Timothy A. Masterson

Pathological Upgrading and Up Staging With Immediate Repeat Biopsy in Patients Eligible for Active Surveillance

PURPOSE Active surveillance with selective delayed intervention is a treatment regimen used in patients with low risk prostate cancer. Decision making is based on pretreatment prostate specific antigen, clinical stage and prostate biopsy results. We reviewed our experience with immediate repeat biopsy in patients eligible for active surveillance with selective delayed intervention. MATERIALS AND METHODS A retrospective review was done of the records of consecutive patients who underwent repeat biopsy within 3 months of a first positive biopsy from March 2002 to June 2007. Patients were considered eligible if they had prostate specific antigen less than 10 ng/ml, clinical stage T2a or less, Gleason pattern 3 or less, 3 or fewer positive cores and no single core with 50% or greater cancer involvement. RESULTS A total of 104 patients met eligibility criteria. Of the 104 repeat biopsies performed 27 (26%) were negative, 59 (57%) had a Gleason score of 6 or less and 17 (16%) had a Gleason score of 7. One patient had a Gleason score of 9, while 10 of 104 (10%) had greater than 3 cores involved on repeat biopsy and 12 (12%) had 50% or greater involvement of at least 1 core. Of 104 cases (27%) 28 were upgraded and/or up staged. Treated cases that were upgraded and/or up staged were more likely to show higher pathological stage and grade at radical prostatectomy than those that were not (p = 0.003 and p = 0.001, respectively). CONCLUSIONS Immediate repeat biopsy in cases of active surveillance with selective delayed intervention resulted in 27% being upgraded or up staged and those were more likely to show higher grade and stage disease at radical prostatectomy. We recommend repeat biopsy because it improved our discrimination of who are the best candidates for active surveillance with selective delayed intervention.

The Association Between Total and Positive Lymph Node Counts, and Disease Progression in Clinically Localized Prostate Cancer

PURPOSE We examined the association between the number of LNs removed, the number of positive LNs and disease progression in patients undergoing pelvic lymph node dissection and radical retropubic prostatectomy for clinically localized prostate cancer. MATERIALS AND METHODS We analyzed 5,038 consecutive patients who underwent radical retropubic prostatectomy between 1983 and 2003. Clinicopathological parameters, including the administration of neoadjuvant hormonal therapy, preoperative prostate specific antigen, specimen Gleason score, surgeon and pathological stage, were collected prospectively in our prostate cancer database. We excluded men treated with radiation or chemotherapy before surgery. BCR was defined as 2 postoperative prostate specific antigen increases greater than 0.2 ng/ml. Cox models were used to determine whether the number of nodes removed or the number of positive nodes predicted freedom from BCR after adjustment for prognostic covariates. RESULTS The 4,611 eligible patients had a median of 9 LNs (IQR 5 to 13) removed. Positive nodes were found in 175 patients (3.8%). Overall the number of LNs removed did not predict freedom from BCR (HR per additional 10 nodes removed 1.02, 95% CI 0.92 to 1.13, p = 0.7). Results were similar in patients receiving and not receiving neoadjuvant hormonal therapy. Finding any LN involvement was associated with a BCR HR of 5.2 (95% CI 4.2 to 6.4, p <0.0005). However, in men without nodal involvement an increased number of nodes removed correlated significantly with freedom from BCR (p = 0.01). CONCLUSIONS Nodal disease increased the risk of progression. Extensive lymphadenectomy enhances the accuracy of surgical staging. However, we were unable to determine that removing more nodes improves freedom from BCR uniformly. Since the proportion of patients with prostate cancer with positive nodes is low, the value of extensive lymphadenectomy requires a multi-institutional, randomized clinical trial.

Cholesterol Sulfate Imaging in Human Prostate Cancer Tissue by Desorption Electrospray Ionization Mass Spectrometry

Development of methods for rapid distinction between cancerous and non-neoplastic tissues is an important goal in disease diagnosis. To this end, desorption electrospray ionization mass spectrometry (DESI-MS) imaging was applied to analyze the lipid profiles of thin tissue sections of 68 samples of human prostate cancer and normal tissue. The disease state of the tissue sections was determined by independent histopathological examination. Cholesterol sulfate was identified as a differentiating compound, found almost exclusively in cancerous tissues including tissue containing precancerous lesions. The presence of cholesterol sulfate in prostate tissues might serve as a tool for prostate cancer diagnosis although confirmation through larger and more diverse cohorts and correlations with clinical outcome data is needed.

Multivariate statistical differentiation of renal cell carcinomas based on lipidomic analysis by ambient ionization imaging mass spectrometry.

AbstractDesorption electrospray ionization (DESI) mass spectrometry (MS) was used in an imaging mode to interrogate the lipid profiles of thin tissue sections of 11 sample pairs of human papillary renal cell carcinoma (RCC) and adjacent normal tissue and nine sample pairs of clear cell RCC and adjacent normal tissue. DESI-MS images showing the spatial distributions of particular glycerophospholipids (GPs) and free fatty acids in the negative ion mode were compared to serial tissue sections stained with hematoxylin and eosin (H&E). Increased absolute intensities as well as changes in relative abundance were seen for particular compounds in the tumor regions of the samples. Multivariate statistical analysis using orthogonal projection to latent structures treated partial least square discriminate analysis (PLS-DA) was used for visualization and classification of the tissue pairs using the full mass spectra as predictors. PLS-DA successfully distinguished tumor from normal tissue for both papillary and clear cell RCC with misclassification rates obtained from the validation set of 14.3% and 7.8%, respectively. It was also used to distinguish papillary and clear cell RCC from each other and from the combined normal tissues with a reasonable misclassification rate of 23%, as determined from the validation set. Overall DESI-MS imaging combined with multivariate statistical analysis shows promise as a molecular pathology technique for diagnosing cancerous and normal tissue on the basis of GP profiles. FigureMolecular disease diagnostics by DESI without sample preparation. a Good information is obtained by mapping the distribution of individual compounds in the tissue (e.g., PI(18:0/20:4). b Even better discrimination between tumor and healthy tissue is achieved using PLS-DA to consider all the data after having established through a training set of samples the features that correlate with disease as recognized by standard H&E stain pathological examination

Multivariate Statistical Identification of Human Bladder Carcinomas Using Ambient Ionization Imaging Mass Spectrometry

Diagnosis of human bladder cancer in untreated tissue sections is achieved by using imaging data from desorption electrospray ionization mass spectrometry (DESI-MS) combined with multivariate statistical analysis. We use the distinctive DESI-MS glycerophospholipid (GP) mass spectral profiles to visually characterize and formally classify twenty pairs (40 tissue samples) of human cancerous and adjacent normal bladder tissue samples. The individual ion images derived from the acquired profiles correlate with standard histological hematoxylin and eosin (H&E)-stained serial sections. The profiles allow us to classify the disease status of the tissue samples with high accuracy as judged by reference histological data. To achieve this, the data from the twenty pairs were divided into a training set and a validation set. Spectra from the tumor and normal regions of each of the tissue sections in the training set were used for orthogonal projection to latent structures (O-PLS) treated partial least-square discriminate analysis (PLS-DA). This predictive model was then validated by using the validation set and showed a 5% error rate for classification and a misclassification rate of 12%. It was also used to create synthetic images of the tissue sections showing pixel-by-pixel disease classification of the tissue and these data agreed well with the independent classification that uses histological data by a certified pathologist. This represents the first application of multivariate statistical methods for classification by ambient ionization although these methods have been applied previously to other MS imaging methods. The results are encouraging in terms of the development of a method that could be utilized in a clinical setting through visualization and diagnosis of intact tissue.

Preservation of ejaculation in patients undergoing nerve-sparing postchemotherapy retroperitoneal lymph node dissection for metastatic testicular cancer.

OBJECTIVES To evaluate the clinical parameters associated with the recovery of ejaculation after nerve-sparing postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for nonseminomatous germ cell tumor. METHODS We queried our institutional database for all patients who had undergone nerve-sparing PC-RPLND from 1995 to 2005 using a bilateral template. Nerve sparing was performed whenever technically feasible and oncologically prudent. Antegrade ejaculation was defined as any seminal fluid expulsion and was determined by patient report. We evaluated the recovery of antegrade ejaculation using clinical and pathologic parameters and fit a logistic regression model to determine which preoperative variables were associated with antegrade ejaculation. RESULTS A total of 341 patients had undergone PC-RPLND during the study period, 136 (40%) with nerve-sparing techniques. Postoperative antegrade ejaculation was reported by 107 of 136 patients (79%) with information available. On multivariate analysis, a right-sided primary testicular tumor (odds ratio 0.4, 95% confidence interval 0.1-1.0, P = .044) and residual masses > or = 5 cm (odds ratio 0.1, 95% confidence interval 0.0-0.7, P = .020) were associated with retrograde ejaculation. However, 40 of 54 patients (74%) with right-sided primary tumors and 4 of 9 patients (44%) with a mass > or = 5 cm reported antegrade ejaculation. The 5-year relapse-free survival rate was 98%, with a median follow-up of 39 months (interquartile range 19-66). CONCLUSIONS Nerve-sparing PC-RPLND is associated with excellent functional return of antegrade ejaculation, is feasible in select patients with bulky disease, and results in excellent oncologic outcomes.

Modified technique for neurovascular bundle preservation during radical prostatectomy: association between technique and recovery of erectile function

To prospectively evaluate whether a modified surgical technique for neurovascular bundle (NVB) preservation during radical prostatectomy (RP) is associated with an improvement in erectile function (EF) recovery after RP.

Prostate Size is Associated With Surgical Difficulty but Not Functional Outcome at 1 Year After Radical Prostatectomy

PURPOSE We assessed the impact of prostate size on operative difficulty as measured by estimated blood loss, operating room time and positive surgical margins. In addition, we assessed the impact on biochemical recurrence and the functional outcomes of potency and continence at 1 year after radical prostatectomy as well as postoperative bladder neck contracture. MATERIALS AND METHODS From 1998 to 2007, 3,067 men underwent radical prostatectomy by 1 of 5 dedicated prostate surgeons with no neoadjuvant or adjuvant therapy. Pathological specimen weight was used as a measure of prostate size. Cox proportional hazards and logistic regression analysis was used to study the association between specimen weight, and biochemical recurrence and surgical margin status, respectively, controlling for adverse pathological features. Continence and potency were analyzed controlling for age, nerve sparing status and surgical approach. RESULTS With increasing prostate size there was increased estimated blood loss (p = 0.013) and operative time (p = 0.004), and a decrease in positive surgical margins (84 of 632 [14%] for 40 gm or less, 99 of 862 [12%] for 41 to 50 gm, 78 of 842 [10%] for 51 to 65 gm, 68 of 731 [10%] for more than 65 gm, p <0.001). Biochemical recurrence was observed in 186 of 2,882 patients followed postoperatively and was not significantly associated with specimen weight (p = 0.3). Complete continence was observed in 1,165 of 1,422 patients (82%) and potency in 425 of 827 (51%) at 1 year. Specimen weight was not significantly associated with potency (p = 0.8), continence (p = 0.08) or bladder neck contracture (p = 0.22). CONCLUSIONS Prostate size does not appear to affect biochemical recurrence or 1-year functional results. However, estimated blood loss and operative time increased with larger prostate size, and positive surgical margins are more often observed in smaller glands.

Differentiation of prostate cancer from normal tissue in radical prostatectomy specimens by desorption electrospray ionization and touch spray ionization mass spectrometry

Radical prostatectomy is a common treatment option for prostate cancer before it has spread beyond the prostate. Examination for surgical margins is performed post-operatively with positive margins reported to occur in 6.5-32% of cases. Rapid identification of cancerous tissue during surgery could improve surgical resection. Desorption electrospray ionization (DESI) is an ambient ionization method which produces mass spectra dominated by lipid signals directly from prostate tissue. With the use of multivariate statistics, these mass spectra can be used to differentiate cancerous and normal tissue. The method was applied to 100 samples from 12 human patients to create a training set of MS data. The quality of the discrimination achieved was evaluated using principal component analysis - linear discriminant analysis (PCA-LDA) and confirmed by histopathology. Cross validation (PCA-LDA) showed >95% accuracy. An even faster and more convenient method, touch spray (TS) mass spectrometry, not previously tested to differentiate diseased tissue, was also evaluated by building a similar MS data base characteristic of tumor and normal tissue. An independent set of 70 non-targeted biopsies from six patients was then used to record lipid profile data resulting in 110 data points for an evaluation dataset for TS-MS. This method gave prediction success rates measured against histopathology of 93%. These results suggest that DESI and TS could be useful in differentiating tumor and normal prostate tissue at surgical margins and that these methods should be evaluated intra-operatively.

Incidence and Risk Factors of Parastomal Hernia in Patients Undergoing Radical Cystectomy and Ileal Conduit Diversion

PURPOSE We evaluate the incidence and risk factors of parastomal hernia formation in patients undergoing radical cystectomy and ileal conduit urinary diversion. MATERIALS AND METHODS We retrospectively reviewed the Indiana University cystectomy database between 2001 and 2011, and identified 516 patients who underwent radical cystectomy and ileal conduit diversion. Overall 199 patients had a clinical followup of at least 12 months and all underwent postoperative staging computerized tomography to confirm the presence of parastomal hernia. The incidence of parastomal hernia is reported with correlations made to demographic, patient level and perioperative risk factors. RESULTS A parastomal hernia developed in 58 patients (29%) at a median followup of 27 months (range 12 to 125). Of these patients 26 (45%) underwent surgical repair due to abdominal discomfort (58%), acute strangulation or obstruction of the small bowel (15%), partial small bowel obstructions (15%) and elective repair for other intra-abdominal procedures (12%). Prior exploratory laparotomy (adjusted HR 1.98, 95% CI 1.97-3.36, p = 0.011) and severe obesity (adjusted HR 4.26, 95% CI 1.52-11.93, p = 0.006) were predictive of parastomal herniation. The cumulative risk of parastomal hernia formation at 1 and 2 years after cystectomy was 12.2% and 22.5%, respectively. CONCLUSIONS We demonstrated that parastomal hernia will develop in nearly a third of patients after radical cystectomy with ileal conduit diversion. Prior laparotomy and severe obesity are independent risk factors. Preoperative counseling and preventative measures regarding parastomal hernia formation should be emphasized, particularly in these at risk patients.