with prostate cancer and a negative initial biopsy trial were detected among 218 patients with preceding systematic biopsies (9.2%) in our hospital. Analysis of the prostatectomy specimens regarding cancer distribution, multifocality, tumour size, Gleason score, and stage was performed using pathohistological techniques and three-dimensional computer reconstruction. RESULTS: Prostatectomy specimens with negative initial biopsies showed more frequently cancer foci in apical (p<0.0001) and dorsal (p<0.02) prostatic compartments, higher incidence of multifocality (p<0.01), and smaller size of carcinoma foci (p<0.00003) compared to carcinomas in 81 stage-matched prostatectomy specimens with positive initial biopsies. Comparing both groups, no significant differences were noted in Gleason score of preoperative biopsies and prostatectomies, prostate weight, prostate-specific antigen (PSA) level, digital rectal examination, and patients age. CONCLUSIONS: Missing the cancer in clinically significant prostate carcinomas by current systematic biopsy techniques may also be due to an apico-dorsal cancer location, particularly in combination with multifocality and small size of carcinoma foci in large prostates. In case of reasonable clinical suspicion of prostate cancer and negative initial biopsy, an early repeat biopsy with special emphasis on the apico-dorsal peripheral zone should be envisaged.