The impact of comorbidity and PSA doubling time on the risk of death in men experiencing PSA failure following radiation therapy with or with androgen deprivation therapy for unfavorable-risk prostate cancer.

BACKGROUND: The optimal management of men with PSA failure following initial prostate cancer (PC) therapy stratified by comorbidity is unknown. We investigated the impact that PSA doubling time (DT) and comorbidity had on the risk of all-cause mortality (ACM), prostate cancer-specific mortality (PCSM) and other-cause mortality (OCM) following PSA failure. METHODS: Between 1995 and 2001, 206 men with unfavorable-risk PC were randomized to receive radiation therapy alone or in combination with 6 months of androgen deprivation therapy (ADT); 108 men experienced PSA failure and formed the study cohort. Cox and Fine-Gray regression analysis was used to determine whether PSA DT was associated with the risk of ACM and PCSM/OCM, respectively, stratified by comorbidity status using a validated metric. RESULTS: After a median follow-up of 13.71 years following PSA failure, 81 of the 108 men (75%) died. Longer PSA DT was associated with a decreased risk of PCSM in men with no/minimal (adjusted hazard ratio (AHR) 0.33, 95% confidence interval (CI) 0.17-0.65, P=0.001) and moderate/severe comorbidity (AHR 0.014, 95% CI 0.002-0.129, P=0.0002). However, because of the different contributions of the risk of OCM to risk of ACM within comorbidity subgroups, increasing PSA DT was only associated with a decreased risk of ACM in men with no/minimal (AHR 0.69, 95% CI 0.50-0.96, P=0.03) but not moderate/severe comorbidity (AHR 0.95, 95% CI 0.51-1.78, P=0.87). CONCLUSIONS: Both the extent of comorbidity and the PSA DT should be taken into consideration when deciding on appropriate management and/or clinical trial eligibility at the time of PSA failure.

Duration of the anti-androgen in men undergoing 6 months of an LHRH agonist and radiation therapy for unfavorable-risk prostate cancer and the risk of death.

BACKGROUND: Whether adding a first-generation anti-androgen (AA) to a luteinizing hormone-releasing hormone agonist in the radiotherapeutic management of unfavorable-risk prostate cancer (PC) reduces the risk of all-cause and PC-specific mortality (ACM and PCSM) among men within differing comorbidity subgroups is unknown. METHODS: Between 1995 and 2001, 206 men with unfavorable-risk PC were enrolled in a randomized trial comparing radiation with or without 6 months of androgen-deprivation therapy (ADT). Partial AA use (median: 4.2 months) occurred in 29 of the 102 men randomized to ADT. Cox, and Fine and Gray's regressions were used to evaluate the impact of full versus partial AA use on PCSM and ACM-risk within comorbidity subgroups. RESULTS: After a median follow-up of 16.62 years, 156 men died. In men with moderate to severe comorbidity increasing death was observed as treatment transitioned from no to partial to full ADT (P=0.02) with an increased ACM-risk with full versus partial AA use (adjusted hazard ratio (AHR), 2.25 (95% confidence interval (CI), 0.94-5.41); P=0.07); whereas only 1 and no PC deaths occurred in men receiving a partial versus full AA course, respectively. Among men with no or minimal comorbidity there was no decrease in ACM (AHR, 0.97 (95% CI, 0.49-1.91); P=0.92) or PCSM-risk (AHR 0.39 (95% CI 0.07-52.18); P=0.28) in comparing full versus partial AA use. CONCLUSION: Increasing AA use by 2 months does not appear to impact survival in men with localized unfavorable-risk PC and no or minimal comorbidity, but may shorten survival in men with moderate to severe comorbidity, raising concern regarding in whom and for how long the AA should be prescribed.

Search for Nucleon and Dinucleon Decays with an Invisible Particle and a Charged Lepton in the Final State at the Super-Kamiokande Experiment.

Search results for nucleon decays p→e^{+}X, p→µ^{+}X, n→νγ (where X is an invisible, massless particle) as well as dinucleon decays np→e^{+}ν, np→µ^{+}ν, and np→τ^{+}ν in the Super-Kamiokande experiment are presented. Using single-ring data from an exposure of 273.4 kton·yr, a search for these decays yields a result consistent with no signal. Accordingly, lower limits on the partial lifetimes of τ_{p→e^{+}X}>7.9×10^{32} yr, τ_{p→µ^{+}X}>4.1×10^{32} yr, τ_{n→νγ}>5.5×10^{32} yr, τ_{np→e^{+}ν}>2.6×10^{32} yr, τ_{np→µ^{+}ν}>2.2×10^{32} yr, and τ_{np→τ^{+}ν}>2.9×10^{31} yr at a 90% confidence level are obtained. Some of these searches are novel.

Search for neutrinos from annihilation of captured low-mass dark matter particles in the sun by super-kamiokande.

Super-Kamiokande (SK) can search for weakly interacting massive particles (WIMPs) by detecting neutrinos produced from WIMP annihilations occurring inside the Sun. In this analysis, we include neutrino events with interaction vertices in the detector in addition to upward-going muons produced in the surrounding rock. Compared to the previous result, which used the upward-going muons only, the signal acceptances for light (few-GeV/c^{2}-200-GeV/c^{2}) WIMPs are significantly increased. We fit 3903 days of SK data to search for the contribution of neutrinos from WIMP annihilation in the Sun. We found no significant excess over expected atmospheric-neutrino background and the result is interpreted in terms of upper limits on WIMP-nucleon elastic scattering cross sections under different assumptions about the annihilation channel. We set the current best limits on the spin-dependent WIMP-proton cross section for WIMP masses below 200 GeV/c^{2} (at 10 GeV/c^{2}, 1.49×10^{-39} cm^{2} for χχ→bb[over ¯] and 1.31×10^{-40} cm^{2} for χχ→τ^{+}τ^{-} annihilation channels), also ruling out some fraction of WIMP candidates with spin-independent coupling in the few-GeV/c^{2} mass range.

Search for nucleon decay via n→ν[over ¯]π0 and p→ν[over ¯]π+ in Super-Kamiokande.

We present the results of searches for nucleon decay via n→ν[over ¯]π0 and p→ν[over ¯]π+ using data from a combined 172.8 kt·yr exposure of Super-Kamiokande-I,-II, and-III. We set lower limits on the partial lifetime for each of these modes: τn→ν[over ¯]π0>1.1×10(33) years and τp→ν[over ¯]π+>3.9×10(32) years at a 90% confidence level.

Search for trilepton nucleon decay via p→e+νν and p→µ+νν in the Super-Kamiokande experiment.

The trilepton nucleon decay modes p→e+νν and p→µ+νν violate |Δ(B-L)| by two units. Using data from a 273.4 kt yr exposure of Super-Kamiokande a search for these decays yields a fit consistent with no signal. Accordingly, lower limits on the partial lifetimes of τp→e+νν>1.7×10(32) years and τp→µ+νν>2.2×10(32) years at a 90% confidence level are obtained. These limits can constrain Grand Unified Theories which allow for such processes.

First indication of terrestrial matter effects on solar neutrino oscillation.

We report an indication that the elastic scattering rate of solar B8 neutrinos with electrons in the Super-Kamiokande detector is larger when the neutrinos pass through Earth during nighttime. We determine the day-night asymmetry, defined as the difference of the average day rate and average night rate divided by the average of those two rates, to be [-3.2 ± 1.1(stat) ± 0.5(syst)]%, which deviates from zero by 2.7 σ. Since the elastic scattering process is mostly sensitive to electron-flavored solar neutrinos, a nonzero day-night asymmetry implies that the flavor oscillations of solar neutrinos are affected by the presence of matter within the neutrinos' flight path. Super-Kamiokande's day-night asymmetry is consistent with neutrino oscillations for 4 × 10(-5) eV(2) ≤ Δm 2(21) ≤ 7 × 10(-5) eV(2) and large mixing values of θ12, at the 68% C.L.

Evidence for the appearance of atmospheric tau neutrinos in super-Kamiokande.

Super-Kamiokande atmospheric neutrino data were fit with an unbinned maximum likelihood method to search for the appearance of tau leptons resulting from the interactions of oscillation-generated tau neutrinos in the detector. Relative to the expectation of unity, the tau normalization is found to be 1.42 ± 0.35(stat)(-0.12)(+0.14)(syst) excluding the no-tau-appearance hypothesis, for which the normalization would be zero, at the 3.8σ level. We estimate that 180.1 ± 44.3(stat)(-15.2)(+17.8) (syst) tau leptons were produced in the 22.5 kton fiducial volume of the detector by tau neutrinos during the 2806 day running period. In future analyses, this large sample of selected tau events will allow the study of charged current tau neutrino interaction physics with oscillation produced tau neutrinos.

Perineural invasion is associated with increased relapse after external beam radiotherapy for men with low-risk prostate cancer and may be a marker for occult, high-grade cancer.

PURPOSE: To investigate the risk of postradiotherapy prostate-specific antigen (PSA) failure on the basis of pretreatment risk factors in prostate cancer patients with and without perineural invasion (PNI) in prostate biopsy specimens and to explain the observation that otherwise low-risk patients with PNI experience decreased freedom from PSA failure after external beam radiotherapy (RT). METHODS AND MATERIALS: The study cohort consisted of 381 patients who underwent RT between 1989 and 2000 for clinically localized prostate cancer. A single genitourinary pathologist scored the absence or presence of PNI on all prostate biopsy specimens. Patients were divided into low-, intermediate- and high-risk subgroups on the basis of their 1992 American Joint Committee on Cancer T-stage, pretreatment PSA level, and Gleason score. Cox regression uni- and multivariate analyses were performed to evaluate whether the presence or absence of PNI in the biopsy specimen was a predictor of the time to post-RT PSA failure for patients in each pretreatment risk group. PSA failure was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. Actuarial PSA failure-free survival was estimated using the Kaplan-Meier method, and comparisons were performed using the log-rank test. RESULTS: Cox regression univariate analysis revealed that PNI was a significant predictor of the time to PSA failure in the low-risk (p = 0.04) and high-risk (p = 0.03) cohorts. The 5-year PSA failure-free survival rate was 50% vs. 80% (p = 0.04) in low-risk patients, 70% vs. 75% (p = 0.72) in intermediate-risk patients, and 29% vs. 53% (p = 0.03) in high-risk patients with and without PNI, respectively. Cox regression multivariate analysis within the high-risk group revealed that a PSA level > or =20 ng/mL (p = 0.01) and Gleason score > or =8 (p = 0.02), but not PNI, were the only significant predictors of the time to PSA failure after RT. However, an association was found between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 8-10 (p = 0.06). The association was stronger between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 7-10 (p = 0. 033). CONCLUSION: A decrement in PSA outcome after RT for low-risk patients with PNI-positive biopsy specimens was found. The association between PNI and high Gleason score provides a possible explanation for the loss of statistical significance of PNI in the Cox regression multivariate analysis of the high-risk cohort. The data suggest that PNI found in the biopsy specimen of an otherwise low-risk patient predicts for occult high-grade disease that is missed owing to the sampling error associated with prostate biopsy. The association between PNI and a high Gleason score argues for the use of more aggressive therapy, such as hormonal therapy with RT and/or dose escalation, in these select patients.

Massive plexiform neurofibroma with associated meningo-encephalocoele and occipital bone defect presenting as a cervical mass.

The commonest skull manifestations in neurofibromatosis involve the orbit, with very few reports about occipital defects. We report a rare case of a 54-year-old lady with a massive plexiform neurofibroma extending from the auricular region down her left neck and into her shoulder, with an associated large left occipital and left petrous bone defect and extensive cerebellar meningo-encephalocoele, which presented with a relatively asymptomatic cervical mass and was treated with resection of the neurofibroma and advancement and rotational skin flaps.

Subclassification of renal cell neoplasms: an update for the practising pathologist.

The classification of renal cell neoplasms has been extensively studied in the last decade, and a standardized nomenclature adopted. Although this system is based on a combination of genetic, histological and immunohistological features, in most cases accurate classification can be based on histological features alone. This review summarizes the key features of the tumours included in this system, and then focuses on diagnostic difficulties that can arise when using this system, as well as reviewing several recently characterized tumours that are not yet included.

Angioplasty with stenting is effective in treating blue toe syndrome.

Blue toe syndrome is a manifestation of distal embolization associated with significant pain and risk of tissue loss. The recommended treatment options for this problem include endarterectomy or bypass with exclusion of the source of emboli. Although focal arterial stenosis can be effectively treated with angioplasty,it is unclear whether performing angioplasty in a lesion suspected of causing distal embolization might actually worsen the condition or what long-term effects this would have in preventing future embolization. The purpose of this study was to evaluate the treatment and outcome of a series of patients with unilateral blue toe syndrome treated with percutaneous angioplasty and stenting. During a 5-year period, a total of 8 patients were identified with unilateral blue toe syndrome. Ankle/brachial indices (ABIs) were obtained, followed by arteriography. The study group included 4 men and 4 women with an age range of 35 to 83 years. Their atherosclerotic risk factors included smoking (8), hypertension (5), diabetes mellitus (3), and hypercholesterolemia (1). One patient had a history of illicit drug use. The patients were followed up by repeat clinical examinations and vascular laboratory studies. Arteriography typically demonstrated a focal preocclusive lesion with thrombus at the distal end of the lesion. Angioplasty and stent placement was technically successful in all cases. The ABIs increased following angioplasty (before 0.81 +/- 0.05; after 1.02 +/-.05). The symptoms resolved in all 8 patients over the ensuing month, and there were no recurrences with a mean follow-up of 18.5 months (range 4 to 36 months). There was 1 death at 4 months associated with preexisting colon carcinoma. Unilateral arterial to arterial emboli were found in association with focal preocclusive lesions. Despite the presence of thrombus in some of the lesions, these patients were not acutely worse following angioplasty. There was good initial angiographic success in all cases. There was also hemodynamic improvement as shown by the increased ankle/brachial indices. Although long-term follow-up is not available, these intermediate results suggest that angioplasty and stenting should be considered a reasonable alternative to standard operative approaches for patients with blue to syndrome associated with embolization from a focal stenosis.

Should atypical squamous cells of undetermined significance (ASCUS) be subcategorized? Accuracy analysis of Papanicolaou smears using receiver operating characteristic curves and implications for the ASCUS/squamous intraepithelial lesion ratio.

We correlated all Papanicolaou test diagnoses over a 6-month period with biopsy results and determined accuracy using receiver operating characteristic curves and biopsy as the "gold standard." Accuracies were calculated using all atypical squamous cells of undetermined significance (ASCUS) cases or by eliminating subsets thereof. Retaining the ASCUS category resulted in significantly greater accuracy for the diagnosis of squamous intraepithelial lesion (SIL) on biopsy compared with eliminating it by diagnosing all such cases as negative. Subcategorization significantly improved the accuracy of the test only when all cases were included. The highest accuracy without subcategorization was achieved when ASCUS, favor reactive, cases were diagnosed as negative, but this threshold was significantly less sensitive than including all ASCUS cases. Increasing or decreasing the estimated ASCUS/SIL ratio from 2.4 without subcategorization significantly reduced accuracy. Similar results were obtained when high-grade SIL on biopsy was used as the gold standard. Use of the ASCUS category significantly improves the accuracy of the Papanicolaou test. Eliminating any subset of ASCUS reduces the ASCUS/SIL ratio but also significantly diminishes the sensitivity of the Papanicolaou test.

Accuracy of thyroid fine-needle aspiration using receiver operator characteristic curves.

Although many large series demonstrate the effectiveness of thyroid fine-needle aspiration (FNA), measuring its accuracy has been suboptimal owing to inappropriate statistical methods. All thyroid fine-needle aspirates were correlated with corresponding histologic and cytologic follow-up for a 4-year period, and the accuracy was determined using receiver operator characteristic curves, which allow inclusion of nondiagnostic and indeterminate cases. There were 1,085 cases, 291 with follow-up. The overall accuracy was 0.90 +/- 0.02 for a single aspiration session. A nondiagnostic aspirate was associated with a significant risk of malignancy (16%). However, 70% of patients who underwent reaspiration had adequate and negative results, and reaspiration significantly increased overall accuracy. Subcategorizing the nondiagnostic category did not affect accuracy, but did define categories with a significantly different change of a negative diagnosis on repeated aspiration. Although subcategories of papillary carcinoma were associated with significantly different risks of carcinoma (40% vs 81%), they did not significantly improve overall accuracy. Receiver operator characteristic curves can be used to define the accuracy of thyroid FNA. This method demonstrates significantly increased accuracy with repeated aspiration of nondiagnostic cases and demonstrates that subcategorization does not improve the overall accuracy of the test.

Estimating the impact on prostate cancer mortality of incorporating prostate-specific antigen testing into screening.

OBJECTIVES: Whether early detection using prostate-specific antigen (PSA) and digital rectal examination (DRE) compared with DRE alone will reduce prostate cancer mortality awaits the results of ongoing prospective randomized trials. However, the impact that early detection could have on prostate cancer-specific survival can be estimated by assuming that PSA failure after radical prostatectomy (RP) will translate into death from prostate cancer. METHODS: The study population consisted of 1274 men with clinically localized prostate cancer who underwent RP in Boston, Massachusetts or Philadelphia, Pennsylvania between 1989 and 2000 and had a preoperative PSA level greater than 4 but not more than 10 ng/mL. The primary endpoint was actuarial freedom from PSA failure (defined as PSA outcome). RESULTS: The relative risk of PSA failure after RP for patients diagnosed with a PSA of greater than 4 to 5, 5 to 6, 6 to 7, or 7 to 8 ng/mL compared with greater than 8 up to 10 ng/mL was 0.3 (95% confidence interval [CI] 0.2 to 0.5), 0.5 (95% CI 0.4 to 0.8), 0.6 (95% CI 0.4 to 0.9), or 0.9 (95% CI 0.6 to 1.3), respectively. On the basis of the estimates of the 5-year PSA outcome, patients with a biopsy Gleason score of 5 or 6 (781 of 1274; 61%) consistently benefited from RP performed when the PSA at diagnosis was greater than 4 to 7 ng/mL compared with greater than 8 to 10 ng/mL (93% versus 78%, P <0.0001). A benefit to early detection was not found for the vast majority (266 of 312; 88%) of patients who had a biopsy Gleason score of 7 or higher. CONCLUSIONS: Early detection using both PSA and DRE-based screening may benefit men who present with biopsy Gleason score 5 or 6 prostate cancer and a PSA level greater than 4 to 7 ng/mL compared with greater than 8 up to 10 ng/mL. This finding awaits validation from ongoing prospective randomized trials.

Estimating the percentage of Papanicolaou smears that can be reproducibly identified: modeling Papanicolaou smear interpretation based on multiple blinded rescreenings.

BACKGROUND: Multiple blinded rescreenings of Papanicolaou (Pap) smears for litigation purposes is based on the assumption that a subset of Pap smears can be reproducibly identified. The size of this subset is not known. METHODS: To estimate the size of the subset of Pap smears that can be reproducibly identified, a model was constructed based on the results of repeated blinded screenings in the AutoPap Primary Screening System Trial. Additional analysis came from data in the literature. RESULTS: Routine and AutoPap-assisted screening both have a detection rate for all detected abnormal cases of < 50%. Models with only two subsets or types of slides each with a different detection rate correlated well with the available data. Data from multiple rapid reviews strongly supported the existence of additional definable subsets. Although the percentage of cases with an expected detection rate of 100% in a three-subset model might have been as high as 30% of the abnormal cases detected in a single review, all estimates that included a second subset of slides with at least a 50% detection rate limited the percentage of slides in the 100% sensitive subset of slides to < 2% of all abnormal slides and < 6% of all abnormal slides detected by a single screening. CONCLUSIONS: Repeated screenings of Pap smears allowed more accurate models of the sensitivity of Pap-smear screening and the overall incidence of abnormal cases. The data strongly supported the existence of multiple subsets of Pap smears, which can be defined by repeated blinded rescreenings. The percentage of slides that can be reproducibly identified was small.

Adequate histologic sampling of breast core needle biopsies.

OBJECTIVE: To determine the degree of histologic sampling necessary for adequate examination of breast core needle biopsy specimens. DESIGN: The results of all breast core needle biopsies (11 and 14 gauge) with a diagnosis of atypical small acinar proliferation or atypical ductal hyperplasia and subsequent excisional biopsies, for a 50-month period were reviewed. Blocks of all cores were sectioned entirely in 8 slides to determine the amount of sectioning needed to detect these foci, and the results were correlated with those from the excision specimen. SETTING: Large community hospital practice. RESULTS: Of 3026 cases, 216 (7.1%) were diagnosed as atypical ductal hyperplasia or atypia not otherwise specified. Subsequent resections were available in 105 (49%) cases, and after review, 95 (92%) qualified as atypical ductal hyperplasia and 2 were determined to be atypical small acinar proliferations. The 2 small acinar proliferations were first detected on the second and fourth slides. Of the atypical ductal hyperplasia cases, 43% were detected on the first slide, 17% on the second, 23% on the third, 8% on the fourth, and 8% on the fifth. No lesions were initially detected after this level. Ductal carcinoma in situ was detected in the excision specimens from 1 case each of those detected initially on the fourth and fifth slides. CONCLUSION: Five sections of breast core needle biopsy specimens are necessary to ensure that all atypical small acinar proliferations and atypical ductal hyperplasia lesions are sampled.

Improved reporting methods for atypia and atypical ductal hyperplasia in breast core needle biopsy specimens. Potential for interlaboratory comparisons.

The incidence of atypia and atypical ductal hyperplasia (ADH) in breast core needle biopsies varies widely (900%). I sought to identify methods to reduce the dependence of this measure on variability in the patient population. The results of all breast core needle biopsies with a diagnosis of ADH or atypia not otherwise specified for a 50-month period were reviewed. These were separated into different groups by age, and the variability of different reporting methods was compared. Of 3,026 cases, 216 were diagnosed as ADH or atypia not otherwise specified. The overall incidence of atypia by age group varied significantly from 0.029 to 0.10. The variability was reduced when atypia was expressed in relation to ductal carcinoma in situ (range, 1.0-2.1) or fibrocystic changes (range, 0.15-0.28). However, variability by age was the least when atypia was expressed in relation to the number of cases performed for calcifications (range, 0.13-0.17). Variability in atypia rates associated with age is reduced significantly when atypia is expressed in relation to the number of biopsies done for calcifications. This method of reporting atypia may allow interlaboratory comparisons with less dependence on the characteristics of the patient population.

Atypical ductal hyperplasia in breast core needle biopsies. Correlation of size of the lesion, complete removal of the lesion, and the incidence of carcinoma in follow-up biopsies.

We reviewed the results of all breast core needle biopsies with a diagnosis of atypical ductal hyperplasia (ADH) or atypia not otherwise specified and subsequent excisional biopsies for a 50-month period and correlated the results. Of 3,026 biopsies, 216 were diagnosed as ADH or atypia not otherwise specified, and subsequent resection was available for 105. After review, 95 qualified as ADH. Subsequent resection showed ductal carcinoma in situ (DCIS) in 13 excisions, ADH in 31, lobular carcinoma in situ in 6, and benign proliferative lesions in the remaining 45. In none of the 8 biopsies in which DCIS was found and radiographs were available for review was the radiographic lesion entirely removed. For comparison, the incidence of carcinoma in resections done for a diagnosis of DCIS, low or intermediate grade (solid, cribriform, or micropapillary type), on core needle biopsy was significantly greater (8 of 10 cases). However, the size of the lesions diagnosed as carcinoma also was significantly greater than that of the lesions diagnosed as ADH, and in none of the 8 biopsies with DCIS at excision was the lesion entirely removed at the time of biopsy. The incidence of carcinoma in excisional biopsies done for a diagnosis of ADH in core needle biopsies in our institution is relatively low, while the incidence of ADH is relatively high. Possible reasons for this include total removal of small lesions at the time of biopsy and use of the diagnostic term ADH for lesions that are not associated with coexistent DCIS.