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PubMed1998

Computer modeling of prostate biopsy: tumor size and location--not clinical significance--determine cancer detection.

PURPOSE: Sampling error is an inherent problem of prostate biopsy, and the determination of clinical significance based on biopsy results is problematic. We quantify the dimensions of these problems by computer simulation. MATERIALS AND METHODS: We constructed 3-dimensional solid computer models of 59 autopsy prostates containing clinically undetected prostate cancer, and performed simulations of the standard prostate biopsy method. RESULTS: Biopsy simulation detected 19 tumors from the 59 prostates, the majority of which were in the most accessible portion of the prostate, the posterior peripheral zone. Using 0.5 cc or greater tumor volume or less than 0.5 cc and Gleason sum 7 or greater as criteria of significance, the model detected 58% (11 of 19) significant tumors and 20% (8 of 40) insignificant tumors. With 0.25 cc or greater tumor volume or less than 0.25 cc and Gleason sum 7 or greater as criteria 15 of 29 significant (52%) and 4 of 30 insignificant (13%) tumors were detected. Among significant tumors defined by either volume criterion there was a statistical difference between detected and undetected tumors in terms of mean tumor volume and mean ratio of tumor volume-to-prostate volume. Among insignificant tumors defined by either criterion there was no such difference. CONCLUSIONS: As much as 20 to 40% of currently detected prostate cancer may be histologically insignificant, as 4 of 19 cancers were detected when 0.25 cc was used as volume determinant of clinical significance and 8 of 19 were detected when 0.5 cc volume was used. These tumors are detected randomly. On the other hand, perhaps only one-half to three-fourths of clinically significant prostate cancers are being detected, and then only because the volume and anatomic location make them hard to miss.

Adult↗

PubMed1999

p53 and bcl-2 immunohistochemistry in pretreatment prostate needle biopsies to predict recurrence of prostate cancer after radical prostatectomy.

PURPOSE: Immunohistochemical staining of radical prostatectomy specimens for p53 and bcl-2 proteins has been shown to correlate with prostate specific antigen (PSA) recurrence in a series of patients at our institution. We analyzed the relationship between staining of diagnostic prostate needle biopsies for p53 and bcl-2, and PSA recurrence. MATERIALS AND METHODS: From 1986 to 1993, 335 radical prostatectomies were performed at our hospital. Of the prostatectomy specimens 199 had been evaluated for p53 and bcl-2 proteins in a prior series. Of 139 patients with biopsy material available for analysis 129 had enough for evaluation of 1 or both markers. Prospectively obtained clinical followup data were available, with a mean followup of 6 years. Commercially available antibodies were used for immunohistochemical staining. RESULTS: The overall PSA recurrence rate was 37.6% for 199 radical prostatectomy cases and 37.9% for 129 with biopsy immunohistochemical staining. Staining of prostatectomies correlated well with PSA recurrence for p53 (p = 0.004) and bcl-2 (p = 0.001). However, biopsy staining did not correlate with prostatectomy staining or PSA recurrence for either marker. CONCLUSIONS: The p53 and bcl-2 biomarkers appear to be important to predict recurrence of prostate cancer when prostatectomy specimens are analyzed but this usefulness is not apparent with immunohistochemical staining of prostate biopsies. This difference may reflect sampling error and/or the heterogeneous nature of prostate cancers, and deserves further study.

Aged↗

PubMed1994

Unusual neoplasms detected in testis cancer patients undergoing post-chemotherapy retroperitoneal lymphadenectomy.

Approximately 30% of patients with disseminated testis cancer who receive platinum-based chemotherapy will experience normalization of tumor markers but have persistent, radiographically evident disease in the retroperitoneum. These patients usually undergo retroperitoneal lymph node dissection. Of 557 patients undergoing post-chemotherapy retroperitoneal lymph node dissection at our university medical center 45 (8.1%) had neoplastic elements distinct from the classical germ cell tumor types within the resected specimens. Examples include various sarcomas in 19 patients (3.7%), other nonsarcomatous nongerm cell cancers in 18 (3.2%) and cystic atypical choriocarcinoma in 8 (1.4%). No distinct patient characteristics or histological patterns in the primary tumor are predictive of these unusual findings in the retroperitoneal lymph node dissection specimen, although sampling error in the orchiectomy specimen could be the reason for this lack of correlation. Surgical resection of these chemoresistant tumors is potentially curative, with disease-free survival in 13 of 19 patients (68.4%) with sarcoma, 10 of 18 (55.6%) with nonsarcomatous cancer and 7 of 8 (87.5%) with cystic atypical choriocarcinoma at a mean followup of 30.6, 42.5 and 24.7 months, respectively.

Combined Modality Therapy↗

PubMed1989

Ultrasound guided transrectal core biopsies of the palpably abnormal prostate.

Ultrasound imaging and ultrasound guided transrectal core biopsies were performed in 251 consecutive men with abnormal prostates on digital rectal examination. A hypoechoic defect on ultrasound was identified in 227 of 251 patients (90 per cent) corresponding to the area of palpable nodularity or abnormal firmness. A mean of 6.25 biopsies were obtained per patient using a commercially available spring-loaded gun. Biopsies were positive for cancer in 165 of the 251 prostates (66 per cent). Palpable nodules more often were hypoechoic and more often contained cancer than less distinct areas of abnormal firmness on digital examination. Among the clinical stages B1, B2 and B3 nodules 70, 76 and 88 per cent, respectively, were positive for cancer, as were 100 per cent of the clinical stage C prostates. Of 77 abnormally firm, nonnodular prostates 36 per cent were positive for cancer. Random biopsy of the contralateral normal lobe in 56 men with clinical stage B1 or B2 nodules showed cancer present contralaterally in 42 and 60 per cent, respectively; 20 per cent had positive biopsies despite a contralateral isoechoic ultrasound. In 78 patients with prior digitally guided biopsies, ultrasound guided biopsies confirmed previously diagnosed cancers in 94 per cent. However, in 23 of 43 patients (53 per cent) with previous negative digitally guided biopsies, ultrasound guided biopsies made the new diagnosis of cancer. Complications, including post-biopsy fever and bleeding, occurred in 6 of 251 patients (2.4 per cent). The combination of the new spring-loaded biopsy guns and transrectal ultrasound guidance of biopsies provides the urologist with a tool that allows multiple prostate cores to be obtained safely and painlessly, reducing the sampling error and increasing the accuracy in diagnosing prostate cancer in the man with a palpable abnormality of the prostate.

Adult↗

PubMed1989

Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate.

Random systematic ultrasound guided transrectal core biopsies of the prostate were compared to directed biopsies of specific hypoechoic defects in 136 men with abnormal prostates on digital rectal examination. Prostate cancer was diagnosed in 83 of 136 patients (62 per cent). In 80 of 83 individuals (94 per cent) the cancer was detected by random systematic biopsies alone. Of 57 men in whom random systematic and directed biopsies were obtained the results of biopsy agreed in 86 per cent, while in 9 per cent random systematic biopsies found cancers missed by directed biopsies and in 5 per cent directed biopsies diagnosed cancers missed by random systematic prostate biopsies. Ultrasound guided random systematic biopsy is simple and easily learned. When combined with additional directed biopsies of the rare hypoechoic areas not included in the pattern of systematic sampling, it provides a highly accurate means to diagnose prostate cancer, minimizing observer and sampling errors. This technique of prostate mapping with 6, 1.5 cm. cores provides valuable additional information on cancer volume, Gleason grade and the potential location of surgically positive margins, all without compromising the operation or the chance for a surgical cure.

Biopsy, Needle↗

PubMed1998

Low dose effects of chemicals as assessed by the flow cytometric in vivo micronucleus assay.

Using flow cytometric automation of the mouse in vivo, micronucleus assay increases the sensitivity of the test. This is achieved through a very large increase in the number of cells scored, by a factor of 100x, which in turn greatly reduces the sampling error. With this method, dose-response relationships of in vivo micronucleus induction for four model agents mitomycin C (MMC), diepoxybutane (DEB), cyclophosphamide (CPA), and colchicine (COL) were studied at low dose levels. For the three clastogens MMC, DEB and CPA, linear dose-response relationships were found over the dose ranges studied, even in the very low dose region (defined as the dose region where the frequency of micronucleated erythrocytes is less than twice the baseline frequency). This is consistent with the view that no threshold should exist for genotoxic agents which target DNA. For COL a dose range was found, in which the frequency of micronucleated erythrocytes did not increase with dose, possibly indicating an in vivo threshold. The flow cytometric in vivo micronucleus assay represents one possibility for in vivo low dose-response studies.

Animals↗

PubMed2004

Electromyography and the immobile vocal fold.

Laryngeal EMG has become a useful tool for the otolaryngologist in the four decades since the pioneering work of Faaborg-Anderson and Buchtal. It is able to distinguish between mechanical limitation and denervation in an immobile vocal fold. In the paralyzed vocal fold, it can guide workup by pointing to the site of the lesion. In the hands of a circumspect clinician, it can provide clinically valuable information regarding prognosis. Useful application of laryngeal EMG must rest on the basic fact that it isa qualitative test. Because of factors like sampling error, interfering signal from neighboring muscles, difficulties in needle placement, and our in-complete understanding of reinnervation physiology, the boundary between sophisticated, subtle interpretation and overreading is particularly difficult to distinguish. EMG diagnosis is based on patterns of abnormalities over time and, like other tests, requires interpretation in a clinical context. As in any such undertaking, there is no substitute for good judgment and experience. The most important benefit of clinical use of laryngeal EMG may be that it has catalyzed and broadened interest in laryngeal neurophysiology in the same way that stroboscopy has focused attention on the structure and function of the vocal fold lamina propria. The continuing refinement of electrodiagnostic approaches to the larynx that has resulted, including quantitative, single-fiber. and vector laryngeal EMG, and evolving methods of nerve conduction testing will continue to yield important insights into mechanisms of neural control that are likely to drive developments in the treatment of vocal fold paralysis in the future.

Action Potentials↗

PubMed2000

Cytological recognition of invasive squamous cancer of the uterine cervix: comparison of conventional light-microscopical screening and neural network-based screening.

Cytologic recognition of invasive or microinvasive cancer of the uterine cervix may present substantial difficulties. In this study, we compared conventional light-microscopical screening of 109,104 cervical smears and neural network-based screening (NNS) of 245,527 smears, all obtained by the spatula-Cytobrush method. Two populations of Dutch women were included in the study: those receiving smears within the framework of the Dutch population screening program ("routine smears") and those receiving smears for other reasons, discussed in the text ("interval smears"). There were 71 smears, from an equal number of biopsy-confirmed invasive squamous carcinomas, 28 of which were microinvasive. The "interval smears" yielded a statistical valid higher prevalence of invasive cancer than "routine smears." Except for 5 smears that contained no evidence of abnormality ("sampling errors"), no false-negative errors occurred in the 52 NNS cases, whereas 4 such errors occurred in the 19 conventionally screened cases. By measuring the amount of cancerous material present in each smear (mapping), it could be documented that NNS was effective even in smears with a small number of cancer cells, whereas the 4 conventional false-negative screening errors occurred in smears of this type. The study showed that cells derived from invasive cancer of the cervix may have large bland nuclei that do not fit the images commonly associated with squamous cancer cells. Neural network-based screening of cervical smears was more effective than conventional screening in the diagnosis of invasive squamous cancer of the uterine cervix.

Carcinoma, Squamous Cell↗

PubMed1997

The relationship of lead in soil to lead in blood and implications for standard setting.

As part of a soil lead regulation process, this review was conducted to determine the association between lead in soil and established human health effects of lead or validated biomarkers of lead exposure. We reviewed only studies where soil exposure could be distinguished from other sources of lead and whose design could reasonably be used to infer a causal relationship between soil lead and either biomarkers or health effects. No such studies of health effects were found. Studies describing a quantitative relationship between soil lead and blood lead did meet our criteria: 22 cross-sectional studies in areas with polluted soil; and three prospective studies of soil lead pollution abatement trials. The cross-sectional studies indicated that, compared to children exposed to soil lead levels of 100 ppm, those exposed to levels of 1000 ppm had mean blood lead concentrations 1.10-1.86 times higher and those exposed to soil lead levels of 2000 ppm had blood lead concentrations 1.13-2.25 times higher. The prospective studies showed effects within the ranges predicted by the cross-sectional studies. Differences in results between studies were surprisingly modest and likely explainable by random sampling error, different explanatory variables included in data analyses and differences in methods of measuring lead in environmental specimens.

Adolescent↗

PubMed1997

Clinical significance of repeat sextant biopsies in prostate cancer patients.

OBJECTIVES: Six random systematic core biopsies (SRSCB) of the prostate is considered by many to represent the standard method of detecting prostate cancer. We sought to evaluate the sensitivity of the transrectal ultrasound (TRU)S-guided needle biopsies in 89 consecutive patients with a history of biopsy-proven prostate cancer. These patients underwent repeat biopsy prior to enrollment in an ongoing, randomized protocol. We also compared the clinical and pathological features of patients with SRSCB-documented prostate carcinoma and negative repeat-sextant biopsy. METHODS: Our study population consisted of 89 patients enrolled in our randomized, prospective study assessing the effect of androgen deprivation therapy in combination with radical prostatectomy for clinically localized prostate cancer. A comparison was made of the patients' rebiopsy results with initial biopsy. Patients having either a positive or negative rebiopsy were analyzed with respect to grade, T stage, prostate-specific antigen (PSA), PSA density (PSAD), organ-confined rate, and final surgical margin status. RESULTS: Repeat sextant biopsy was positive for prostate cancer in 71 (80%) patients and negative in 18 (20%) patients. There was no significant difference between patients with a negative or positive rebiopsy with respect to PSA or PSAD. There was a trend toward greater prostate volumes in the negative-rebiopsy group (P = 0.08) and lower clinical stage in the negative rebiopsy (P = 0.025) group. In patients with a negative repeat biopsy, the organ-confined (OC) rate was 77% (14/18 patients), as compared to the positive-rebiopsy group of 56% (40/71 patients) (P = 0.08). Similarly, the margin-positive rate in the negative-rebiopsy group was 17% (3/18 patients), as compared to the positive-rebiopsy group who had a margin-positive rate of 44% (31/71 patients) (P = 0.03). CONCLUSIONS: In patients with clinically localized disease, the sensitivity of SRSCB in detecting carcinoma is 80%. The results of this study highlight the potential sampling error of the SRSCB and the implication of a negative rebiopsy in patients with clinically significant prostate cancer.

Androgen Antagonists↗

PubMed1999

Three-dimensional computer-simulated prostate models: lateral prostate biopsies increase the detection rate of prostate cancer.

OBJECTIVES: Urologists routinely use the systematic sextant needle biopsy technique to detect prostate cancer. However, recent evidence suggests that this technique has a significant sampling error. We developed a novel three-dimensional (3D) computer-assisted prostate biopsy simulator based on whole-mounted step-sectioned radical prostatectomy specimens to compare the diagnostic accuracy of various prostate needle biopsy protocols. METHODS: We obtained digital images of 201 step-sectioned whole-mounted radical prostatectomy specimens. 3D computer simulation software was developed to accurately depict the anatomy of the prostate and all individual tumor foci. Additional peripheral devices were incorporated into the system to perform interactive prostate biopsies. We obtained 18 biopsies of each prostate model to determine the detection rates of various biopsy protocols. RESULTS: The 10- and 12-pattern biopsy protocols had a 99.0% detection rate; the traditional sextant biopsy protocol rate was only 72.6%. The 5-region biopsy protocol had a 90.5% detection rate and the 14-pattern, which includes all the biopsies used in the patterns above, only added 1 additional positive case (99.5%). Transitional zone and seminal vesicle biopsies did not result in a significantly increased detection rate when added to the patterns above. Only one positive model was obtained when the transitional zone biopsies were added. The lateral sextant pattern had a detection rate of 95.5%, and the 4-pattern lateral biopsy protocol had a 93.5% detection rate. CONCLUSIONS: Our results suggest that all the biopsy protocols that use laterally placed biopsies based on the 5-region anatomic model are superior to the routinely used sextant prostate biopsy pattern. Lateral biopsies in the mid and apical zones of the gland are the most important.

Biopsy, Needle↗

PubMed1995

The influence of prostate size on cancer detection.

OBJECTIVES: To determine if cancer detection rates vary with prostate size using a sextant core biopsy pattern. METHODS: We reviewed 1021 transrectal ultrasound (TRUS)-guided sextant pattern prostate biopsies to determine if cancer detection varied based on prostate size. Prostate size was determined using a computer generated elliptical estimation method. Sextant core biopsies were taken, and the patients divided into groups based on estimated size of the prostate and biopsy outcome. Large prostates were those that were estimated by TRUS as 50 cc or more. Prostates were considered small if they were less than 50 cc. Groups were compared based on size and biopsy outcome. RESULTS: Adenocarcinoma was detected in 33% (334 of 1021) of the patients. Large prostates were noted in 34% (346 of 1021), of which 23% (80 of 346) had cancer detected by sextant biopsy. Small prostates were noted in 66% (675 of 1021), of which 38% (254 of 675) had cancer detected. The difference in cancer detection in large and small glands using a sextant pattern was statistically significant (P < 0.01). Patients with positive biopsies had significantly smaller prostate sizes (40 cc +/- 26) when compared with those with negative biopsies (51 cc +/- 33) (P < 0.01). Only 14% (8 of 58) of patients with gland sizes 100 cc or greater had positive sextant biopsies while 49% (118 of 239) with prostates 25 cc or less had cancer detected. Multivariate statistical analysis was used to control for differences in age, prostate-specific antigen (PSA), PSA density, TRUS findings, and digital rectal examination between the large and small prostate groups. The difference in cancer detection persisted (P < 0.05) CONCLUSIONS: Currently no evidence exists to support differing cancer rates based on gland size alone. Our cancer detection rate using a sextant pattern was higher in men with prostates less than 50 cc, and patients diagnosed with cancer had significantly smaller prostates than those with a negative sextant biopsy. Our data suggest that significant sampling error may occur in men with large glands, and more biopsies may be needed under these circumstances. The effects of tumor volume, focality, and specimen size in relation to overall gland size may contribute to these findings.

Adenocarcinoma↗

PubMed2000

A microtiter trypan blue absorbance assay for the quantitative determination of excitotoxic neuronal injury in cell culture.

An automated method for the determination of neuronal cell death using trypan blue is described. Following various excitotoxic insults, murine mixed cortical cell cultures are stained with trypan blue (0.05%; 15 min), followed by SDS (1%) lysis. The absorbance of the dye is measured spectrophotometrically at 590 nm using a microtiter plate reader. When compared to the biochemical lactate dehydrogenase assay, no statistical difference in the calculated levels of excitotoxic neuronal cell death was noted between the assays in any given paradigm. This method is fast and reliable. It eliminates the need for cell counting, thus allowing for high volume sample analysis with a minimum of sample error. Utility of this trypan blue absorbance spectrophotometric assay is likely to extend beyond the study of excitotoxic neuronal injury and should complement existing methods for measuring neuronal viability and cytotoxicity in cell culture.

Absorption↗

PubMed2000

Ethological confirmatory factor analysis of anxiety-like behaviour in the murine elevated plus-maze.

The elevated plus-maze has been used in animal research to measure anxiety since 1985 and is currently the most widely used animal model of anxiety. Since this paradigm has been the subject of several principal components analyses, it is well qualified for confirmatory factor analysis research. The current report builds on the substantial theoretical knowledge and empirical data obtained from these structural analyses with a view to obtain further progress in the evolution of our understanding of animal anxiety in the elevated plus-maze. The purpose of the present report was two-fold: (a) to test if the a piori imposition of a 3-factor model, or a competing 2-factor elevated plus-maze model, would fit our sample (n=200 CD-1 mice) data in each of two trials within an inferential confirmatory factor analytic framework; (b) provide a well-fitting model that confers indicator variables that can most effectively and parsimoniously measure underlying constructs of elevated plus-maze behaviour. Multiple model-fitting criteria were used, and issues related to data non-normality, outliers, replicability of the model, sampling error and error of approximation in the estimation of final model fit were addressed. The final 2-factor model, with estimated error covariance between two different pairs of indicator variables, was a good fit on the trial-1 data, although it was necessary to allow unprotected stretch attends to non-significantly cross-load on factor-2. A 2-factor model also fit the trial-2 data from the present analysis, although it was necessary to allow closed arm time ratio to negatively cross-load on factor-1. These results indicate that inferential hypothesis testing and model building procedures within a confirmatory factor analysis framework produces interpretable animal anxiety indices in the elevated plus-maze. Moreover, a 2-factor, rather than a 3-factor model, parsimoniously and unambiguously explained the underlying constructs of anxiety-like mouse behaviour in the elevated plus-maze in the present study. Taken together, a reduction in the growing number of behavioural indices reported in elevated plus-maze pharmacological studies is suggested.

Animals↗

PubMed1983

The invisible dermatoses.

It is understandable that clinically normal skin may show abnormalities when examined with the light microscope, but paradoxical that biopsy of a clinically significant skin disorder may show a histologic picture that looks like normal skin. From the perspective of the dermatopathologist, the invisible dermatoses are clinically evident skin diseases that show a histologic picture resembling normal skin. A strategy for approaching the problem of the invisible dermatoses is to first examine the epidermis for fungi, cornoid lamellae (disseminated superficial actinic porokeratosis), and absence of the granular layer (dominant ichthyosis vulgaris). The cutis is then studied for hyalin deposition (macular amyloidosis), mast cells, microfilaria, dermal melanocytosis, silver granules, and absence of sweat glands (anhidrotic ectodermal dysplasia). Special stains may be required to uncover conditions like anetoderma and nevus elasticus. Comparison of the specimen with normal skin may disclose atrophoderma, lipoatrophy, vitiligo, or café au lait spot. Finally, technical problems should be considered, including sampling errors and mixup of specimens, either by the clinician or the laboratory.

Biopsy↗

PubMed1988

Malignant blue nevus. Case report and literature review.

A well-documented case of malignant blue nevus is presented, along with an in-depth review of the literature. Malignant blue nevus is a rare form of malignant melanoma. A cellular blue nevus is the precursor lesion. The scalp is the most common site. The tumor often presents clinically as a progressively enlarging or multinodular blue-black lesion. The histologic pattern is fascicular dense collections of pigmented, pleomorphic spindle cells. Because of marked regional histologic variation within a malignant blue nevus, however, sampling error can cause delay in recognition of malignancy. A high clinical index of suspicion and appropriate biopsy technique are necessary to reach an early diagnosis. The most common site of metastasis of a malignant blue nevus is the lymph node. The phenomenon of benign lymph node nevus cell metastasis, which may occur with benign blue nevi, must be differentiated from a true malignant metastasis of a malignant blue nevus.

Aged↗

PubMed1991

Work-related stress and depression among physicians pursuing postgraduate training in emergency medicine: an international study.

STUDY OBJECTIVE: To compare the levels of work-related stress and depression reported by physicians-in-training in emergency medicine in three survey sites and to determine the effects of gender and marital status on stress and depression among these physicians. DESIGN: Cross-sectional mail surveys. SETTING AND TYPE OF PARTICIPANTS: Physicians-in-training in the United States, United Kingdom, and Australasia. INTERVENTION: Questionnaires requesting demographic information and including scales assessing work-related stress and depression were administered. MEASUREMENTS AND RESULTS: A 3 x 2 x 2 multivariate analysis of variance in which survey site, gender, and marital status were independent variables and stress and depression scale scores were dependent variables revealed significant differences when stress and depression were analyzed simultaneously. Univariate analyses of variance revealed significant differences in stress by survey site and gender and in depression for all three independent variables. Comparison of adjusted means revealed that respondents from the United Kingdom reported significantly higher levels of stress than did respondents from the United States and that women reported significantly higher levels than men. Respondents from the United States reported significantly higher levels of depression than did respondents from the other countries, women reported higher levels than men, and unmarried respondents reported higher levels than married respondents. CONCLUSION: Despite limitations resulting from self-report bias, cross-sectional survey methodology, sampling error, and differences in training among the three survey sites, the respondents experienced similar levels of stress and depression attributable to anticipated sources.

Australia↗

PubMed2001

Trials within trials: confirmatory subgroup analyses in controlled clinical experiments.

Subgroup analyses remain a popular and necessary component of controlled clinical trials. However, lack of prospective specification, inadequate sample size, inability to maintain power, and the cumulative effect of sampling error can complicate their interpretation. This article demonstrates that clinical trial design tools that would allow the medical community to draw confirmatory and not just exploratory conclusions from specific subgroup evaluations are available to methodologists. Distinct from the use of a treatment by subgroup interaction term, this methodology provides an evaluation of the effect of an intervention within a particular subgroup stratum prospectively declared to be of interest to the investigators. The necessary prespecification of stratum-specific type I error rates, when combined with (1) a stratum-specific event rate in the subgroup, (2) a stratum-specific primary endpoint, (3) a stratum-specific endpoint precision, and/or (4) a stratum-specific efficacy, satisfies the requirements for a subgroup stratum's "stand-alone" interpretation at the trial's conclusion.

Clinical Trials as Topic↗