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Supplementary Figure S3. (A) Experimental scheme. Sera and tumor measurements were collected from BALB/c mice on days 0, 8, 17, 24, and 30 (n= 9). (B) α-Her2 IgG levels were quantified from sera and correlated with tumor volume. Mean D2F2/E2 volume (mm3) and α-Her2 IgG (Ab5 equivalent μg/mL) are plotted on the left and right y-axis respectively. (C) Three mice were euthanized at day 17 to collect spleens for IFN-γ ELISPOT. Splenocytes were isolated and stimulated with either EKB or KB 3T3 lines for 48hr (n=3/group). **P

The rising prevalence of insulin resistance (IR), metabolic syndrome, and type 2 diabetes are associated with increases in abdominal mesenteric fat. Adipocytes are sensitive to low temperatures, making cryolipolysis of mesenteric fat an attractive treatment modality to potentially reduce IR.We aimed to determine whether (1) cryolipolysis is safe in reducing the volume of the mesenteric fat and (2) reduction in mesenteric fat volume reduces indices of IR and glycemic dysfunction.Indiana University School of Medicine.A novel cooling device and method delivered cryolipolysis in a controlled manner to avoid tissue ablative temperatures. Ossabaw pigs (n = 8) were fed a high-fat diet for 9 months to develop visceral obesity, IR, and metabolic syndrome. Following laparotomy, mesenteric fat cryolipolysis (MFC) was performed in 5 pigs, while 3 served as sham surgery controls. The volume of the mesenteric fat was measured by computed tomography and compared with indices of glucose intolerance before and at 3 and 6 months postprocedure.MFC safely reduced mesenteric fat volume by ∼30% at 3 months, which was maintained at 6 months. Body weight did not change in either the MFC or sham surgery control groups. Measure of glycemic control, insulin sensitivity, and blood pressure significantly improved after MFC compared with sham controls.MFC reduces the volume of mesenteric fat and improves glycemic control in obese, IR Ossabaw pigs, without adverse effects.

To assess the technical feasibility and outcomes of adrenal metastases cryoablation.This is an IRB approved retrospective review of adrenal metastases cryoablation between April 2003 and October 2018. Forty percutaneous cryoablation procedures were performed on 40 adrenal metastases in 34 patients. Histology, tumor size, ablation zone size, major vessel proximity, local recurrences, complications, and anesthesia-managed hypertension monitoring was collected. Complications were graded according to the Common Terminology of Complications and Adverse Events (CTCAE).Mean tumor and ablation size was 3.2 cm and 5.2 cm, respectively. Local recurrence rate was 10.0% (N = 4/40) for a mean follow-up time of 1.8 years. Recurrences for tumors 3 cm (21.0%, N = 4/19) was greater than for tumors ≤ 3 cm (0.0%, N = 0/21) (p = 0.027). Proximity of major vasculature (i.e., IVCaorta) did not statistically effect recurrence rates (p = 0.52), however, those that recurred near vasculature were 4 cm. Major complication (≥ grade 3) rate was 5.0% (N = 2/40), with one major complication attributable to the procedure. Immediate escalation of blood pressure during the passive stick phase (between freeze cycles) or post procedure thaw phase was greater in patients with residual adrenal tissue (N = 21/38) versus masses replacing the entire adrenal gland (N = 17/38), (p = 0.0020). Lower blood pressure elevation was noted in patients with residual adrenal tissue who were pre-treated with alpha blockade (p = 0.015).CT-guided percutaneous cryoablation is a safe, effective and low morbidity alternative for patients with adrenal metastases. Transient hypertension is related only to residual viable adrenal tissue but can be safely managed and prophylactically treated.

Purpose To retrospectively assess long-term outcomes of percutaneous renal cryoablation, including factors affecting complications and local recurrence rates. Materials and Methods A total of 357 computed tomographic (CT) fluoroscopy–guided percutaneous cryoablation procedures were performed for 382 masses in 302 outpatients; 347 were biopsy-proven renal-cell carcinoma (RCC) or Bosniak category > III masses (n = 28). Benign pathologic conditions (n = 18) or metastatic non-RCC disease (n = 17) were included to analyze procedural complication rate, but recurrence rates, tumor staging, and nephrometry score were limited to RCCs. The average tumor diameter was 2.9 cm (range, 1–10.3 cm), and median nephrometry score for RCC was 8 (mean, 7.4). Protection of adjacent vital structures was performed in 34% of procedures (n = 121), and ureteral stent placement was performed for 9.2% (n = 33). All major complications were graded per surgical Clavien–Dindo criteria. Results The average CT-visible cryoablation zone diameter was 5 cm (range, 2.5–10.5 cm). Grade ≥ 3 complications occurred in 2.8% of procedures (n = 10), and appeared related to only high nephrometry scores ( P = .0086) and larger tumors ( P = .0034). No significant changes in renal function before and after the procedure were noted ( P = .18). At a mean follow-up of 31.8 months, the local tumor recurrence rate was 3.2% (11 of 347) for RCC, and no significant difference was noted between tumors larger or smaller than 3 cm ( P = .15). The difference reached significance only among the small number of stage ≥ T2 RCC tumors ( P = .0039). Conclusions Long-term follow-up of percutaneous renal cryoablation demonstrates low recurrence rates with preserved renal function, even for patients with high nephrometry scores and body mass index, assuming thorough cytotoxic technique and protection measures.

The objective of this study is to present cryoablation as a minimally invasive definitive treatment for abdominal wall endometriosis. We describe our experience with the outpatient application of cryoablation to treat symptomatic abdominal wall endometriosis in three patients.This feasibility study shows that minimally invasive cryoablation treated abdominal wall endometriosis in three patients and provided a prompt clinical response.

Objectives: The objectives of the study were to report long-term experience with percutaneous thoracic cryoablation, including both malignant pleural and primary pulmonary tumors, assessing factors affecting complications and local recurrence rates. Material and Methods: After Institutional Review Board approval and Health Insurance Accountability Act compliance, a retrospective review of 50 patients who underwent 85 CT fluoroscopic-guided percutaneous cryoablation procedures for 116 masses, consisting of non-small cell lung cancer (n = 61), small cell lung cancer (n = 1), mesothelioma (n = 16) and malignant profile fibrous tumors (n = 38) was performed. Tumor size and location (central vs. peripheral) were noted in relation to major vasculature. Hydrodissection and/or esophageal warming balloons were utilized for the protection of crucial structures. Complications were graded according to standardized Common Terminology Criteria for Adverse Events criteria. Patients were followed by CT and/or MRI at 1, 3, 6, 12, 18, and 24 months and yearly, thereafter. Results: Mean tumor diameter was 3.3 cm and 3.0 cm for primary lung tumors (PLTs) and malignant pleural tumors (MPTs), respectively. The mean number of cryoprobes utilized was 3.7 per tumor, which produced ablation zones with CT visible ice mean diameters of 5.3 cm. Hydrodissection and/or warming balloon protections were used in 15.3% (n = 13/85). Grade ≥3 complications were limited to tumors >3 cm (8.2% = 7/85; P = 0.0042), but did not appear significant for central location. At a mean follow-up of 17.0 months, overall local tumor recurrence was 6.9% (n = 8/116). Pleural tumors had lower recurrence rates than PLTs (1.8% [n = 1/54] vs. 11.3% [n = 7/62], respectively; P < 0.21). Tumors >3 cm or central location had statistically significant higher recurrence rates, (P = 0.021) and (P = 0.039), respectively. Central recurrences occurred predominantly in tumors >3 cm (20%, n = 5/25). Conclusion: With appropriate pre-treatment, evaluation, and procedural criteria, percutaneous cryoablation of both primary lung and pleural tumors is safe and produces very low local recurrence rates, especially for tumors ≤3 cm.

Both mammography and standard ultrasound (US) rely upon subjective criteria within the breast imaging reporting and data system (BI-RADS) to provide more uniform interpretation outcomes, as well as differentiation and risk stratification of associated abnormalities. In addition, the technical performance and professional interpretation of both tests suffer from machine and operator dependence. Breast MR has become the new gold standard for screening of high-risk women but has cost and access limitations in extending screening to the entire population. We have been developing a new technique for breast imaging that is based on ultrasound tomography which quantifies tissue characteristics while also producing 3-D images of breast anatomy. Results are presented from clinical studies that utilize this method. Informed consent was obtained from all patients, prospectively recruited in an IRB-approved protocol following HIPAA guidelines. Images were produced by tomographic algorithms for reflection, sound speed and attenuation. All images were reviewed by a board-certified radiologist who has more than 20 years of experience in breast imaging and US-technology development. In the first phase of the study, UST images were compared to multi-modal imaging to determine the appearance of lesions and breast parenchyma. In the second phase of the study, correlative comparisons with MR breast imaging were used to establish basic operational capabilities of the UST system including the identification and characterization of parenchymal patterns. Our study demonstrated a high degree of correlation of breast tissue structures relative to fat subtracted contrast enhanced MRI. With a scan duration of ~ 1-3 minutes, no significant motion artifacts were observed.

Renal artery stenosis is increasing in prevalence. Angioplasty plus stenting has not proven to be better than medical management. There has been a reluctance to use available denervation methodologies in this condition. We studied conscious, chronically instrumented, two-kidney, one-clip (2K-1C) Goldblatt rats, a model of renovascular hypertension, to test the hypothesis that renal denervation by cryoablation (cryo-DNX) of the renal nerve to the clipped kidney decreases mean arterial pressure (MAP), plasma and tissue ANG II, and contralateral renal sympathetic nerve activity (RSNA). Five-week-old male Sprague-Dawley rats underwent sham (ShC) or right renal artery clipping (2K-1C), placement of telemetry transmitters, and pair-feeding with a 0.4% NaCl diet. After 6 wk, rats were randomly assigned to cryo-DNX or sham cryotreatment (sham DNX) of the renal nerve to the clipped kidney. MAP was elevated in 2K-1C and decreased significantly in both ShC cryo-DNX and 2K-1C cryo-DNX. Tissue norepinephrine was ∼85% lower in cryo-DNX kidneys. Plasma ANG II was higher in 2K-1C sham DNX but not in 2K-1C cryo-DNX vs ShC. Renal tissue ANG II in the clipped kidney decreased after cryo-DNX. Baseline integrated RSNA of the unclipped kidney was threefold higher in 2K-1C versus ShC and decreased in 2K-1C cryo-DNX to values similar to ShC. Maximum reflex response of RSNA to baroreceptor unloading in 2K-1C was lower after cryo-DNX. Thus, denervation by cryoablation of the renal nerve to the clipped kidney decreases not only MAP but also plasma and renal tissue ANG II levels and RSNA to the contralateral kidney in conscious, freely moving 2K-1C rats.

Breast density is one of the strongest predictors of breast cancer risk. Women with the densest breasts are four- to six-times more likely to develop cancer compared with those with the lowest densities. Breast density is generally assessed using mammographic imaging; however, this approach has limitations. Magnetic resonance imaging and ultrasound tomography are some alternative imaging modalities that can aid mammography in patient screening and the measurement of breast density. As breast density becomes more commonly discussed, knowledge of the advantages and limitations of breast density as a marker of risk will become more critical. This review article discusses the relationship between breast density and breast cancer risk, lists the benefits and drawbacks of using multiple different imaging modalities to measure density and briefly discusses how breast density will be applied to aid in breast cancer prevention and treatment.

Cryoablation is a promising minimally invasive technology for cancer treatment. However, no study was reported concerning the effect of cryoablation on cancer stem-like cells (CSCs) that are capable of reinitiating tumor growth after conventional chemotherapy. Using a biomimetic 3D mammosphere model, we found that cryoablation alone could significantly but incompletely destroy CD44+CD133+ CSCs. Moreover, the combination of cryoablation and conventional chemotherapy using free doxorubicin (fDOX) does not significantly enhance destruction of the CSCs over the individual treatments. We develop a novel combined treatment of cryoablation and nanoparticle-encapsulated doxorubicin (nDOX) that is capable of achieving nearly complete elimination of the CSCs (from 16.6 to 0.6%). This is attributed in part to the much-enhanced uptake of nDOX (compared to fDOX) by the CSCs. Collectively, this study demonstrates the great potential of a combined therapy of cryoablation and nanodrug for improved cancer treatment by eliminating the root of cancer — the CSCs.

A population of 165 women with negative mammographic screens also received an ultrasound tomography (UST) exam at the Karmanos Cancer Institute (KCI) in Detroit, MI. Standard statistical techniques were employed to measure the associations between the various mammographic and UST related density measures and various participant characteristics such as age, weight and height. The Mammographic percent density (MPD) was found to have similar strength associations with UST mean sound speed (Spearman coefficient, rs = 0.722, p < 0.001) and UST median sound speed (rs = 0.737, p < 0.001). Both were stronger than the associations between MPD with two separate measures of UST percent density, a k-means (rs = 0.568, p < 0.001) or a threshold (rs = 0.715, p < 0.001) measure. Segmentation of the UST sound speed images into dense and non-dense volumes showed weak to moderate associations with the mammographically equivalent measures. Relationships were found to be inversely and weakly associated between age and the UST mean sound speed (rs = −0.239, p = 0.002), UST median sound speed (rs = −0.226, p= 0.004) and MPD (rs = −0.204, p= 0.008). Relationships were found to be inversely and moderately associated between BMI and the UST mean sound speed (rs = −0.429, p < 0.001), UST median sound speed (rs = −0.447, p < 0.001) and MPD (rs = −0.489, p < 0.001). The results confirm and strengthen findings presented in previous work indicating that UST sound speed imaging yields viable markers of breast density in a manner consistent with mammography, the current clinical standard. These results lay the groundwork for further studies to assess the role of sound speed imaging in risk prediction.

To report our long-term experience with percutaneous cryotherapy for primary and metastatic liver tumors, including historical perspectives on complications over time and local recurrence rates.Following IRB approval under HIPAA compliance, 342 CT fluoroscopic-guided, percutaneous cryotherapy procedures were performed for 443 masses in 212 outpatients with hepatocellular carcinoma (HCC; N = 36), or metastatic disease (N = 176), grouped as colorectal carcinoma (CRC) and non-CRC metastases. Tumor and ablation sizes were noted in relation to adjacent vasculature. All complications were graded according to standardized criteria. Patients were followed by CT and/or MRI at 1, 3, 6, 12, 18, 24 months and yearly thereafter. Local recurrences were defined as either "procedural" within the ice ablation zone, or "satellite" within 1 cm of the ablation rim to evaluate recurrence patterns.Average tumor diameter of 2.8 cm was treated by average cryoprobe number of 4.5, which produced CT-visible ice ablation zone diameters averaging 5.2 cm. Grade3 complications were primarily hematologic [N = 20/342; (5.8%)], and appeared related to pre-procedural anemia/thrombocytopenia, carcinoid tumor type, and large ablation volumes. No significant central biliary leak, strictures, or bilomas were noted. At a mean follow-up of 1.8 years, local tumor recurrences were 5.5%, 11.1%, and 9.4% for HCC, CRC, and non-CRC metastases, respectively, consisting mainly of satellite foci. No significant difference was noted for local recurrences near major blood vessels or tumors3 cm diameter.Percutaneous hepatic cryotherapy is a well-visualized, safe procedure that produces very low local recurrence rates, even for tumors near vasculature and diameters over 3 cm. Cryoablation deserves to be in the armamentarium of percutaneous hepatic ablation, especially with careful patient selection for tumors4 cm and patients with platelet counts100,000. Percutaneous hepatic cryoablation represents a highly flexible technique with particular benefits near central biliary structures and/or adjacent crucial structures.

Although there have been many reports on the use of cryosurgery to ablate hepatic malignancies none have specifically examined the relationship of complication rates to the extent of cryoablation. A retrospective review from January 1997 to May 2002 identified 98 patients treated with hepatic cryotherapy. The extent of the cryosurgery was determined by the total number of lesions (TNL) and total estimated area (TEA) of the lesions from preoperative evaluation by CT scan and intraoperative evaluation by ultrasound. The major complication rate was 11 per cent. The 30-day mortality was 0 per cent, but the late procedure-related mortality was 2 per cent. Increasing the extent of cryotherapy measured by intraoperative ultrasound demonstrated significant increases in the complication rate and length of stay (LOS). With cryoablation of TEA ≥30 cm2 there was a significant increase in the overall complication rate (56% vs 23%; P = 0.003) and LOS (8.8 ± 6.9 vs 6.1 ± 4.2; P = 0.022) compared with TEA 2. Performance of concurrent procedures also led to a significant increase in complications (69% vs 29%; P = 0.010) and LOS (8.6 ± 6.8 vs 6.0 ± 4.0; P = 0.019). Multivariate analysis, however, showed intraoperative TEA ≥30 cm2 to be the most significant independent predictor of increased complications and prolonged LOS.

SummaryApproximately 10 years ago, simultaneous advances in freezing and ultrasound technology allowed localized treatment methods for liver tumors to expand beyond surgical resection. Any technology causing localized tissue destruction requires practical delivery and accurate monitoring techniques

BACKGROUND Estimates of cost-effectiveness for prostate carcinoma screening require a review of current data, modeling efforts, and perspectives on societal impact and costs. METHODS Recent data from the cancer registry of the Michigan Department of Community Health was assessed for incidence trends in relation to age groups and racial differences. Differences in tumor biology between African-American men (AAM) and white men were assessed from a large clinical biopsy series. A review of the literature addressing Markoff modeling to obtain estimates of treatment, screening efficacy, and costs were evaluated. RESULTS The decline in the incidence of prostate carcinoma since 1992 primarily affected men age > 70 years whereas younger men (age 45-70 years) maintained a 100% greater incidence of localized disease than in 1989, when prostate specific antigen screening became more common. The rate of distant disease has decreased by 60% for both age groups. In the current biopsy series, AAM have distinctly more cores involved with carcinoma and have a higher number of carcinoma cores involved with a Gleason score ≥ 7 in men age ≤ 70 years with a PSA level ≤ 10 ng/mL (P < 0.05). Markoff models reviewed in the literature demonstrated significant sensitivity to progression, complication, and comorbidity rates. Recent models suggested significant increases in quality-adjusted life expectancy for men choosing radical prostatectomy over watchful waiting if they were age < 70 years and had no severe comorbidities. Original cost estimates from benefit-cost analysis showed similar results of cost per carcinoma and cost per quality-adjusted life-year extension as later cost-effectiveness models. CONCLUSIONS Current diagnostic trends toward the persistent increased detection of localized prostate carcinoma in younger men, combined with a marked reduction in distant stage disease, suggest significant potential mortality reductions. These trends may have greater implications for AAM, but further research is needed to produce models of mortality reduction from emerging data. Cancer 1997; 80:1864-70. © 1997 American Cancer Society.

BACKGROUND. The American Cancer Society National Prostate Cancer Detection Project (ACS-NPCDP) was established in 1987. The experience of the ACS-NPCDP demonstrates the yield and impact of periodic examinations for the early detection of prostate cancer. METHODS. A cohort of 2999 well men ages 55-70 years was tested annually at 10 clinical centers by prostate specific antigen (PSA), transrectal ultrasound (TRUS), and digital rectal examination (DRE). Biopsies were performed on men with suspicious findings. Pathologic findings were reviewed. The initial study outcomes were the detection yield of multimodality testing and the comparative sensitivity and specificity of the different tests employed. Longer term outcomes included patient quality of life and survival. RESULTS. The cancer detection rate declined significantly across the years of intervention. DRE had lower sensitivity than TRUS or PSA, particularly in later years of follow-up. The specificity of TRUS was lower than that of DRE. Fewer than 9% of the cancers detected in this study were clinically advanced at the time of diagnosis. Ninety-four percent of patients in whom cancer was detected are alive after an average follow-up of 54 months. In one case, death occurred after surgery. Two deaths were attributed to prostate cancer, and eleven other deaths were unrelated to prostate cancer or its treatment. CONCLUSIONS. Results of the ACS-NPCDP indicate that a combined-modality approach to prostate cancer detection yields high levels of early detection with infrequent adverse outcomes. Continued follow-up is required to evaluate long term morbidity and mortality.

BACKGROUND. The American Cancer Society-National Prostate Cancer Detection Project (ACS-NIPCDP) is a multidisciplinary evaluation of early prostate cancer detection interventions. This report summarizes the experience of the investigators to date and dcscribes the overall and relative performance ofthe different detection modalities studied in this project. METHODS. Two thousand nine hundred ninety-nine men aged 55 to 70 years at entry who were not already under evaluation for prosrate cancer were recruited to participate in up to 5 annual examinations by prostate specific antigen (PSA), digital rectal examination (DRE), and transrectal ultrasound (TRUS). In the course of 5 years of intervention, ACS-NI’CDI’ investigators have completed 9937 examinations, recommended 1215 biopsies, and detected 203 cancers. RESULTS. I.oss to cohort follow-up was greatest in the first year. Overall, TRUS led to twice the number of recommendations for biopsy compared with [>RE (8.9% versus 4.4%). Elevated PSA was observed in 13.0% of 9535 measurements performed. The overall cancer detection rate declined significantly during the five years of intervention. Detection was significantly associated with age and symptom status at entry. DRE: had lower sensitivity compared withlRUS or PSA, particularly in later years of rollow-up. The specificity of TRtJS was lower than that for LIRE. PSA was elevated in 69.2% of examinations that led to cancer detection. compared with only 10.9% when cancer was not found. PSA level, PSA density, and PSA change were all related to the presence of cancer. Less than 6% of the cancers detected in this study were clinically advanced at the time of diagnosis. CONCLUSIONS. These data quantify the yield of early cancer detection that may be expected when I’SA. DRE, and TRUS are used in populations comparable to the men participating in the ACS-KPCDP. Continued follow-up and further research is needed to assess whether men receiving early prostate cancer interventions benefit as a result. Cancer 1996; 77:150-9. C 1996 Ainericatf Cfmcer Society.

Background. Cryotherapy of the prostate has been reintroduced clinically due to improved ultrasound guidance and cryotechnology. Recent data have emerged from the authors' canine histopathology study that corresponds with other encouraging reports from human studies. Methods. Six mongrel dogs received cryotherapy to the entire prostate and were observed for selected periods of day to 12 weeks with transrectal ultrasound (TRUS) follow-up. Some technical limitations of the canine model prohibited complete comparison with more extensive techniques in humans. Results. TRUS monitoring of posterior ice-ball progression proved to be highly accurate and correlated with subtotal necrosis of the rectal wall sparing the mucosal layer with millimeter accuracy. Scattered residual glands remained at the distal apex in one dog and in the posterolateral periphery of a larger volume prostate. Without adequate urethral warming, central sloughing was noted in longer term animals. Histology demonstrated hemorrhagic infarction with subsequent ingrowth of transitional epithelium from the urethra, producing reepithelialization of glandular spaces along the residual collagenous architecture. Conclusions. Accurate TRUS monitoring of prostate cryotherapy allows thorough yet careful extension of the ice ball through the posterior aspect of the prostate. Unique histologic changes may account for unremarkable TRUS appearance after cryotherapy as well as some of the benign, atypical, glands seen on follow-up biopsies in humans. These findings may explain the remarkably low residual cancer in humans and encourages further studies on this low morbidity, lower cost definitive therapy. Cancer 1995 ;75 :1957-62.

Transrectal ultrasound (TRUS) evaluation of the prostate gland should be reserved for men with a suspected result of digital rectal examination (DRE) or prostate-specific antigen (PSA). However, we questioned the recent emphasis of linking suspected screening parameters with automatic biopsy of all patients without regard for TRUS diagnostic criteria. Beyond hypoechoic patterns of intraglandular tumor spread, TRUS assists in cancer risk evaluation through gland volume adjustments of moderate elevations in PSA. Gland volume has minimal longitudinal measurement variation (less than 5 cc) for men with prostate volume less than 50 cc, thereby producing less relative variability over time than PSA. The optimal decision level for PSA density (ng/ml/cc) is 0.12 ng/ml/cc and is a stronger risk parameter than the subjective results of DRE or TRUS. Therefore, a biopsy approach tailored to patients with positive predictive values greater than 10% was developed, and it included patients with PSA density greater than 0.12 ng/ml/cc or concurrently suspicious DRE and TRUS. Significant reductions in low-risk biopsy (that is, a positive predictive value less than 10%) thus can be achieved, even beyond those attainable using age-related criteria and with comparable sensitivity. The rationale for performing a modified sextant biopsy technique in the axial projection and possibilities for directed staging biopsies are presented. Cancer 1995 ;75 :1805-13.

Background. Prostate specific antigen (PSA) is the most accurate and objective test for of detecting early prostate cancer, yet false-positive elevations have resulted in costly biopsies of many patients at relatively low risk for prostate cancer. A biopsy approach tailored to positive predictive values above 10% is described and the cost implications of improved specificity are addressed by benefit-cost analysis. Methods. Data from recent biopsy decision analyses allowed calculations of overall sensitivity, specificity, and prevalence for various proposed screening options. These were incorporated into the benefit-cost equation, including updates in minor cost changes. Projected 1-year results of systematic biopsy of all patients with suspicious PSA and/or digital rectal examination (DRE) versus the tailored biopsy approach (i.e., biopsy of all patients with PSA density >0.12 ng/ml/cc or concurrently suspicious DRE and transrectal ultrasound) were compared for each screening option. Results. The tailored biopsy approach produced consistent increases in specificity for all screening options, with comparable mild losses in cancer sensitivity. The benefit-cost equation is most sensitive to fluctuations in screening test specificity such that only mild increases in specificity (i.e., 5%) produced marked reductions (50%) in net cost per individual screened. These reductions are greatest for screening approaches using lower PSA values or those including DRE. Conclusions. The most cost-effective approach for any PSA-based, prostate cancer early detection appears to require the use of biopsy protocols tailored to patients at higher risk for prostate cancer. Cancer 1995 ;75 : 1987-93.

Background. In hopes of limiting low-yield prostate biopsies, results of digital rectal examination (DRE), transrectal ultrasound (TRUS), prostate specific antigen (PSA) and age-related PSA values, gland-volume-adjusted PSA levels, and longitudinal PSA changes were analyzed to identify their cost-effectiveness as prognostic indicators in screening, biopsy, and follow-up of patients with prostate cancer. Methods. Twenty-nine hundred men with complete data sets from an initial cohort of 2999 men with an annual follow-up for up to 5 years were examined. Intrapatient PSA and gland-volume variability, optimal PSA operating points (o. P.), and test performance scores were determined for each parameter. Decision analysis was then applied retrospectively to each parameter to determine the cancer detection yield, biopsy requirements, and costs for commonly used detection strategies. Results. For the initial screening decision, the optimal PSA o. p. was 3.0 ng/ml but increased to 5.0 ng/ml in combination with DRE, whereas age-related PSA performed no better than did PSA. The mean intrapatient variability in TRUS gland volume (+5.5 cc) relative to mean volume (34 cc) was 16%, which was less than the 28% (0.64/2.3 ng/mll relative variability for PSA. For biopsy decisions, using PSA density (PSAD) with a level of 0.12 ng/ml/cc there was no significant difference in accuracy compared with the systematic biopsy of all patients with elevated PSA or age-related PSA levels. Rather than perform systematic biopsy on all patients with PSA levels greater than 4 ng/ml, decision analysis showed that a 16-55% reduction in biopsies could be achieved with a respective cancer loss of 4–25% by limiting biopsy to patients with an increased PSAD level and/or abnormal results of DRE. Using age-related PSA criteria in combination with DRE reduced biopsies by 12% but resulted in minimal cost reductions. The greatest biopsy reduction relative to cancer yield and lowest cost per cancer detected occurred with PSAD-driven biopsy strategies. During follow-up, longitudinal changes in absolute PSA and PSAD levels were significantly better (P < 0.05) than the percentage change in PSA levels per year. Conclusions. Cost-effective prostate cancer detection with PSA as a parameter is better achieved if screening and biopsy decisions are not linked intimately. A tailored-biopsy approach for patients with disproportionately elevated PSA levels of suspicious DRE results in the greatest biopsy reduction by selecting lower risk groups for more conservative follow-up.

Early detection of prostate cancer has produced distinct stage migration of prostate cancer to earlier, more curable disease through optimized combined use of digital rectal exam (DRE), transrectal ultrasound, and prostate specific antigen (PSA). Currently available and emerging data can be assessed according to the World Health Organization's established criteria. As a significant public health problem, prostate cancer meets almost all the criteria for screening. While concerns about incomplete natural history, progression rates, and the need for better prognostic factors are valid, important social and public health issues also need to be considered

Background. Different indexes that may enhance the early detection capability of prostate specific antigen (PSA) have been proposed. In addition to the indexes relating to the normal PSA level, there are data suggesting the usefulness of the PSA level relative to prostate gland volume (PSA density), age-referenced PSA level, and PSA change. Little research comparing the sensitivity and specificity of these measures in the same population has been reported. Methods. All subjects were participants in the American Cancer Society National Prostate Cancer Detection Project. Specificity was studied in 2011 men without prostate cancer, and sensitivity was determined for 171 men with prostate cancer. Results. Prostate specific antigen change showed the highest specificity (96.4%), and PSA density the lowest (85.3%). The most sensitive index was PSA density, which was positive for 74.7% of the 171 cases of known cancer. A PSA change of more than 0.75 ng/ml per year was the least sensitive index (54.8%). Sensitivity and specificity varied in a narrow range. Improved performance in specificity was achieved only with the loss of sensitivity. Conclusions. None of the alternative indexes commonly used in general early detection practice demonstrated particular advantage when compared with the normal PSA concentration, defined as no more than 4.0 ng/ml.

Methods. The diagnostic performance of transrectal ultrasound (TRUS) gland volume and prostate specific antigen (PSA) results were evaluated in 204 men consecutively scheduled to undergo transurethral prostatic resection (TUR). Results. Nonpalpable prostate cancer was detected by TRUS alone in 18% (29 of 161) and by TUR alone in 9% (14/161), for an overall cancer incidence of 27%. A predicted PSA value (TRUS gland volume × 0.20 ng/ml/g = polyclonal PSA) was used for comparison with serum PSA for each patient. TRUS positive predictive value improved from 52% to 86% when serum PSA exceeded the predicted value. The specificity and positive predictive value of PSA at 2.5 ng/ml were 23% and 37%, respectively, which increased to 88% and 72%, respectively, when serum PSA exceeded the predicted value. Conclusions. Predicted PSA values produce decision levels near the 95th percentile for each patient and assist individual biopsy decisions better than grouped gland volume ranges. Wider application of TRUS and PSA in any clinical setting or early detection program is now possible.

In a study population, can digital rectal examination (DRE), transrectal ultrasound (TRUS), and prostate specific antigen (PSA) (monoclonal) effectively detect the majority of clinically relevant cancer? If this is possible, the remaining patients could then be considered for chemopreventive protocols. The American Cancer Society/National Prostate Cancer Detection Project (ACS/NPCDP) had a cancer detection rate of 2.4% for its initial year utilizing PSA, DRE and TRUS. TRUS and PSA detected 73% more cancer than DRE alone. TRUS detected a greater percentage of cancers than DRE (85% vs. 64%). PSA wasor = 4 ng/ml for 66% of prostate cancer patients; 11% of cancer patients had PSA2 ng/ml. PSA decision levels based on gland volume detected a subgroup at the 95th percentile that had a nine-fold increased risk for cancer. In a separate study differentiating benign prostatic hypertrophy (BPH) and cancer, we found 0.12 +/- 0.13 ng/ml/gm for serum PSA (sPSA)/gm BPH. This study proved that predicted PSA (pPSA) = gland volume x 0.12; this equation also functioned at the 95th percentile for any individual patient. Individual patient assessment: 1. Entry level PSA = 2 ng/ml. 2. Those patients with PSA2 ng/ml have TRUS determination of gland volume (performed by technician). 3. pPSA = gland volume x 0.12. If sPSApPSA then: 4. (sPSA-pPSA)/2 = predicted volume (cc) of cancer; 5. 3 square root of volume of cancer = mean diameter (cm) of cancer. Thus, these results should detect the majority of clinically relevant cancer (0.5 cc). PSA combined with TRUS and DRE can identify high risk groups for cancer.

Fibroadenomas comprise between 30% and 50% of all breast biopsies. Despite their benign nature, many women have their fibroadenomas surgically removed. We previously reported on a minimally invasive therapy using cryoablation to treat fibroadenomas. We now report on 12-month followup using this technique.A prospective, nonrandomized trial was initiated in June 2000 with IRB approval. The Visica Treatment System was used to cryoablate 70 biopsy-proved fibroadenomas in 57 patients using a freeze-thaw-freeze cycle lasting 6 to 30 minutes. Each patient was serially evaluated for safety, efficacy, and satisfaction.Fifty-seven fibroadenomas (mean 2.1 cm, range 0.8 to 4.2 cm) in 47 patients were followed for 12 months. At 1 year, with 89% median tumor volume reduction measured by ultrasonography, 75% of fibroadenomas were nonpalpable. There were no adverse events and only minor complications. Two patients (4%) had their lesions excised after 12 months; pathology revealed no viable fibroadenoma. Serial mammograms showed resorption of the fibroadenoma leaving minimal residual density without calcifications. Cosmesis was excellent with no volume deficit, as no tissue is removed. Ninety-one percent of patients were satisfied at 12 months.Cryoablation is safe and effective in treating breast fibroadenomas. It offers a nonsurgical, office-based treatment that is well tolerated by patients and accurately monitored with ultrasonographic guidance. At 12 months we found progressive tumor volume reduction and reduced palpability, with no volume deficit, excellent cosmesis, and satisfied patients. Ultrasonography-guided cryoablation is a preferred option for treatment of breast fibroadenomas without open surgery.

Transrectal ultrasound (TRUS) has undergone a continuous evolutionary process, in part owing to continued advances in computer and transducer components. The pace of technologic advancement, however, sometimes exceeds our clinical abilities to ascertain its benefit. In addition, there has been a tendency to view diagnostic parameters on an individual basis, rather than as a continuum of additive risk factors. TRUS was crucial in revolutionizing prostate biopsy techniques, yet its role in diagnosis and individual risk assessment has been more controversial. Political incentives and medical territoriality have played a role, but there is little question about the operator-dependent nature of ultrasound. This may be especially true for TRUS because equipment quality and operator experience vary significantly from tertiary medical facilities to private offices. It is, therefore, important to understand the effects of multiple different risk factors on biopsy outcomes. The American College of Radiology, the American Urologic Association, and the American Cancer Society have recommended that TRUS evaluation be limited to patients with either abnormal digital rectal examination (DRE) or elevated prostate-specific antigen (PSA) level. The assessment of prostate cancer (PCa) risk factors thus begins before TRUS examination and includes positive family history, race, and age. All of these parameters affect pretest probability of cancer being present, yet few physicians (let alone ultrasound technologists) attempt to assess TRUS findings in relation to individual patient risk criteria. Therefore, this article focuses on more than descriptive TRUS findings and presents the impact of other risk factors on the likelihood of biopsy revealing cancer. Perhaps many debates surrounding the test performance of TRUS findings or biopsy outcomes could be mollified if these pretest probabilities could be viewed on a relative risk gradient, or continuum. In this manner, it may become easier to understand the rationale for more tailored biopsy strategies 18 that will continue to emerge as more patient-specific testing allows for easier clinical application. In other words, thorough understanding of each patient's risk for prostate cancer is just as important as understanding the likelihood of any TRUS finding being worthy of a targeted biopsy in that region.

BACKGROUND The pathophysiology of increased color Doppler (CD) flow has not previously been addressed in histologic evaluations of microvascular parameters. In this study, the authors attempted to define the differences between benign and malignant biopsy cores found in regions of the prostate with normal and high CD flow. METHODS Forty patients were retrospectively chosen for CD histologic comparison, each of whom had a core from a sextant biopsy with the following characteristics: malignant tissue with distinct increased CD flow (n = 11), malignant tissue with normal CD flow (n = 10), benign tissue with distinctly increased CD flow (n = 9), or benign tissue with normal CD flow (n = 10). All biopsy cores were stained with factor VIII-related antigen to identify microvasculature and to determine the number of microvessels per square millimeter (mm2) in an average cross-sectional area of microvessels, the percentage of tissue occupied by microvasculature, and the Gleason score. RESULTS In biopsies of benign tissue, high CD flow was associated with greater numbers (P < 0.025) of vessels of similar size than in normal flow benign biopsies. Biopsies of malignant tissue contained significantly greater numbers (P < 0.01) of much smaller vessels (P < 0.0005) than biopsies of benign tissue. In biopsies of malignant tissue, no significant differences in microvasculature parameters were noted between high and normal CD flow, yet biopsies with high CD flow had average Gleason score of 6.7 compared with only 5.9 for biopsies with normal CD flow (P < 0.025). CONCLUSIONS Increased CD flow in biopsies of benign tissue was correlated with a greater number of vessels/mm2, yet all biopsies of malignant tissue had more vessels/mm2 than those of benign tissue. Increased CD flow in biopsies of malignant tissue cannot be explained by standard microvasculature analysis but significantly guides biopsies to regions with a greater Gleason score. Cancer 1998;83:135-140. © 1998 American Cancer Society.

A method and system for examining tissue are provided in which the tissue is maintained in a position so that it may be insonified with a plurality of pulsed spherical or cylindrical acoustic waves. The insonifying acoustic waves are scattered by the tissue so that scattered acoustic radiation including a mix of reflected and transmitted acoustic waves is received. A representation of a portion of the tissue is then derived from the received scattered acoustic radiation.

A study was undertaken to assess the ability of transrectal ultrasound (TR/US), digital rectal examination (DRE), and Prostate Specific Antigen (PSA), to diagnose persistent prostate cancer following an I-125 seed implant (SI). Twenty-six patients formed the study group. The median follow-up time was 38 months, and the range was 20 to 60 months. Eighty-eight percent (23/26) had suspicious lesions on TR/US, followed by ultrasound-guided biopsies. Biopsies were performed only on those patients having suspicious lesions on TR/US. Histologically proven adenocarcinoma was found in 81% (21/26) of the patients. Statistical evaluation was done using tissue obtained at biopsy as the gold standard. The sensitivities for the DRE and PSA were 33% and 76%, respectively. The specificities for DRE and PSA were 50% and 0%, respectively. The positive predictive values for cancer were 91% by TR/US, 100% by DRE, and 89% by PSA. The negative predictive values were 13% for DRE and 0% for PSA. Overall detection rates (N = 26) were 81% for TR/US, 27% for DRE, and 62% for PSA. We conclude that ultrasound criteria for the presence of cancer are the same for both the post-irradiated prostate and the untreated prostate, and that TR/US is the most sensitive testmore » for the diagnosis of persistent local cancer following I125 seed implantation.« less

Magnetic resonance images (MRI) of 22 patients with roentgenographically normal hips were reviewed retrospectively and the findings cat- egorized according to age. With increasing maturi- ty, the MR intensity of the femoral heads on spin echo images increased, as marrow fat became a dominant tissue in the head. The femoral head pat- tern was relatively inhomogeneous, with a broad band of diminished intensity extending in a poster- omedial to anterolateral direction, corresponding to the pattern of trabecular bone. The femoral cap- ital epiphyses were visible in younger patients as structures of bright intensity which remained evi- dent through early adulthood. The articular carti- lage of the hip joint was noted as a distinctive "'halo" around the femoral head. An understand- ing of the MR pattern of the normal hip will aid in the early recognition of pathologic conditions, such as osteonecrosis.

Percutaneous absolute ethanol injections and Nd:YAG laser ablations were performed bilaterally in canine prostates (N = 13) using transrectal ultrasound guidance. Seventy one percent (10/14) of the ethanol injections produced an intraglandular focus of hemorrhagic necrosis. Associated morbidity of ethanol injections included necrosis of the external prostatic sphincter and mucosa of the urethra and bladder. Ninety two percent (11/12) of the laser ablations produced intraglandular foci of thermal tissue damage, which had distinct margins of transition between necrotic and viable cells. The areas of ablation were well visualized by ultrasound and had minimal associated morbidity. The results of this study indicate the technical feasibility of transrectal ultrasound to accurately guide localized ablations in the prostate. Percutaneous laser ablation using transrectal ultrasound guidance deserves further investigation as a potential treatment of localized prostate cancer.

Percutaneous absolute ethanol injections and Nd:YAG laser ablations were performed bilaterally in canine prostates (N = 13) using transrectal ultrasound guidance. Seventy-one percent (10/14) of the ethanol injections produced an intraglandular focus of hemorrhagic necrosis. Associated morbidity of ethanol injections included necrosis of the external prostatic sphincter and mucosa of the urethra and bladder. Ninety-two percent (11/12) of the laser ablations produced intraglandular foci of thermal tissue damage, which had distinct margins of transition between necrotic and viable cells. The areas of ablation were well visualized by ultrasound and had minimal associated morbidity. The results of this study demonstrate the technical feasibility and low potential morbidity of transrectal ultrasound guided Nd:YAG laser ablations in the canine prostate.

Hallervorden-Spatz disease (HSD) is a movement disorder with neuropathology including abnormal iron storage, disordered myelination, and loss of brain substance. Cranial magnetic resonance (MR) imaging of two patients with HSD provided good quality imaging of these patients' atrophic brain stems and cerebella, regions partially degraded by beam-hardening artifact on X-ray CT. Magnetic resonance also demonstrated signal aberrations in the lentiform nuclei and surrounding white matter consistent with iron storage or disordered myelination. However, quantification of relaxation times of these lesions was not specific for either process. The diagnosis of HSD remains one of exclusion, with MR providing helpful but not definitive information.