Electrical property sensing biopsy needle for prostate cancer detection.

BACKGROUND: Significant electrical property differences have been demonstrated to exist between malignant and benign prostate tissues. We evaluated how well a custom designed clinically deployable electrical property sensing biopsy needle is able to discriminate between these tissue types in an ex vivo prostate model. METHODS: An electrical impedance spectroscopy (EIS) sensing biopsy (Bx) needle was developed to record resistive (ρR) and reactive (ρX) components of electrical impedance from 100 Hz to 1 MHz. Standard twelve-core biopsy protocols were followed, in which the EIS-Bx device was used to gauge electrical properties prior to extracting tissue cores through biopsy needle firing from 36 ex vivo human prostates. Histopathological assessment of the cores was statistically compared to the impedance spectrum gauged from each core. RESULTS: The magnitudes of the mean resistive and reactive components were significantly higher in cancer tissues (P < 0.05). ROC curves showed that ρR at 63.09 kHz was optimal for discriminating cancer from benign tissues; this parameter had 75.4% specificity, 76.1% sensitivity, and ROC AUC of 0.779. Similarly, 251.1 kHz was optimal when using ρX to discriminate cancer from benign tissues; this parameter had a 77.9% specificity, 71.4% sensitivity, and ROC AUC of 0.79. CONCLUSION: Significant electrical property differences noted between benign and malignant prostate tissues suggest the potential efficacy an EIS-Bx device would provide for cancer detection in a clinical setting. By sensing a greater fraction of the prostate's volume in real-time, the EIS-Bx device has the potential to improve the accuracy of cancer grading and volume estimation made with current biopsy procedures.

GSTM1 null and NAT2 slow acetylation genotypes, smoking intensity and bladder cancer risk: results from the New England bladder cancer study and NAT2 meta-analysis.

Associations between bladder cancer risk and NAT2 and GSTM1 polymorphisms have emerged as some of the most consistent findings in the genetic epidemiology of common metabolic polymorphisms and cancer, but their interaction with tobacco use, intensity and duration remain unclear. In a New England population-based case-control study of urothelial carcinoma, we collected mouthwash samples from 1088 of 1171 cases (92.9%) and 1282 of 1418 controls (91.2%) for genotype analysis of GSTM1, GSTT1 and NAT2 polymorphisms. Odds ratios and 95% confidence intervals of bladder cancer among New England Bladder Cancer Study subjects with one or two inactive GSTM1 alleles (i.e. the 'null' genotype) were 1.26 (0.85-1.88) and 1.54 (1.05-2.25), respectively (P-trend = 0.008), compared with those with two active copies. GSTT1 inactive alleles were not associated with risk. NAT2 slow acetylation status was not associated with risk among never (1.04; 0.71-1.51), former (0.95; 0.75-1.20) or current smokers (1.33; 0.91-1.95); however, a relationship emerged when smoking intensity was evaluated. Among slow acetylators who ever smoked at least 40 cigarettes/day, risk was elevated among ever (1.82; 1.14-2.91, P-interaction = 0.07) and current heavy smokers (3.16; 1.22-8.19, P-interaction = 0.03) compared with rapid acetylators in each category; but was not observed at lower intensities. In contrast, the effect of GSTM1-null genotype was not greater among smokers, regardless of intensity. Meta-analysis of the NAT2 associations with bladder cancer showed a highly significant relationship. Findings from this large USA population-based study provided evidence that the NAT2 slow acetylation genotype interacts with tobacco smoking as a function of exposure intensity.

DNA methylation profiles delineate etiologic heterogeneity and clinically important subgroups of bladder cancer.

DNA methylation profiles can be used to define molecular cancer subtypes that may better inform disease etiology and clinical decision-making. This investigation aimed to create DNA methylation profiles of bladder cancer based on CpG methylation from almost 800 cancer-related genes and to then examine the relationship of those profiles with exposures related to risk and clinical characteristics. DNA, derived from formalin-fixed paraffin-embedded tumor samples obtained from incident cases involved in a population-based case-control study of bladder cancer in New Hampshire, was used for methylation profiling on the Illumina GoldenGate Methylation Bead Array. Unsupervised clustering of those loci with the greatest change in methylation between tumor and non-diseased tissue was performed to defined molecular subgroups of disease, and univariate tests of association followed by multinomial logistic regression was used to examine the association between these classes, bladder cancer risk factors and clinical phenotypes. Membership in the two most methylated classes was significantly associated with invasive disease (P < 0.001 for both class 3 and 4). Male gender (P = 0.04) and age >70 years (P = 0.05) was associated with membership in one of the most methylated classes. Finally, average water arsenic levels in the highest percentile predicted membership in an intermediately methylated class of tumors (P = 0.02 for both classes). Exposures and demographic associated with increased risk of bladder cancer specifically associate with particular subgroups of tumors defined by DNA methylation profiling and these subgroups may define more aggressive disease.

Glucocorticoid therapy and risk of bladder cancer.

BACKGROUND: Use of immunosuppressive drugs post organ transplantation, and prolonged use of glucorticoids for other conditions have been associated with subsequent risk of certain malignancies, that is, skin cancers and lymphoma. There is evidence that the incidence of bladder cancer is also elevated among organ transplant recipients, however, it is unknown whether other groups of patients, that is, those taking oral glucocorticoids, likewise are at an increased risk. METHODS: In a population-based case-control study in New Hampshire, USA, we compared the use of glucocorticoids in 786 bladder cancer cases and in 1083 controls. We used unconditional logistic regression analysis to compute adjusted odds ratios (ORs) associated with oral glucocorticoid use. RESULTS: In our analysis, the risk of bladder cancer was related to a history of prolonged oral glucocorticoid use (OR=1.85, 95% CI=1.24-2.76, adjusted for age, gender and smoking). Associations with oral glucocorticoid use were stronger for invasive tumours (OR=2.12, 95% CI=1.17-3.85) and tumours with high (3+) p53 staining intensity (OR=2.35, 95% CI=1.26-4.36). CONCLUSION: Our results raise the possibility of an increased risk of bladder cancer from systemic use of glucocorticoids, and a potential role of immune surveillance in bladder cancer aetiology.

Occurrence of fibrin and tissue factor antigen in human small cell carcinoma of the lung.

Fibrin was detected by specific immunofluorescence in tissue obtained from five of six cases of small cell carcinoma of the lung. Dense specific fluorescence was observed in the connective tissue stroma surrounding metastatic tumor nodules and frequently in the scant extracellular stroma surrounding individual viable tumor cells and small tumor cell clusters. When observed by electron microscopy, the fibrin hugged tumor cell plasma membranes and, in some areas, seemed to envelop the cells. Fluorescent staining of tumor cells, but not the stroma, was observed with an antibody to tissue factor. These findings suggest that local activation of coagulation occurs in small cell carcinoma of the lung. Deposited fibrin may contribute to the growth and spread of this particular type of cancer.

Expression of Fas(APO-1/CD95) in tumor-infiltrating and peripheral blood lymphocytes in patients with renal cell carcinoma.

The functional expression of Fas-ligand on tumor cells reported in a variety of neoplasms has been proposed by several groups as a mechanism of tumor escape from immunological detection. To better support this hypothesis, we have evaluated and quantified for the first time the presence of the Fas(CD95)-R molecule on tumor-infiltrating lymphocytes and on matched peripheral blood lymphocytes (PBLs) of renal cell cancer patients. By two-color flow cytometry we have detected a significant increase in the Fas(CD95)-R expression on tumor-infiltrating lymphocytes compared with matched patient and normal volunteer PBLs. We also observed a decreased expression of the Fas(CD95)-R expression on PBLs from renal cell cancer patients compared with normal healthy controls. The Fas(CD95)-R expression was observed predominantly on the CD4+ subset in all three groups. These different distributions of the Fas(CD95)-R molecule support the hypothesis that the Fas(CD95)-R/Fas(CD95)-L pathway and tumor microenvironment play a major role in the modulation of T-cell function and differentiation to either memory and activation or apoptosis.

T-cell receptor zeta-chain expression on tumor-infiltrating lymphocytes from renal cell carcinoma.

Loss of the T-cell receptor-associated zeta chain in tumor-infiltrating lymphocytes (TILs) has been proposed as one mechanism of acquired immunosuppression in cancer patients. Recent reports suggest that zeta-chain loss may be related to contaminating monocyte/macrophage protease activity. Using flow cytometry and Western blot analysis, we have confirmed the expression of zeta chain in matched peripheral blood mononuclear cells and TILs from eight patients with primary renal cell carcinoma, when the cells were exposed to sufficient quantity of protease inhibitors. A small decrease in zeta-chain expression was found in three TIL samples. The loss of zeta-chain expression that was noted by others may be related to differences in laboratory method, and the small changes we have noted are unlikely to be sufficient in explaining the immunosuppression of TILs.

Multiple rheumatoid nodules of the renal cortex.

We report the findings of a large localized collection of rheumatoid nodules in the renal cortex of a male patient with long-standing seropositive rheumatoid arthritis. Rheumatoid nodules are a rare occurrence in the urinary tract, with only two previous reports of renal involvement, to our knowledge. A possible relationship, on the basis of immunologically mediated mechanisms, to accompanying chronic pyelonephritis is proposed.

Severe liver injury due to phenelzine with unique hepatic deposition of extracellular material.

Severe acute and chronic hepatic damage occurred in a white man who had taken phenelzine sulfate (Nardil) 45 mg daily for 70 days. Liver biopsy showed a mixed hepatitic and cholestatic pattern with extracellular deposition of a unique homogeneous collagenous substance. Portal cirrhosis developed and has persisted. The patient was found to have a "rapid acetylator phenotype" and high rate of metabolism of antipyrine. These innate factors may have predisposed to hepatic injury due to phenelzine.

Chronic lymphocytic leukemia with coexistent Hodgkin's disease. Implications for the origin of the Reed-Sternberg cell.

The association of chronic lymphocytic leukemia (CLL) and Hodgkin's disease has been controversial. Pleomorphic lymphoreticular cells resembling Reed-Sternberg cells have been observed in Richter's syndrome. Although most observers have favored the view that these cells are a component of a pleomorphic non-Hodgkin's lymphoma, some cases of histologically typical Hodgkin's disease have been described. We have studied two cases that appear to represent composite CLL and Hodgkin's disease, providing evidence for an interrelationship of these two disorders. Classic Reed-Sternberg cells and variants (RS-H) were seen in a background that was otherwise typical of CLL. Both patients initially presented with characteristic findings of CLL in the peripheral blood and bone marrow. The first patient was found to have RS-H cells within lymph nodes at initial presentation, and ultimately progressed to develop a disseminated lymphoma characteristic of Hodgkin's disease. In the second patient, RS-H cells were not discovered until 5 years later. Immunophenotypic studies confirmed these morphologic impressions. The predominant lymphocyte population had a phenotype consistent with B-cell CLL. By contrast, the RS-H cells were strongly positive for CD15 (Leu M1) with staining of the Golgi region and cell membrane. Additionally, the RS-H cells were surrounded by rosettes of lymphocytes that marked as T cells. In both of the patients, a small percentage of RS-H cells expressed positivity for the B-cell marker L-26, which may indicate an origin from the underlying CLL. These findings support a B-cell origin for the malignant cell in some cases of Hodgkin's disease and suggest that Hodgkin's disease in some patients may be related to or derived from a coexisting lymphoid malignancy.

Tissue-shrinkage correction factor in the calculation of prostate cancer volume.

Many studies that have calculated prostate cancer volumes from microscopic slides have used correction factors, ranging from 1.22 to 1.5, to compensate for tissue shrinkage during tissue processing. We undertook a study to measure tissue shrinkage directly because our experience suggested less shrinkage than that reported by others. Ten prostatectomy specimens were processed in a uniform manner. Multiple identical linear measurements were taken at four stages of processing: in the fresh state, following fixation, following processing, and from the microscopic slide. Linear shrinkage following fixation was minimal (4.1%) but increased to 14.5% following tissue processing. With rehydration and expansion on the flotation bath, tissues swelled so that net linear tissue shrinkage was 4.3%, and net volumetric tissue shrinkage was 12.4%, which translates into a correction factor for tissue shrinkage of 1.14. The following variables had no statistically significant effect on shrinkage: concentration of formalin, whole-mount versus quadrant sections, thickness of tissue slices, length of time in the alcohol dehydration steps, and temperature of the flotation bath over a range of 35 to 45 degrees C. This study suggests that (a) tissue-shrinkage correction factors that have been used in some previous studies may not be applicable for all laboratories because of interlaboratory variations in tissue-processing procedures or differences in measuring shrinkage; and (b) some calculated tumor volumes that have been used for prognostic thresholds may be high because of inflated tissue-shrinkage correction factors.

A rare lymphoepithelial cyst of the pancreas.

Reported is a case of a rare lymphoepithelial cyst of the tail of the pancreas that developed in a young man with no symptoms. To the authors' knowledge, it is the first case described to be entirely situated within the pancreas, thus confirming its pancreatic origin. Biologic behavior appears to be entirely benign, and the primary importance of its recognition is in the distinction from cystic malignant neoplasms.

Paratesticular multicystic mass of Wolffian, probably paradidymal, origin.

A unilateral multicystic mass in the connective tissue adjacent to the vas deferens in a 46-year-old man is reported. Anatomically, it was distinct from the epididymis and vas and contained no sperm. The epithelial lining was simple, ciliated, and cuboidal to columnar. The cysts were surrounded by connective tissue collars containing smooth muscle. The authors postulate that this lesion represents a cystic hyperplasia of vestigial Wolffian duct remnants, based on its unique histologic features and the exclusion of other plausible explanations. The supraepididymal, paravasal location suggests origin in the paradidymis.

A comprehensive quality assessment program on the autopsy service.

Many previous studies have established the value of the autopsy in assessing clinical diagnostic accuracy. None has described, however, the use of the autopsy as an ongoing, prospective audit of clinical and pathologic performance. The authors herein outline the process and report the initial results of a comprehensive quality assessment program on their autopsy service. Particular emphasis was placed on evaluation of the responsiveness of the autopsy to clinical questions and interests. The four parts of the overall program included an epidemiologic survey of causes of death in the authors' patient population, a determination of the clinical significance of autopsy findings, an assessment of clinical factors that may have contributed to death, and a quality control mechanism of the autopsy itself. The process can be adapted to a variety of hospital settings.

Bilateral testicular carcinoma in situ in persistent müllerian duct syndrome: a case report and literature review.

Bilateral testicular carcinoma in situ in a 17-year-old patient with persistent müllerian duct syndrome is reported. The pertinent literature is reviewed and the management of both testicular carcinoma in situ and persistent müllerian duct syndrome is discussed.

Nucleolar organizer regions as discriminators for the diagnosis of well-differentiated adenocarcinoma of the prostate.

This study sought to determine whether nucleolar organizer region (NOR) counts might be of diagnostic use specifically in the frequently difficult identification of well-differentiated prostate cancer. Total silver-stained NOR (AgNOR) counts on sections were done in 50 consecutive nuclei from 22 cases of well-differentiated adenocarcinoma composed exclusively of Gleason grades 1 or 2 and in 50 consecutive nuclei in foci of benign glands on the same slide. Malignant nuclei contained a mean of 4.84 AgNORs; benign nuclei, 3.39 AgNORs. This difference was statistically highly significant (P < .0001), but there was considerable overlap of mean AgNOR counts between malignant and benign groups. Thus, to obtain a rule requiring a specificity of greater than 95% using the mean AgNOR count as a definition of malignancy, the maximum sensitivity possible was only 32%. Despite the overlap in mean AgNOR counts, however, in all but one case the mean count for malignant nuclei was greater than that for benign nuclei. This suggests that the diagnostic potential of AgNOR counts might be better realized by a comparison of counts between a suspicious focus and an adjacent focus of benign glands.

Florid xanthomatous pelvic lymph node reaction to metastatic prostatic adenocarcinoma. A sequela of preoperative androgen deprivation therapy.

We describe a florid xanthomatous histiocytic reaction in the pelvic lymph nodes of a patient treated with androgen deprivation therapy prior to radical prostatectomy. The xanthomatous reaction was so marked that it nearly obscured the presence of metastatic carcinoma in the same lymph nodes. A similar histiocytic reaction was also present in association with carcinoma in the prostatectomy specimen, a finding that was not identified in pretreatment biopsy specimens. No other known cause of pronounced histiocytic lymph node proliferation was present in this patient. Only one brief description of a xanthomatous reaction in lymph nodes associated with this treatment has been previously recorded in the literature to our knowledge. Other patients from our institution who were treated similarly preoperatively all had lymph nodes negative for tumor, and none demonstrated a xanthomatous tissue reaction, suggesting that this reaction may be a marker for metastatic tumor in the same lymph node.

Epididymitis nodosa. An epididymal lesion analogous to vasitis nodosa.

We studied eight cases of an epididymal lesion resembling vasitis nodosa. Four cases were encountered among a group of patients who underwent epididymectomy for pain following vasectomy. The other four cases occurred in the absence of that history. The lesion probably represents a regenerative effort following rupture of a duct resulting from long-standing obstruction, either locally or at some point distally in the ductal system. Recognition is important to prevent misdiagnosis as a neoplasm.

A real-time electrical impedance sensing biopsy needle.

Diagnostic confirmation of cancer in solid organs is based on biopsy findings. In a standard 12-core prostate biopsy protocol, conventional biopsy needles sample only 0.95% (∼0.228 cm³) of a typical 24-cm³ prostate gland. The primary objective of this study was to enhance the sensitivity of standard biopsy protocol by gauging electrical properties of tissue simultaneously with tissue extraction for histopathology analysis. A conventional biopsy (Bx) needle was instrumented with an electrical impedance spectroscopy (EIS) sensor to interrogate the tissue volume surrounding the needle tip. The EIS-Bx device was evaluated in a series of saline bath and ex vivo porcine experiments. It was found to sense a volume of 0.286 cm³ of tissue around the needle tip. EIS measurements were recorded from three ex vivo human prostates using the device, and the extracted biopsy cores were histologically assessed. Prostate conductivity σ ranged from 0.179 to 0.3310 S/m for benign tissues and 0.0746 to 0.0837 S/m for malignant tissues at frequencies ranging from 1 to 100 kHz. Relative permittivity ϵ(r) ranged from 2.10×106 to 2.9 × 104 for benign and 6.63×105 to 5.3 × 10³ for cancer tissues over the same frequency range. Both are found to be significantly higher in normal prostate tissues than in malignant tissue (p < 0.00001).

Electrical impedance spectroscopy for prostate cancer diagnosis.

Electrical impedance was recorded at 21 discrete frequencies (1 to 100 kHz) from 27 ex vivo human prostates. These electrical properties were measured by using custom designed Electrical Impedance Spectroscopy (EIS) sensing biopsy (Bx) needles. EIS-Bx needles gauge the electrical properties of tissue in tandem with the tissue extraction (used for histopathological assessment). The EIS-Bx probe has a signal-to-noise ratio (SNR) of 65 dB across the frequency range (1 kHz to 100 kHz). A total of 36 cancers and 288 benign regions were sampled from 27 human prostates. Mean resistance (R) of prostate decreased from 537.27 Ω to 126.74 Ω for benign tissues and 999.52 Ω to 340.67 Ω for malignant tissues across the 1 kHz - 100 kHz spectral range. Likewise, mean reactance (X) ranged from -391.41 Ω to -62.6 Ω for benign and -675.09 Ω to -162.28 Ω for cancer tissues over the same frequency range. Both R and X values are found to be significantly lower in normal prostate tissues than in malignant tissue (p<0.001). Further testing to evaluate the clinical efficacy of this coupled device is underway.