Lesional activation of Tc 17 cells in Behçet disease and psoriasis supports HLA class I-mediated autoimmune responses.

BACKGROUND: Behçet disease (BD) presents with lymphocytic and neutrophilic vasculitis of unknown aetiology. HLA-B*51, the endoplasmic reticulum aminopeptidase 1 (ERAP1), and interleukin 23 receptor (IL23R)/IL12R are genetic risk factors. IL-23 regulates IL-17A, which controls the recruitment and activation of neutrophils. OBJECTIVES: To determine pathological changes in BD skin lesions related to the complex genetic predisposition. METHODS: We characterized the expression of IL-17A and IL-23A in various cell types by immunohistological double staining of sections from papulopustular skin lesions of acute attacks of BD and psoriasis vulgaris lesions, another HLA-class I-associated T-cell-mediated autoimmune disease in which excessive T-cell-derived IL-17A production promotes neutrophil activation. RESULTS: We found that in BD lesions, as in psoriasis, actively expanding CD8+ T cells were the predominant source of IL-17A. IL-17A+ CD8+ T (Tc 17) cells outnumbered infiltrating IL-17A+ CD4+ T cells. Unlike the epidermal localization of CD8+ T cells in psoriasis, Tc 17 cells in BD lesions mainly infiltrated the perivascular tissue and the blood vessel walls of dermis and subcutaneous tissue. They co-localised with a marked IL-23A expression by CD11c+ dendritic cells and CD68+ macrophages. IL-17A expression was associated with extensive recruitment of neutrophils around blood vessels that formed neutrophil extracellular traps (NETs). CONCLUSIONS: In BD, the genetic predisposition may mediate antigen-specific activation and differentiation of a Tc 17 response, possibly targeting endothelial (auto)antigens. Neutrophils recruited by IL-17A in this process may enhance tissue damage by extensive NET formation (NETosis). Thus, the IL-23/IL-17 axis presumably controls neutrophilic inflammation in BD vasculitis in the context of a predominant antigen-specific CD8+ T-cell response.

Genetic relationships among Vietnamese local pigs investigated using genome-wide SNP markers.

Vietnam is one of the most important countries for pig domestication, and a total of 26 local breeds have been reported. In the present study, genetic relationships among the various pig breeds were investigated using 90 samples collected from local pigs (15 breeds) in 15 distantly separated, distinct areas of the country and six samples from Landrace pigs in Hanoi as an out-group of a common Western breed. All samples were genotyped using the Illumina Porcine SNP60 v2 Genotyping BeadChip. We used 15 160-15 217 SNPs that showed a high degree of polymorphism in the Vietnamese breeds for identifying genetic relationships among the Vietnamese breeds. Principal components analysis showed that most pigs indigenous to Vietnam formed clusters correlated with their original geographic locations. Some Vietnamese breeds formed a cluster that was genetically related to the Western breed Landrace, suggesting the possibility of crossbreeding. These findings will be useful for the conservation and management of Vietnamese local pig breeds.

Validation of the distress and impact thermometer and the changes of mood during the first 6 months of treatment in gynecological cancer patients: a Kansai Clinical Oncology Group (KCOG)-G1103 prospective study.

PURPOSE: To verify distress and impact thermometer (DIT) for screening emotional distress in gynecological cancer patients by Hospital Anxiety and Depression Scale total (HADS-T) as gold standard and to assess emotional changes by DIT and HADS-T. METHODS: A prospective study was conducted in newly diagnosed gynecological cancer patients during the peri-treatment period after the cancer diagnosis followed by 6-month. We defined a HADS-T score of ≥11 as being indicative of emotional distress. RESULTS: 117 patients were enrolled between May 1, 2011 and March 31, 2012, and 95 were eligible. The median age was 54 years (range 31-77). (1) From the baseline to 3-month, distress (DIT-D) ≥4 with Impact (DIT-I) ≥2 exhibited sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) of 0.776 [95 % confidential interval (CI) 0.688, 0.850], 0.889 (95 % CI 0.824, 0.954), 0.868 (95 % CI 0.792, 0.949), and 0.808 (95 % CI 0.731, 0.886), respectively. (2) At 6-month, DIT-D ≥2 with DIT-I ≥1 exhibited sensitivity, specificity, PPV and NPV of 0.893 (95 % CI 0.778, 1), 0.825 (95 % CI 0.707, 0.942), 0.781 (95 % CI 0.638, 0.928), and 0.917 (95 % CI 0.826, 1). (3) At 6-month, the HADS-T, DIT-D, and DIT-I scores in individual patients were significantly reduced by a mean of 4.57 (p < 0.0001), 2.34 (p < 0.0001), and 1.10 (p = 0.0031), respectively, compared with those scores of baseline (Student's paired t test), but still remained high. CONCLUSIONS: (1) On acute phase within 3-month setting, DIT; DIT-D ≥4 with DIT-I ≥2, is a reliable cut-off to screen emotional distress among gynecological cancer patients. (2) The patients' moods had improved, but not completely recovered at 6-month after the diagnosis.

Low FOXA1 expression predicts good response to neo-adjuvant chemotherapy resulting in good outcomes for luminal HER2-negative breast cancer cases.

BACKGROUND: FOXA1 expression is a good prognostic marker for endocrine therapy in hormone-positive breast cancer. We retrospectively examined breast cancer patients with luminal human epidermal growth factor receptor 2 (HER2)-negative tumours, as defined by immunohistochemistry, who received neo-adjuvant chemotherapy (NAC) and investigated the relationship between treatment effects and FOXA1 expression. METHODS: Biopsy specimens from 103 luminal HER2-negative tumours were immunohistochemically examined. FOXA1 effects on chemo-sensitivity were also investigated employing in vitro experiments. RESULTS: FOXA1 and Ki67 expressions independently predicted a pathological complete response (pCR). Knockdown of FOXA1 by siRNA boosted the chemo-effect in oestrogen receptor-positive cells. The Cox hazards model revealed a pCR to be the strongest factor predicting a good patient outcome. CONCLUSIONS: Our present study showed low FOXA1 expression to be associated with a good response to NAC in luminal HER2-negative breast cancer. Improved outcomes of these patients suggest that NAC should be recommended to patients with low FOXA1 tumours.

Cancer stem-like cells of ovarian clear cell carcinoma are enriched in the ALDH-high population associated with an accelerated scavenging system in reactive oxygen species.

OBJECTIVE: In ovarian cancer cases, recurrence after chemotherapy is frequently observed, suggesting the involvement of ovarian cancer stem-like cells (CSCs). The chemoresistance of ovarian clear cell carcinomas is particularly strong in comparison to other epithelial ovarian cancer subtypes. We investigated the relationship between a CSC marker, aldehyde dehydrogenase 1 (ALDH1), and clinical prognosis using ovarian clear cell carcinoma tissue samples. Furthermore, we investigated the antioxidant mechanism by which CSCs maintain a lower reactive oxygen species (ROS) level, which provides protection from chemotherapeutic agents. METHODS: Immunohistochemical staining was performed to examine the CSC markers (CD133, CD44, ALDH1) using ovarian clear cell carcinoma tissue samples (n=81). Clear cell carcinoma cell lines (KOC-7C, OVTOKO) are separated into the ALDH-high and ALDH-low populations by ALDEFLUOR assay and fluorescence-activated cell sorting (FACS). We compared the intracellular ROS level, mRNA level of the antioxidant enzymes and Nrf2 expression of the two populations. RESULTS: High ALDH1 expression levels are related to advanced stage in clear cell carcinoma cases. ALDH1 expression significantly reduced progression free survival. Other markers are not related to clinical stage and prognosis. ALDH-high cells contained a lower ROS level than ALDH-low cells. Antioxidant enzymes were upregulated in ALDH-high cells. ALDH-high cells showed increased expression of Nrf2, a key transcriptional factor of the antioxidant system. CONCLUSIONS: ALDH-positive CSCs might have increased Nrf2-induced antioxidant scavengers, which lower ROS level relevant to chemoresistance in ovarian clear cell carcinoma.

Genome-wide association QTL mapping for teat number in a purebred population of Duroc pigs.

Because of increasing litter size in Western pig breeds, additional teats are desirable to increase the capacity for nursing offspring. We applied genome-wide SNP markers to detect QTL regions that affect teat number in a Duroc population. We phenotyped 1024 animals for total teat number. A total of 36 588 SNPs on autosomes were used in the analysis. The estimated heritability for teat number was 0.34 ± 0.05 on the basis of a genomic relationship matrix constructed from all SNP markers. Using a BayesC method, we identified a total of 18 QTL regions that affected teat number in Duroc pigs; 9 of the 18 regions were newly detected.

The impact of rare cancer and early-line treatments on the benefit of comprehensive genome profiling-based precision oncology.

BACKGROUND: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP. MATERIALS AND METHODS: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response. RESULTS: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively). CONCLUSION: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types.

Clinical significance of serum growth-regulated oncogene alpha (GROalpha) in patients with gynecological cancer.

PURPOSE OF INVESTIGATION: To assess the clinical relevance of serum growth-regulated oncogene alpha (GROalpha) levels in gynecological cancer, we investigated its concentration in distinguishing patients with cervical cancer, endometrial cancer, ovarian cancer, benign ovarian tumor and control. METHODS: Preoperative serum GROalpha levels were measured in women with cervical cancer (n=46), endometrial cancer (n=39), ovarian cancer (n=124), benign ovarian tumors (n=52), and normal controls (n=38) using an enzyme-linked immunosorbent assay. RESULTS: Statistical analyses showed that the serum GROalpha concentration was significantly elevated in the cervical cancer, endometrial cancer and ovarian cancer patients compared with controls. Using GROalpha levels, the receiver operating characteristic (ROC) of cervical cancer (AUC approximately 0.775), endometrial cancer (AUC approximately 0.799), ovarian cancer (AUC approximately 0.749) and benign ovarian tumors (AUC approximately 0.568) vs. controls were identified. CONCLUSION: Our findings suggest that serum GROalpha measurement as a molecular marker might contribute to detection and diagnosis of gynecological cancer.

Efficacy and safety of pregabalin for treating neuropathic pain associated with diabetic peripheral neuropathy: a 14 week, randomized, double-blind, placebo-controlled trial.

AIMS: To evaluate the efficacy, safety and pharmacokinetics of pregabalin in treating neuropathic pain associated with diabetic peripheral neuropathy in Japanese patients. METHODS: A randomized, double-blind, placebo-controlled, multicentre 14 week clinical trial was conducted. Japanese patients with diabetic peripheral neuropathy (n = 317) were randomized to receive placebo or pregabalin at 300 or 600 mg/day. The primary efficacy measure was a change of mean pain score from baseline to end-point from patients' daily pain diaries. RESULTS: Significant reductions in pain were observed in patients treated with pregabalin at 300 and 600 mg/day vs. placebo (P < 0.05). Improvements in weekly pain scores were observed as early as week 1 and were sustained throughout the study period (300 and 600 mg/day difference from placebo at study end-point, -0.63 and -0.74, respectively). Pregabalin produced significant improvements in weekly sleep interference scores, the short-form McGill Pain Questionnaire, the Medical Outcomes Study-Sleep Scale, the 36-item Short-Form Health Survey scale, and the Patient and Clinical Global Impression of Change. Patient impressions of numbness, pain and paraesthesia were also significantly improved. Regarding treatment responders, 29.1 and 35.6% of patients treated with 300 and 600 mg/day, respectively, reported ≥ 50% improvement in mean pain scores (vs. 21.5% for placebo). Pregabalin was well tolerated; somnolence (26%), dizziness (24%), peripheral oedema (13%) and weight gain (11%) were the most common adverse events and generally were reported as mild to moderate. CONCLUSIONS: Pregabalin was effective in reducing pain and improving sleep disturbances due to pain, and was well tolerated in Japanese patients with painful DPN.

Perturbations of both nonregulatory and regulatory FOXP3+ T cells in patients with malignant melanoma.

BACKGROUND: 'FOXP3+ regulatory T cells' (Tregs) are reported to be increased in tumour-bearing hosts including patients with melanoma, leading to tumour immune suppression. However, this idea is challenged by recent evidence that the 'FOXP3+ Treg' fraction in fact contains activated 'nonregulatory' T cells. Also, FOXP3+ T cells are reported to have functionally and kinetically distinct subsets. OBJECTIVES: To investigate whether either or both of regulatory and 'nonregulatory' FOXP3+ T cells are perturbed in patients with melanoma. METHODS: FOXP3+ T cells were classified into three subsets, namely CD45RO+FOXP3(low) nonregulatory T cells, CD45RO+FOXP3(high) effector Tregs, and CD45RO-FOXP3(low) naïve Tregs, according to their expression levels of FOXP3 and CD45RO. The percentage and cytokine production of these FOXP3+ T-cell subsets were assessed by flow cytometry. RESULTS: Both regulatory and nonregulatory T cells were increased in patients with melanoma. Moreover, we found three unexpected perturbations in FOXP3+ T-cell subsets: (i) patients with melanoma showed higher frequencies of FOXP3(low) nonregulatory T cells, which decreased and normalized after tumour removal; (ii) FOXP3(low) naïve Tregs containing higher frequencies of interferon-γ+ cells increased with tumour progression; and (iii) CD45RO+FOXP3(high) effector Tregs were pronouncedly infiltrated around tumour tissues. CONCLUSIONS: These findings demonstrate that patients with melanoma have distinct and differential perturbation of both regulatory and nonregulatory FOXP3+ T cells. The degree of perturbation is associated with tumour burden and progression, suggesting that the perturbation reflects fundamental pathophysiological processes in patients with melanoma. The presented analysis provides a practical approach to investigate the immunological environment of cancer patients.

Malonyl-CoA: acetyl-CoA cycling. A new micromethod for determination of acyl-CoAs with malonate decarboxylase.

A new micromethod for determination of acetyl-CoA and malonyl-CoA using malonate decarboxylase is described. This enzyme catalyzes decarboxylation of malonate in a cyclic manner and produces acetate in proportion to the amount of a given acyl-CoA, such as acetyl-CoA, malonyl-CoA or propionyl-CoA. The acetate generated is converted to acetylphosphate by acetate kinase (EC 2.7.2.1) added at the same time and is determined spectrophotometrically as acetohydroxamate. The sensitivity of this method is high enough to detect 10(-12) mol of acetyl-CoA or malonyl-CoA. The simplicity of the method allows more than 30 samples to be analyzed at the same time without any prior extraction step. Although this method does not distinguish between acetyl-CoA and malonyl-CoA, malonyl-CoA alone can be measured by elimination of acetyl-CoA with citrate synthetase (EC 4.1.3.7).

Radiation therapy of invasive thymoma.

Between 1978 and 1987, 30 cases of invasive thymomas were treated with radiotherapy after surgery. Surgical therapy consisted of total resection in 15 patients, subtotal resection in 1 patient, and biopsy in 14 patients. Myasthenia gravis (MG) was associated in nine patients (MG(+) group), but in 21 patients there was no evidence of myasthenia gravis (MG(-) group). Irradiation in the dose range of 30 to 58.7 Gy was delivered. The total average 5-year survival rate was 71.8%; it was 39.2% in MG(+) group and 78.3% in MG(-) group, though there was no significant statistical difference. Myasthenia gravis was well controlled by the tumorectomy and associated radiotherapy in 7 of the 9 patients. However, in 3 of 7 patients (42.9%) myasthenia gravis recurred at 2 years, 2 years and 7 months, and 5 years and 8 months after initial therapy. Total body irradiation of 2 Gy with 0.1 Gy fractions was administered for uncontrollable myasthenia gravis in one patient with marked improvement. Radiation therapy is an important therapeutic modality for unresectable malignant thymoma as well as for postoperative combined therapy. Total body irradiation may be an effective method to treat patients with otherwise resistant myasthenia gravis.

Clinical and pathological significance of the level and extent of capsular invasion in clinical stage T1-2 prostate cancer.

This study was performed to assess the relationship between the level and extent of prostatic capsular invasion (PCI) by cancer and the clinical and pathological features and prognosis of early-stage prostate cancer. We conducted a retrospective analysis of the clinical (age, stage, grade, prostate specific antigen [PSA] level) and pathological (tumor volume, stage, grade, surgical margins) features of 688 patients treated with radical prostatectomy to determine the pathological features and probability of recurrence associated with various levels of PCI. Radical prostatectomy specimens were serially sectioned and examined by whole-mount technique. Progression-free probabilities (PFP) after radical prostatectomy were determined by Kaplan-Meier and Cox proportional hazards regression analysis. Progression was defined as a rising serum PSA < or = 0.4 ng/mL or clinical evidence of recurrent cancer. Increasing clinical stage, Gleason grade in the biopsy specimen, and pretreatment serum PSA levels were each associated with increasing levels of PCI (P < .001). In the radical prostatectomy specimen, increasing levels of PCI were significantly associated with increasing tumor volume (P < .001), Gleason grade (P < .0001), seminal vesicle involvement (SVI, P < .001) and lymph node metastases (+LN, P < .001). None of 138 patients without capsular invasion had SVI or lymph node metastases (+LN), and all remained free of progression, even though some had large volume (up to 6.26 cm3) or poorly differentiated (Gleason sum up to 8) cancers. Invasion into the capsule (n = 271) was occasionally associated with SVI (6%) or +LN (3%) and a significantly (log-rank test) lower PFP of 87% at 5 years. Focal and extensive extraprostatic extension (EPE) were associated with progressively increased risk of SVI and +LN and lower PFP (73% and 42%, respectively). In a multivariate analysis, the level of PCI was an independent prognostic factor (P < .001). There is a strong association between the level of invasion of cancer into or through the prostatic capsule and the volume, grade, pathological stage, and rate of recurrence after radical prostatectomy. Prostate cancer does not appear to metastasize in the absence of invasion into the capsule regardless of the volume or grade of the intracapsular tumor. Subclassification of patients according to the levels of PCI provides valuable prognostic information.

Dynorphin mRNA expression in dorsal horn neurons after traumatic spinal cord injury: temporal and spatial analysis using in situ hybridization.

Dynorphin, an endogenous opioid, may contribute to secondary nervous tissue damage following spinal cord injury. The temporal and spatial distribution of preprodynorphin (PPD) mRNA expression in the injured rat spinal cord was examined by in situ hybridization. Rats were subjected to traumatic spinal cord injury at the T13 spinal segment using the weight-drop method. Motor function of these rats was evaluated by their ability to maintain their position on an inclined plane. Two double-labeling experiments revealed that increased PPD mRNA and dynorphin peptide expression were found exclusively in dorsal horn neurons. Neurons exhibiting an increase in the level of PPD mRNA were concentrated in the superficial laminae and the neck of dorsal horn within several spinal segments from the epicenter of the injury at 24 and 48 h after injury. A number of neurons showing increased PPD mRNA were found in gray matter adjacent to the injury areas. Segments caudal to the injury site exhibited a long-lasting elevation of PPD mRNA in neurons, compared to the rostral segments. The number of neurons expressing PPD mRNA in each rat was significantly positively correlated with its motor dysfunction. These findings suggest that increased expression of dynorphin mRNA and peptide in dorsal horn neurons occurs after traumatic spinal cord injury. This also supports the hypothesis that the dynorphin has a pathological role in secondary tissue damage and neurological dysfunction after spinal cord injury.

Ultrasound biomicroscopic analysis of anterior proliferative vitreoretinopathy.

PURPOSE: To report the use of ultrasound biomicroscopy for preoperative assessment of anterior proliferative vitreoretinopathy. METHODS: Case report. In a 35-year-old man with tractional retinal detachment and anterior proliferative vitreoretinopathy, we used ultrasound biomicroscopy with UX-02 (Rion Co Ltd, Tokyo, Japan) to perform the preoperative analysis of the ciliary body, anterior vitreous, and detached peripheral retina. RESULTS: In all meridians, the posterior insertion of the vitreous was drawn anteriorly, creating a retinal trough, and the meridian distance between the anterior and posterior vitreous base insertions was reduced. Retinochoroidal detachment was detected posterior to the anterior vitreous base insertion. Based on these imagings, sclerotomy locations were selected. CONCLUSION: Ultrasound biomicroscopy may be useful to assess anterior proliferative vitreoretinopathy preoperatively and to decide on sclerotomy sites.

A resected case of giant leiomyosarcoma of the pancreas.

Leiomyosarcoma of the pancreas is very rare. We report a case of giant leiomyosarcoma of the pancreas treated by distal pancreatectomy. A 53-year-old female was admitted with an large abdominal mass. Computed tomography, magnetic resonance imaging, and ultrasonography revealed a huge tumor adjacent to the pancreas. However, we could not identify the primary organ with these imagings. Angiographic findings strongly suggested that the tumor originated from the pancreas, as main feeding arteries arose from the great pancreatic artery. Fourteen days after trans-catheteric arterial embolization, we performed a distal pancreatectomy with splenectomy; the patient's postoperative course was uneventful. Histologically, we confirmed the diagnosis as a leiomyosarcoma originating from the pancreas.

Clostridial population and the intestinal lesions in chickens infected with Clostridium perfringens and Eimeria necatrix.

Chickens infected with Clostridium perfringens and Eimeria necatrix were examined bacteriologically and pathologically. When chickens were inoculated with 1.0 x 10(8) C. perfringens and/or 2 x 10(4) E. necatrix sporulated oocysts, populations of C. perfringens in the intestinal contents were examined on 3, 5 and 7 days after E. necatrix inoculation. In both groups infected with E. necatrix, the mean clostridial counts were significantly higher than those of uninfected controls. The concurrent infection had no enhancing effects on increasing the clostridial population more than E. necatrix-alone. Mortality of 4-day-old chickens inoculated on 5 consecutive days with C.perfringens after receiving E. necatrix was higher than those of chickens inoculated with the both organisms. However, intestinal lesions of the concurrently infected group were not different from E. necatrix-alone-infected group on 5 and 7 days after the coccidial infection. When chickens received a large dose (1.5 x 10(9)) of C. perfringens after the inoculation with E. necatrix, edema in the duodenum through jejunum were observed early after the bacterial broth inoculation. These results suggest that the concurrent infection with E. necatrix and C. perfringens increases clostridial population in the intestine of the chickens and has synergic effects on mortality and edema in the upper intestine.

Analysis of splenic and thymic lymphocyte subpopulations in chickens infected with Salmonella enteritidis.

Lymphocytes expressing CD3, CD4, CD8, pan lymphocyte, IgA, IgG and IgM cell surface antigens were assessed by in the spleen and thymus of chickens following infection with Salmonella enteritidis using flow cytometric analysis. At 6 days post primary infection and 2 days post secondary infection with S. enteritidis, the percentages of IgA+ and IgM+ lymphocytes in the spleen were significantly increased (P < 0.05). At 2 days post secondary infection with S. enteritidis, the percentage of CD4+ T lymphocyte in the spleen and CD8+ T lymphocyte percentage in the thymus were significantly increased (P < 0.05). These results indicate that S. enteritidis infection induces changes in the spleen and thymus that reflect the dynamics of the host protective immune response.

High grade prostatic intraepithelial neoplasia in prostates removed following irradiation failure in the treatment of prostatic adenocarcinoma.

Prostatic Intraepithelial Neoplasia (PIN) is widely considered to be a precursor lesion for adenocarcinoma of the prostate. No information is available, however, on the sensitivity of PIN to irradiation or the distribution of residual PIN after radiotherapy. We studied a series of forty-six totally embedded, whole mounted, serially sectioned prostates removed by salvage radical retropubic prostatectomy following irradiation failure in which no hormonal therapy/ablation had been undertaken. The mean age of patients was 65 (56-74) years, the mean dose of radiotherapy was 7,266 (6,000-9,000) cGy (15 external beam, 27 external beam plus iridium or gold seed, 3 iodine, and 1 unknown) and the mean interval for irradiation therapy to prostatectomy was 60 (16-145) months. Thirty-two (70%) of the patients had high grade PIN within the prostatectomy specimen. The pattern of PIN was recorded as described by Bostwick and co workers. The frequency of the different patterns per positive case paralleled in rank those in Bostwick's series of non-irradiated prostates, with the most common to least common per patient being: tufting (78.1%), micropapillary (59.3%), cribriform (34.4%) and flat (15.6%). However, the mean number of foci of PIN per prostate was less than in Bostwick's series (7.1 foci vs. 17 foci). There was no statistically significant difference between groups with or without high grade PIN with regard to various clinical factors (last preoperative serum PSA, age, dose of radiotherapy, interval from irradiation therapy to prostatectomy, Kaplan-Meier survival), or pathologic factors (presence of confined tumor, extracapsular extension, positive surgical margins, seminal vesicle invasion, or positive lymph nodes on permanent sections). We conclude that high grade PIN is common in the prostates of patients who have failed irradiation therapy and that, theoretically, not all recurrent tumors derive from regrowth of the initial, incompletely eradicated tumor. However, because there was no significant difference between the two groups with regard to the clinical and pathologic parameters listed, we consider it likely that most recurrent tumors derive from the initial incompletely eradicated tumor.