Cellular Density in Adult Glioma, Estimated with MR Imaging Data and a Machine Learning Algorithm, Has Prognostic Power Approaching World Health Organization Histologic Grading in a Cohort of 1181 Patients.

BACKGROUND AND PURPOSE: Recent advances in machine learning have enabled image-based prediction of local tissue pathology in gliomas, but the clinical usefulness of these predictions is unknown. We aimed to evaluate the prognostic ability of imaging-based estimates of cellular density for patients with gliomas, with comparison to the gold standard reference of World Health Organization grading. MATERIALS AND METHODS: Data from 1181 (207 grade II, 246 grade III, 728 grade IV) previously untreated patients with gliomas from a single institution were analyzed. A pretrained random forest model estimated voxelwise tumor cellularity using MR imaging data. Maximum cellular density was correlated with the World Health Organization grade and actual survival, correcting for covariates of age and performance status. RESULTS: A maximum estimated cellular density of >7681 nuclei/mm2 was associated with a worse prognosis and a univariate hazard ratio of 4.21 (P < .001); the multivariate hazard ratio after adjusting for covariates of age and performance status was 2.91 (P < .001). The concordance index between maximum cellular density (adjusted for covariates) and survival was 0.734. The hazard ratio for a high World Health Organization grade (IV) was 7.57 univariate (P < .001) and 5.25 multivariate (P < .001). The concordance index for World Health Organization grading (adjusted for covariates) was 0.761. The maximum cellular density was an independent predictor of overall survival, and a Cox model using World Health Organization grade, maximum cellular density, age, and Karnofsky performance status had a higher concordance (C = 0.764; range 0.748-0.781) than the component predictors. CONCLUSIONS: Image-based estimation of glioma cellularity is a promising biomarker for predicting survival, approaching the prognostic power of World Health Organization grading, with added values of early availability, low risk, and low cost.

Estimating Local Cellular Density in Glioma Using MR Imaging Data.

BACKGROUND AND PURPOSE: Increased cellular density is a hallmark of gliomas, both in the bulk of the tumor and in areas of tumor infiltration into surrounding brain. Altered cellular density causes altered imaging findings, but the degree to which cellular density can be quantitatively estimated from imaging is unknown. The purpose of this study was to discover the best MR imaging and processing techniques to make quantitative and spatially specific estimates of cellular density. MATERIALS AND METHODS: We collected stereotactic biopsies in a prospective imaging clinical trial targeting untreated patients with gliomas at our institution undergoing their first resection. The data included preoperative MR imaging with conventional anatomic, diffusion, perfusion, and permeability sequences and quantitative histopathology on biopsy samples. We then used multiple machine learning methodologies to estimate cellular density using local intensity information from the MR images and quantitative cellular density measurements at the biopsy coordinates as the criterion standard. RESULTS: The random forest methodology estimated cellular density with R 2 = 0.59 between predicted and observed values using 4 input imaging sequences chosen from our full set of imaging data (T2, fractional anisotropy, CBF, and area under the curve from permeability imaging). Limiting input to conventional MR images (T1 pre- and postcontrast, T2, and FLAIR) yielded slightly degraded performance (R2 = 0.52). Outputs were also reported as graphic maps. CONCLUSIONS: Cellular density can be estimated with moderate-to-strong correlations using MR imaging inputs. The random forest machine learning model provided the best estimates. These spatially specific estimates of cellular density will likely be useful in guiding both diagnosis and treatment.

Imaging-Based Algorithm for the Local Grading of Glioma.

BACKGROUND AND PURPOSE: Gliomas are highly heterogeneous tumors, and optimal treatment depends on identifying and locating the highest grade disease present. Imaging techniques for doing so are generally not validated against the histopathologic criterion standard. The purpose of this work was to estimate the local glioma grade using a machine learning model trained on preoperative image data and spatially specific tumor samples. The value of imaging in patients with brain tumor can be enhanced if pathologic data can be estimated from imaging input using predictive models. MATERIALS AND METHODS: Patients with gliomas were enrolled in a prospective clinical imaging trial between 2013 and 2016. MR imaging was performed with anatomic, diffusion, permeability, and perfusion sequences, followed by image-guided stereotactic biopsy before resection. An imaging description was developed for each biopsy, and multiclass machine learning models were built to predict the World Health Organization grade. Models were assessed on classification accuracy, Cohen κ, precision, and recall. RESULTS: Twenty-three patients (with 7/9/7 grade II/III/IV gliomas) had analyzable imaging-pathologic pairs, yielding 52 biopsy sites. The random forest method was the best algorithm tested. Tumor grade was predicted at 96% accuracy (κ = 0.93) using 4 inputs (T2, ADC, CBV, and transfer constant from dynamic contrast-enhanced imaging). By means of the conventional imaging only, the overall accuracy decreased (89% overall, κ = 0.79) and 43% of high-grade samples were misclassified as lower-grade disease. CONCLUSIONS: We found that local pathologic grade can be predicted with a high accuracy using clinical imaging data. Advanced imaging data improved this accuracy, adding value to conventional imaging. Confirmatory imaging trials are justified.

Machine learning-based texture analysis for differentiation of large adrenal cortical tumours on CT.

AIM: To compare the efficacy of computed tomography (CT) texture analysis and conventional evaluation by radiologists for differentiation between large adrenal adenomas and carcinomas. MATERIALS AND METHODS: Quantitative CT texture analysis was used to evaluate 54 histopathologically proven adrenal masses (mean size=5.9 cm; range=4.1-10 cm) from 54 patients referred to Anderson Cancer Center from January 2002 through April 2014. The patient group included 32 women (mean age at mass evaluation=59 years) and 22 men (mean age at mass evaluation=61 years). Adrenal lesions seen on precontrast and venous-phase CT images were labelled by three different readers, and the labels were used to generate intensity- and geometry-based textural features. The textural features and the attenuation values were considered as input values for a random forest-based classifier. Similarly, the adrenal lesions were classified by two different radiologists based on morphological criteria. Prediction accuracy and interobserver agreement were compared. RESULTS: The textural predictive model achieved a mean accuracy of 82%, whereas the mean accuracy for the radiologists was 68.5% (p<0.0001). The interobserver agreements between the predictive model and radiologists 1 and 2 were 0.44 (p<0.0005; 95% confidence interval [CI]: 0.25-0.62) and 0.47 (p<0.0005; 95% CI: 0.28-0.66), respectively. The Dice similarity coefficient between the readers' image labels was 0.875±0.04. CONCLUSION: CT texture analysis of large adrenal adenomas and carcinomas is likely to improve CT evaluation of adrenal cortical tumours.

Body mass index as a prognostic factor in endometrioid adenocarcinoma of the endometrium.

OBJECTIVE: To determine if body mass index (BMI) influences tumor expression of HER-2/neu, estrogen and progesterone receptors (ER/PR), and survival in women with endometrial adenocarcinoma. METHODS: Patients diagnosed between January 1992 and December 2001 with endometrioid adenocarcinoma of the uterus were identified. Clinical and pathologic data were retrospectively collected. HER-2/neu, estrogen and progesterone receptor expression were determined by immunohistochemistry. Differences in these variables and other prognostic factors were analyzed and correlated with effect on survival. RESULTS: One-hundred-sixty-five patients were included in this analysis. Lower BMI was associated with high stage (p=0.04) and HER-2/neu expression (p=0.04). Black race, high grade, high stage and lack of ER/PR expression were all associated with decreased survival. Despite having better prognostic factors, women with a BMI >25 had a lower survival than women with a BMI <25 (p=0.36). When five-year survival rates were calculated for BMI category and stratified by prognostic factors, for almost every high risk factor, survival was lower in overweight patients. CONCLUSION: In patients with endometrioid adenocarcinoma, low BMI is associated with high stage and tumor expression of HER-2/neu. Despite better prognostic factors, overweight women experience poorer survival.

Clothing size as an indicator of adiposity, ischaemic heart disease and cardiovascular risks.

OBJECTIVE: To relate subjects' clothing sizes to waist circumference, body mass index (BMI) and to the risks of ischaemic heart disease, hypertension and diabetes mellitus, and to derive cut-off levels of clothing size that correspond to increased health risks. DESIGN: Cross-sectional study. Setting Glasgow Royal Infirmary. PARTICIPANTS: A stratified subsample of 201 men and 161 women aged 27-67 years from the Glasgow monitoring coronary (MONICA) risk factor survey. MAIN OUTCOME MEASURES: Measured waist, weight and height, blood pressure and history of ischaemic heart disease (angina, myocardial infarction or angioplasty), hypertension and diabetes mellitus, and medications. RESULTS: There were 15.5% of men and 11.2% of women with ischaemic heart disease, 14.9% of men and 12.4% of women with hypertension, and 4.5% of men and 3.1% of women with diabetes mellitus. Age and smoking adjusted prevalences of these cardiovascular risks, as well as increased adiposity (waist circumference > or =102 cm in men, > or =88 cm in women or BMI > or = 30 kg m(-2)) rose with increasing clothing size. Clothing size correlated (P < 0.001) linearly with indices of adiposity. Clothing sizes which correspond to waist circumference action level 1 (94 cm in men, 80 cm in women) and action level 2 (102 cm in men, 88 cm in women) or to standardized BMI cut-offs (25 and 30 kg m(-2)) were estimated. Height has minimal influences on clothing size. Compared with men with trouser waist below 36 inches or women with UK dress size below 16, the age and smoking adjusted odds ratios for the risk of having at least one of the major health problems (ischaemic heart disease, hypertension or diabetes mellitus) were 3.9 (95% CI: 1.8-8.3) in men and 7.0 (95% CI: 2.5-19.4) in women who had trouser size > or =38 inches or UK dress size > or =18, respectively. CONCLUSIONS: The present study showed that men and women with large clothing size are at increased risk of ischaemic heart disease, hypertension and diabetes mellitus. Men's trouser size equal or larger than 38 in the UK and USA or 97 in Europe and women's dress size equal or larger than 18 in the UK or 16 in the USA or 48 in Europe could be used to promote self-awareness of increased health risks by the general public.

Toward the ethical evaluation and use of maternal-fetal surgery.

BACKGROUND: Important clinical, social, and ethical questions are associated with the evaluation and use of surgical approaches aimed at correcting fetal anatomic abnormalities. In particular, the expansion of maternal-fetal surgery to ameliorate nonlethal fetal conditions has intensified the need to address issues about the adequacy of technology assessment and the safety of those who undergo these novel procedures. APPROACH: After discussions at a multidisciplinary conference, we reviewed the development and current practices of maternal-fetal surgery and analyzed the relevant ethical issues concerning the use of maternal-fetal surgery for nonlethal conditions, focusing on the correction of myelomeningocele. FINDINGS: Characterizing nonvalidated maternal-fetal surgery procedures as "innovative therapy" blurs the boundaries between research and therapy and creates uncertainty about the obligations of clinicians and researchers. Further, maternal-fetal surgery raises ethical issues related to maternal risks and benefits, informed consent, distinguishing lethal from nonlethal conditions, withholding unproven treatments, entrepreneurship, and prioritization. RECOMMENDATIONS: To help ensure that maternal-fetal surgery will be studied and eventually applied in a scientifically and ethically sound manner, we offer several recommendations. First, innovation in maternal-fetal surgery should be conducted and evaluated as research. Second, women must be considered research subjects in these trials. Third, the informed consent process must ensure adequate comprehension and genuine voluntariness in those considering participation. Fourth, discriminatory and fearful attitudes toward individuals with disabilities should be addressed explicitly prior to making a decision to proceed with maternal-fetal surgery in an attempt to correct such disabilities. Fifth, maternal-fetal surgery should not be performed for cosmetic indications unless and until there is reliable evidence that maternal-fetal surgery can be performed safely and that long-term side effects on women and their offspring are minimal. Sixth, centers of excellence should be established for conducting research and providing maternal-fetal surgery. Seventh, funding for research on maternal-fetal surgery should be considered in the context of societal needs.

Psychosexual aspects of vulvar vestibulitis.

OBJECTIVE: To explore the psychological, interpersonal and sexual correlates of vulvar vestibulitis via qualitative and quantitative analysis. STUDY DESIGN: Sixty-nine women diagnosed with vestibulitis were recruited from a vulvar/vaginal disease clinic to complete a comprehensive quantitative and qualitative questionnaire designed to assess general health concerns, mental health, sexual functioning and interpersonal relationships. RESULTS: The majority of participants reported drastic changes in sexuality associated with the onset of vestibulitis. Upon developing vestibulitis, 88% reported decreased interest in sexual activity, 87% indicated that they were less willing to participate in sexual activity, and 94% maintained that they were less able to participate in sexual activity. High levels of frustration and symptoms of depression also were frequently reported. CONCLUSION: Vulvar vestibulitis is associated with significant changes in sexuality, intimate relationships and psychological well-being. When treating women with vestibulitis, medical professionals should consider the psychological and sexual aspects of the disease in addition to physical concerns.

Psychological and sexual functioning in women with vulvar vestibulitis.

OBJECTIVE: The purpose of the study was to compare psychological and sexual functioning in women with vestibulitis with healthy controls. It was hypothesized that women with vestibulitis would experience greater psychological stress and sexual dissatisfaction than controls. STUDY DESIGN: Fifty-two women with vestibulitis recruited from a vulvovaginal disease clinic and 46 healthy controls recruited from an outpatient gynecology clinic completed five standardized measures of psychological and sexual functioning. Multivariate analyses of variance and covariance were used to examine group differences. RESULTS: Women with vestibulitis reported significantly higher scores than controls on the measures of depression (p < or = 0.001), psychological distress (p < or = 0.001) and sexual depression (p < or = 0.001). They reported significantly lower scores on the measures of sexual satisfaction (p < or = 0.001), sexual behavior (p < or = 0.001) and sexual self-esteem (p < or = 0.01). CONCLUSION: The results of this study highlight the importance of addressing psychological distress and sexual dissatisfaction in women with vestibulitis.

Procedure-related miscarriages and Down syndrome-affected births: implications for prenatal testing based on women's preferences.

OBJECTIVE: To determine how pregnant women of varying ages, races, ethnicities, and socioeconomic backgrounds value procedure-related miscarriage and Down-syndrome-affected birth. METHODS: We studied cross-sectionally 534 sociodemographically diverse pregnant women who sought care at obstetric clinics and practices throughout the San Francisco Bay area. Preferences for procedure-related miscarriage and the birth of an infant affected by Down syndrome were assessed using the time trade-off and standard gamble metrics. Because current guidelines assume that procedure-related miscarriage and Down syndrome-affected birth are valued equally, we calculated the difference in preference scores for those two outcomes. We also collected detailed information on demographics, attitudes, and beliefs. RESULTS: On average, procedure-related miscarriage was preferable to Down syndrome-affected birth, as evidenced by positive differences in preference scores for them (time trade-off difference: mean = 0.09, median = 0.06; standard gamble difference: mean = 0.11, median = 0.02; P <.001 for both, one-sample sign test). There was substantial subject-to-subject variation in preferences that correlated strongly with attitudes about miscarriage, Down syndrome, and diagnostic testing. CONCLUSION: Pregnant women tend to find the prospect of a Down syndrome-affected birth more burdensome than a procedure-related miscarriage, calling into question the equal risk threshold for prenatal diagnosis. Individual preferences for those outcomes varied profoundly. Current guidelines do not appropriately consider individual preferences in lower-risk women, and the process for developing prenatal testing guidelines should be reconsidered to better reflect individual values.

Factors influencing obstetric and gynecologic patients' decisions toward medical student involvement in the outpatient setting.

OBJECTIVE: We sought to determine the reasons for obstetric and gynecologic patients' acceptance or refusal of medical student participation in their outpatient care. STUDY DESIGN: A descriptive and analytic cross-sectional study of 180 patients at the University of California, San Francisco, was done to identify factors involved in patient acceptance or refusal of medical student participation in their outpatient obstetric-gynecologic visit. Responses were analyzed by Cochran-Mantel-Haenszel tests for rank order tests of factors involved in the decision to accept or decline medical student participation and chi(2) or Fisher exact tests for comparison of data among different groups. RESULTS: Reasons for accepting medical student involvement included the desire to contribute to the training of future physicians and the desire for the highest standard of care. Reasons for refusing medical student involvement included the protection of patient privacy and the low comfort level with the examination. The acceptance rate for medical students during the obstetric visits was 89.1%, and that during the gynecologic visits was 81.4%. CONCLUSION: Private faculty patients, as well as Medicaid patients, have a high acceptance of both male and female medical students in the obstetric-gynecologic outpatient setting.

Preferences of women facing a prenatal diagnostic choice: long-term outcomes matter most.

Women aged 35 or older who wish to undergo prenatal diagnosis for chromosomal disorders are typically offered a choice between chorionic villus sampling or amniocentesis. These two tests are performed at different times and impose differing miscarriage risks. In deciding which test to use, therefore, women need to consider both short-term consequences (e.g. timing of pregnancy loss, should it occur) and long-term consequences (e.g. whether a pregnancy loss is followed by a future birth). We examined how women seeking prenatal diagnostic services value the outcomes of testing. We conducted a cross-sectional study of 72 women seeking genetic counselling at the University of California at San Francisco or Kaiser San Francisco. We measured preferences for outcomes (utilities) of prenatal diagnosis using the standard gamble metric. We also assessed demographics and attitudes via questionnaire. We observed no differences in mean utilities assigned to first- versus second-trimester pregnancy losses with similar long-term sequelae. Utilities for losses followed by future birth, however, were significantly higher than utilities for losses without future birth (range 0.91 to 0.93 versus 0.84 to 0.86, p<0.05 for all comparisons). In addition, we observed substantial variation in utilities across women. Long-term outcomes matter most to these women. In presenting prenatal diagnostic options to their patients, clinicians should include discussion of outcomes such as the likelihood of future birth in the event of a pregnancy loss. Furthermore, the substantial variation in utilities we observed suggests that future prenatal testing policies should account for the preferences of the individual woman.

Pituitary adenomas and granular cell tumors. Incidence, cell type, and location of tumor in 100 pituitary glands at autopsy.

Incidentally detected pituitary adenomas were investigated in 100 pituitary glands at autopsy to determine the number, cell type, and location of tumors, and the presence of coexisting granular cell tumors in the neurohypophysis. Pituitary glands were sagittally sectioned at 1.5-mm intervals in toto and embedded in 1 cassette to orient location of each tumor. Twenty-four pituitary glands harbored adenomas, most smaller than 3 mm and the largest 6 x 5 x 4 mm. Two pituitary glands contained double adenomas of immunocytochemically different cell types. Of the 26 adenomas, 10 had lactotrophs, 2 had mixed lactotrophs-somatotrophs, 1 had mixed lactotrophs-luteinizing hormone cells, and 12 were nonfunctioning. One adenoma with adenocorticotropic hormone cells was also detected. Thus 25 of 26 (96%) adenomas were either lactotrophic or nonfunctioning; this percentage is much higher than that of surgically resected tumors. Twenty-two tumors were contiguous with or adjacent to the capsule from which the adenomas originated. Nine granular cell tumors were noted in the neurohypophysis; 3 coexisted with pituitary adenomas. Fourteen additional cases revealed small granular cell nests. Thus the incidental finding of nonfunctioning pituitary adenomas is relatively common in adults (24% of cases in this study), and the coexistence of pituitary adenomas and granular cell tumors may suggest a possible histogenic connection between anterior and posterior pituitary tumorigenesis.

Decisions about prenatal testing for chromosomal disorders: perceptions of a diverse group of pregnant women.

We conducted a study to elucidate factors influencing women's decisions regarding prenatal genetic screening for and diagnosis of chromosomal disorders and to learn about their experiences with these tests and with the medical system. Using focus group interviews and questionnaire assessments, we obtained detailed impressions of a diverse group of 75 pregnant women. Participants varied with respect to race/ethnicity, religious background, and reproductive history, as well as in their decisions about use of prenatal screening and diagnostic testing. Substantial variation surfaced in attitudes toward testing. Factors influencing women's views included available resources, feelings about having a child with Down syndrome, moral beliefs, family and social influences, perceptions of one's own health, the difficulty of becoming pregnant, and willingness to put the fetus at elevated miscarriage risk. Such findings indicate that age-based policies regarding access to prenatal diagnoses that, among other reasons, are based on the balance of risks between bearing a child with a chromosomal abnormality versus procedure-related loss are incompatible with the range of concerns that women bring to this decision and the weight individual women may assign to the outcomes.

Reproductive health under managed care: expanding provider obligations.

The discussion of ethical issues in managed care can be focused on two general areas. The first of these is the impact of the shift toward managed care on the fiduciary relationship between health care professional and patient, including the issue of trust, the potential for conflict of interest, and the impact of cost-saving strategies on the clinician's ability to address a patient's health care needs. The second is the attention to justice that managed care demands. Health care professionals must take issues in both areas into account, attempting to balance obligations to individual patients with obligations to patients collectively. Strategies for doing so are discussed.

Is HIV infection a risk factor for advanced cervical cancer?

OBJECTIVES: To compare HIV-infected and HIV-negative women with invasive cervical cancer with respect to predictors of advanced disease. METHODS: A retrospective analysis of 28 HIV-positive and 132 HIV-negative women with invasive cervical carcinoma was conducted and the two groups were compared with regard to stage of disease, demographic and behavioral variables, and risk factors for advanced disease. RESULTS: Overall, HIV-infected women were more likely to have advanced disease, because 78% of HIV-positive women had Stage II to IV compared with 55% of HIV-negative women (odds ratio [OR] = 3.1; p = .03). Substance abuse was strongly associated with HIV infection, as were high-risk sexual variables. Although HIV infection was associated with a threefold increase in advance stage cervical cancer in a univariate analysis, only symptom duration and lack of a recent Papanicolaou smear were significant predictors of advanced disease in a multiple logistic regression analysis. CONCLUSIONS: The major predictors of advanced cervical cancer are similar in HIV-positive and HIV-negative women, although the reasons for these predictors may be very different. It is likely that a large proportion of HIV-positive patients with cervical cancer acquire HIV infection after initiation of the neoplastic process.

What hysterectomy [corrected] patients want to know about the roles of residents and medical students in their care.

PURPOSE: To determine what patients want to know regarding the participation of trainees in their care. METHOD: In 1995, questionnaires were sent to 111 women who had undergone elective hysterectomies between September 1992 and June 1994 at two teaching hospitals at the University of California, San Francisco, School of Medicine. The questionnaires asked the women about their awareness of and attitudes toward the participation of residents and medical students in their care and about how they thought physicians should communicate information regarding residents to patients. RESULTS: Fifty-nine women (68%) returned the questionnaire. Thirty-seven of them (63%) knew that a resident had been involved in their care. Eighty percent of the respondents felt it important to know how residents were supervised and what they would do during the operation. Nearly half did not know whether a medical student had been involved in their care. Over 90% agreed that the attending gynecologist should tell patients that a resident would participate in the operation as well as what the resident would do. Most believed that residents are adequately supervised and that medical students have time to provide more attention to patients. CONCLUSIONS: Most of the women wanted to know about the participation and specific roles of residents and students. Attending physicians should take the initiative to talk with patients about the roles of trainees. Open discussions can promote patient autonomy, maintain public confidence in academic health institutions, and benefit future patients.