External Validation of a Digital Pathology-based Multimodal Artificial Intelligence Architecture in the NRG/RTOG 9902 Phase 3 Trial.

BACKGROUND: Accurate risk stratification is critical to guide management decisions in localized prostate cancer (PCa). Previously, we had developed and validated a multimodal artificial intelligence (MMAI) model generated from digital histopathology and clinical features. Here, we externally validate this model on men with high-risk or locally advanced PCa treated and followed as part of a phase 3 randomized control trial. OBJECTIVE: To externally validate the MMAI model on men with high-risk or locally advanced PCa treated and followed as part of a phase 3 randomized control trial. DESIGN, SETTING, AND PARTICIPANTS: Our validation cohort included 318 localized high-risk PCa patients from NRG/RTOG 9902 with available histopathology (337 [85%] of the 397 patients enrolled into the trial had available slides, of which 19 [5.6%] failed due to poor image quality). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Two previously locked prognostic MMAI models were validated for their intended endpoint: distant metastasis (DM) and PCa-specific mortality (PCSM). Individual clinical factors and the number of National Comprehensive Cancer Network (NCCN) high-risk features served as comparators. Subdistribution hazard ratio (sHR) was reported per standard deviation increase of the score with corresponding 95% confidence interval (CI) using Fine-Gray or Cox proportional hazards models. RESULTS AND LIMITATIONS: The DM and PCSM MMAI algorithms were significantly and independently associated with the risk of DM (sHR [95% CI] = 2.33 [1.60-3.38], p < 0.001) and PCSM, respectively (sHR [95% CI] = 3.54 [2.38-5.28], p < 0.001) when compared against other prognostic clinical factors and NCCN high-risk features. The lower 75% of patients by DM MMAI had estimated 5- and 10-yr DM rates of 4% and 7%, and the highest quartile had average 5- and 10-yr DM rates of 19% and 32%, respectively (p < 0.001). Similar results were observed for the PCSM MMAI algorithm. CONCLUSIONS: We externally validated the prognostic ability of MMAI models previously developed among men with localized high-risk disease. MMAI prognostic models further risk stratify beyond the clinical and pathological variables for DM and PCSM in a population of men already at a high risk for disease progression. This study provides evidence for consistent validation of our deep learning MMAI models to improve prognostication and enable more informed decision-making for patient care. PATIENT SUMMARY: This paper presents a novel approach using images from pathology slides along with clinical variables to validate artificial intelligence (computer-generated) prognostic models. When implemented, clinicians can offer a more personalized and tailored prognostic discussion for men with localized prostate cancer.

The mutual benefits of research in wild animal species and human-assisted reproduction.

Studying the reproductive biology of wild animal species produces knowledge beneficial to their management and conservation. However, wild species also share intriguing similarities in reproductive biology with humans, thereby offering alternative models for better understanding the etiology of infertility and developing innovative treatments. The purpose of this review is to raise awareness in different scientific communities about intriguing connections between wild animals and humans regarding infertility syndromes or improvement of fertility preservation. The objectives are to (1) highlight commonalities between wild species and human fertility, (2) demonstrate that research in wild species-assisted reproductive technologies can greatly enhance success in human reproductive medicine, and (3) recognize that human fertility preservation is highly inspiring and relevant to wild species conservation. In addition to having similar biological traits in some wild species and humans, the fact of sharing the same natural environment and the common needs for more options in fertility preservation are strong incentives to build more bridges that will eventually benefit both animal conservation and human reproductive medicine.

Oogenesis: Prospects and challenges for the future.

Oogenesis serves a singular role in the reproductive success of plants and animals. Of their remarkable differentiation pathway what stands out is the ability of oocytes to transform from a single cell into the totipotent lineages that seed the early embryo. As our understanding that commonalities between diverse organisms at the genetic, cellular and molecular levels are conserved to achieve successful reproduction, the notion that embryogenesis presupposes oogenesis has entered the day-to-day parlance of regenerative medicine and stem cell biology. With emphasis on the mammalian oocyte, this review will cover (1) current concepts regarding the birth, survival and growth of oocytes that depends on complex patterns of cell communication between germ line and soma, (2) the notion of "maternal inheritance" from a genetic and epigenetic perspective, and (3) the relative value of model systems with reference to current clinical and biotechnology applications.

Effects of feeding distillers dried grains with solubles, high-protein distillers dried grains, and corn germ to growing-finishing pigs on pig performance, carcass quality, and the palatability of pork.

An experiment was conducted to investigate pig performance, carcass quality, and palatability of pork from pigs fed distillers dried grains with solubles (DDGS), high-protein distillers dried grains (HPDDG), and corn germ. Eighty-four pigs (initial BW, 22 +/- 1.7 kg) were allotted to 7 dietary treatments with 6 replicates per treatment and 2 pigs per pen. Diets were fed for 114 d in a 3-phase program. The control treatment was based on corn and soybean meal. Two treatments were formulated using 10 or 20% DDGS in each phase. Two additional treatments contained HP-DDG in amounts sufficient to substitute for either 50 or 100% of the soybean meal used in the control treatment. An additional 2 treatments contained 5 or 10% corn germ, which was calculated to provide the same amount of fat as 10 or 20% DDGS. Results showed that for the entire experiment, pig performance was not affected by DDGS or HP-DDG, but final BW increased (linear, P < 0.05) as corn germ was included in the diets. Carcass composition and muscle quality were not affected by DDGS, but LM area and LM depth decreased (linear, P < 0.05) as HP-DDG was added to the diets. Lean meat percentage increased and drip loss decreased as corn germ was included in the diets (quadratic, P < 0.05). There was no effect of DDGS on fat quality except that belly firmness decreased (linear, P < 0.05) as dietary DDGS concentration increased. Including HP-DDG or corn germ in the diets did not affect fat quality, except that the iodine value increased (linear, P < 0.05) in pigs fed HP-DDG diets and decreased (linear, P < 0.05) in pigs fed corn germ diets. Cooking loss, shear force, and bacon distortion score were not affected by the inclusion of DDGS, HP-DDG, or corn germ in the diets, and the overall palatability of the bacon and pork chops was not affected by dietary treatment. In conclusion, feeding 20% DDGS or high levels of HP-DDG to growing-finishing pigs did not negatively affect overall pig performance, carcass composition, muscle quality, or palatability but may decrease fat quality. Feeding up to 10% corn germ did not negatively affect pig performance, carcass composition, carcass quality, or pork palatability but increased final BW of the pigs and reduced the iodine value of belly fat.

Energy, phosphorus, and amino acid digestibility of high-protein distillers dried grains and corn germ fed to growing pigs.

Three experiments were conducted to measure energy, P, and AA digestibility in 2 novel co-products from the ethanol industry [i.e., high-protein distillers dried grains (HP DDG) and corn germ]. These products are produced by dehulling and degerming corn before it enters the fermentation process. Experiment 1 was an energy balance experiment conducted to measure DE and ME in HP DDG, corn germ, and corn. Six growing pigs (initial BW, 48.9 +/- 1.99 kg) were placed in metabolism cages and fed diets based on corn, corn and HP DDG, or corn and corn germ. Pigs were allotted to a replicated, 3 x 3 Latin square design. The DE and ME in corn (4,056 and 3,972 kcal/kg of DM, respectively) did not differ from the DE and ME in corn germ (3,979 and 3,866 kcal/kg of DM, respectively). However, HP DDG contained more (P < 0.05) energy (4,763 kcal of DE/kg of DM and 4,476 kcal of ME/kg of DM) than corn or corn germ. Experiment 2 was conducted to measure apparent total tract digestibility (ATTD) and true total tract digestibility of P in HP DDG and corn germ. Thirty growing pigs (initial BW, 33.2 +/- 7.18 kg) were placed in metabolism cages and fed a diet based on HP DDG or corn germ. A P-free diet was used to measure endogenous P losses. Pigs were assigned to treatments in a randomized complete block design, with 10 replications per treatment. The ATTD and the retention of P were calculated for the diets containing HP DDG and corn germ, and the endogenous loss of P was estimated from pigs fed the P-free diet. The ATTD was lower (P < 0.05) in corn germ (28.6%) than in the HP DDG (59.6%). The retention of P was also lower (P < 0.05) in pigs fed corn germ (26.7%) than in pigs fed HP DDG (58.9%). The endogenous loss of P was estimated to be 211 +/- 39 mg per kg of DMI. The true total tract digestibility of P for HP DDG and corn germ was calculated to be 69.3 and 33.7%, respectively. In Exp. 3, apparent ileal digestibility and standardized ileal digestibility values of CP and AA in HP DDG and corn germ were measured using 6 growing pigs (initial BW, 78.2 +/- 11.4 kg) allotted to a replicated, 3 x 3 Latin square design. The apparent ileal digestibility for CP and all AA except Arg and Pro, and the standardized ileal digestibility for CP and all AA except Arg, Lys, Gly, and Pro were greater (P < 0.05) in HP DDG than in corn germ. It was concluded that HP DDG has a greater digestibility of energy, P, and most AA than corn germ.

One-step versus two-step culture of mouse preimplantation embryos: is there a difference?

BACKGROUND: A comparison has been made of the development of mouse zygotes in either one-step or two-step culture systems. METHODS: Embryo culture, blastocyst cell counts and embryo transfer were done. RESULTS: No significant differences were observed in the proportions of blastocysts, rates of hatching, numbers of cells in the inner cell mass (ICM) and trophectoderm (TE) that developed in protocols: one-step culture in potassium-enriched simplex optimized medium supplemented with glucose and amino acids (KSOMg(AA)), two-step culture in KSOMg(AA)/KSOMg(AA), and two-step culture in G1.2/G2.2. No gross abnormalities were observed in the fetuses that developed from zygotes in the one-step protocol using KSOMg(AA) and a two-step protocol using G1.2/G2.2. The body weights of these two groups of fetuses were not significantly different and no developmental abnormalities were observed. No significant differences were observed in the proportions of blastocysts, rates of hatching, numbers of cells in the ICM and TE that developed in protocols: one-step culture in KSOMg(AA), two-step culture in KSOMg(AA)/KSOMg(AA), and two-step culture in DM2/DM1. EDTA is not toxic to the initial cleavage stages of development at a concentration of 0.01 mmol/l in KSOMg(AA). CONCLUSIONS: Two-step culture protocols are sufficient for the support of preimplantation mouse development in vitro but they are not necessary.

Mouse embryo development following IVF in media containing either L-glutamine or glycyl-L-glutamine.

BACKGROUND: The development of the mouse zygote following fertilization in vitro in a KSOM-type medium containing either L-glutamine or glycyl-L-glutamine has been examined, and compared with the development of mouse zygotes produced by natural fertilization. METHODS: Mouse IVF, embryo culture and embryo transfer. RESULTS: Fertilization rates, development to the blastocyst stage, implantation rate, gross fetal development and fetal body weight are not different in a KSOM-type medium containing either L-glutamine or glycyl-L-glutamine. No evidence of abnormal fetal development, such as exencephaly, was observed. The replacement of L-glutamine with glycyl-L-glutamine favoured the development of relatively more inner cell mass cells than trophectoderm cells, and reduced the numbers of pyknotic and fragmented nuclei in the blastocysts that developed in vitro. CONCLUSIONS: There is no evidence that the presence of glutamine in the medium used for IVF influences significantly the subsequent development of the zygote. Replacing glutamine with glycyl-L-glutamine may be advantageous.

Identification of dorsal root ganglion neurons that innervate the common bile duct of rats.

Pain originating in the bile duct is common and many patients who have suffered from it report that it is one of the most intense forms of pain that they have experienced. Many uncertainties remain about the mechanisms underlying pain originating in the bile duct. For example, the dorsal root ganglion (DRG) neurons that give rise to the sensory innervation of the common bile duct (CBD) have not been identified and examined in any species. The goal of the present study was to determine the number, distribution, and size of DRG neurons that innervate the CBD in rats. Injections of WGA-HRP or CTB-HRP were restricted to the lumen of the bile duct. Injections of WGA-HRP labeled a mean number of about 500 DRG neurons bilaterally throughout all thoracic and upper lumbar levels. Injections of CTB-HRP labeled smaller numbers of DRG neurons. Application of colchicine onto the surface of the CBD reduced the number of cells labeled following injections of WGA-HRP into the lumen of the CBD by roughly 86%, suggesting that tracer had not spread in large amounts out of the CBD and labeled afferent fibers in other tissues. Approximately 85% of the neurons labeled with WGA-HRP had cell bodies that were classified as small; the remainder were medium in size. Injections of CTB-HRP labeled cell bodies of varying sizes, including a few large diameter cell bodies. These results indicate that a large number of primarily small DRG cells, located bilaterally at many segmental levels, provide a rich innervation of the common bile duct.

The emerging science of very early detection of disease outbreaks.

A surge of development of new public health surveillance systems designed to provide more timely detection of outbreaks suggests that public health has a new requirement: extreme timeliness of detection. The authors review previous work relevant to measuring timeliness and to defining timeliness requirements. Using signal detection theory and decision theory, the authors identify strategies to improve timeliness of detection and position ongoing system development within that framework.

Evidence that glucose is not always an inhibitor of mouse preimplantation development in vitro.

A factorial experimental design was used to examine the effects of 16 combinations of four concentrations of glucose (0.20, 0.60, 1.8, 5.4 mmol/l) and four concentrations of potassium dihydrogen phosphate (KH(2)PO(4); 0.05, 0.15, 0.45, 1.35 mmol/l) on the development in vitro of outbred CF1 mouse zygotes. Three responses were measured: (i) the number of zona-enclosed blastocysts; (ii) the number of blastocysts that started to hatch; and (iii) the total cell counts in the blastocysts. General linear modelling was used to estimate the most parsimonious two-dimensional concentration-response surfaces that represent the three responses to the different concentrations of glucose and KH(2)PO(4). There were no significant interactions between the effects of glucose and KH(2)PO(4) in all cases. Thus, the effects of glucose and phosphate are independent. No significant effects of glucose on blastocyst formation and the initiation of hatching were observed. Increasing the concentration of KH(2)PO(4) inhibited slightly (

IVF of mouse ova in a simplex optimized medium supplemented with amino acids.

The addition of amino acids to a modified simplex optimized medium (mKSOM) did not increase the percentage of blastocysts that develop from CF1 mouse ova fertilized in vitro. In contrast, the percentage of blastocysts that began to hatch and the number of cells in these blastocysts, particularly in the inner cell mass, was increased. The added amino acids also supported the development of a more organized extracellular matrix in the same blastocysts. The results suggest that zygotes produced in amino acid-supplemented mKSOM have a greater developmental potential, perhaps developing at a faster rate, than zygotes produced in mKSOM. This enhanced developmental potential may be caused by the alleviation of osmotic stress on the ova and zygotes by the amino acids that are osmolytes. The fertilization of human ova in vitro may benefit from the inclusion of free amino acids in the fertilizing medium. The availability of a medium that can be used to support both IVF and preimplantation development in the mouse is likely to benefit the recovery of mouse strains from cryopreserved spermatozoa.

Clinical highlights from the National Cancer Data Base, 2000.

The National Cancer Data Base (NCDB) is the empirical data collection and analysis arm of the American College of Surgeons Commission on Cancer, and is supported in part by the American Cancer Society. The NCDB collects oncology patient demographic information, diagnostic and treatment information, and outcomes data from a broad spectrum of hospital-based cancer registries throughout the US, ranging from large research and teaching facilities to small community hospitals. Through this unique network, data are aggregated and reported back to participating hospitals to allow individual facilities to evaluate local patient care practices and outcomes. This article highlights the principal findings of articles published in 1999 and early 2000 that used NCDB data as the empirical basis of their analyses. Included among these are articles on breast cancer, gastric carcinoma, head and neck cancers, leukemia, liver carcinoma, lung cancer, parathyroid tumors, prostate carcinoma, small bowel adenocarcinoma, testicular malignancies, and vulvar melanoma. These articles are based on cases diagnosed between 1985 and 1996. The NCDB has accrued more than 6.4 million cancer cases for this time period. Sufficient numbers of rare cancers are reported to the NCDB to permit some types of clinical evaluation not possible using other data sources.

Patterns of inpatient surgeries for the top four cancers in the United States, National Hospital Discharge Survey, 1988-95.

BACKGROUND: At a time when the population is aging and medical practices are rapidly changing, ongoing surveillance of surgical treatments for cancer is valuable for health services planning. METHODS: We used data from the National Hospital Discharge Survey for patients with discharge diagnoses of lung, prostate, female breast, and colorectal cancer during 1988-95 to estimate population-based rates and numbers of inpatient surgical procedures. RESULTS: In 1988-91, rates of lobectomy for lung cancer were significantly higher in males than females. By 1994-95, the male/female differences had largely disappeared due to increasing trends among females and decreasing trends among males. During 1988-95, surgeries on the large intestine for colorectal cancer, including right hemicolectomy and sigmoidectomy, decreased significantly, as did abdominoperineal resections of the rectum. Anterior resections of the rectum increased significantly. Radical prostatectomies for prostate cancer increased from 34,000 in 1988-89 to 104,000 in 1992-93 and then decreased to 87,000 in 1994-95; rates followed a similar pattern. Finally, the number and rates of inpatient mastectomies for female breast cancer decreased over the study period (from 219,000 to 180,000 and from 78.8 to 61.5 per 100,000, respectively). CONCLUSION: These trends in inpatient surgeries for the major cancers in the US probably reflect changes in disease occurrence and modified treatment recommendations.

Amino acids and preimplantation development of the mouse in protein-free potassium simplex optimized medium.

Development of outbred CF1 mouse zygotes in vitro was studied in a chemically defined, protein-free medium both with and without amino acids. The addition of amino acids to protein-free potassium simplex optimized medium (KSOM) had little effect on the proportion of embryos that developed at least to the zona-enclosed blastocyst stage. In contrast, amino acids stimulated very significantly, in a dilution-dependent way, the proportion of blastocysts that at least partially or completely hatched. Amino acids also stimulated cell proliferation in both the trophectoderm and inner cell mass (ICM) cells, at rates that favored proliferation of cells in the ICM; had no effect on the incidence of cell death (oncosis or apoptosis); and improved development of the basement membranes, which form on the blastocoelic surface of the trophectoderm and between the primitive endoderm and the primitive ectoderm. Thus, KSOM, supplemented with amino acids but containing no protein supplements, supports development of a newly fertilized ovum to the late blastocyst stage, in which its normal, three-dimensional structure is preserved and in which the ICM has been partitioned into the primitive ectoderm and primitive endoderm.

Purchasing oncology services. Kerr L. White Institute/American Cancer Society Task Force on Purchasing Oncology Services.

BACKGROUND: A multidisciplinary panel representing various stakeholders in the health care delivery and oncology services marketplace was convened to develop specific criteria for healthcare purchasers to consider when evaluating the structures and processes of health plans. These rank ordered criteria also can be used by oncologic service providers and health plan designers as a yardstick for the services they offer. METHODS: A multidisciplinary 31-member Task Force was assembled by the Kerr L. White Institute and the American Cancer Society in March 1997. Task Force members were selected for their ability to offer expert insight as purchasers, suppliers, policymakers, consumers, or stakeholders in the health care marketplace. A preference-weighted majority voting rule was used to identify the three most important recommendations of the 10 that were generated through a modified Delphi technique. To test the practicality of the top three recommendations, leaders of large managed care organizations (MCOs) were surveyed; the results of this survey then were compared with the results of the Task Force survey. RESULTS: The three most important recommendations from the Task Force were that health plans provide access to: 1) comprehensive cancer care, 2) preventive and screening services, and 3) second opinions and treatment options supported by scientific evidence. The difference between the responses of the Task Force and the MCOs was that MCOs placed the highest importance on evidence-based decision-making, with their next three rankings coinciding with those identified by the Task Force. CONCLUSIONS: The value of these summary recommendations will be realized through their use by both purchasers and suppliers to influence the structure and content of the delivery of oncologic services.

National Cancer Data Base survey of breast cancer management for patients from low income zip codes.

BACKGROUND: The National Cancer Data Base (NCDB), a joint project of the American College of Surgeons Commission on Cancer and the American Cancer Society, is a cancer management and outcomes data base for health care organizations. It provides a comparative summary of patient care that is used by participating hospitals and communities for self-assessment. The most current (1995-1996) breast cancer data on patients from low income zip codes are described here. METHODS: Since 1989, eight Calls for Data have been issued, yielding a total of 191,714 reports of non-Hispanic white patients with breast cancer for the years analyzed, 1995-1996. A total of 1961 hospital cancer registries have participated in at least one of the Calls for Data. RESULTS: A diverse range of breast cancer cases was reported from a variety of geographic locations and medical care environments. There were general similarities in the treatment of patients from the different income groups; however, some differences were reported. Among patients from lower income zip codes, 60.7% were age 60 years or older, compared with 55.1% from other income zip code groups. The AJCC stage distribution was reported as less favorable for patients from low income zip codes than for other patients. The percentage of patients from low income zip codes diagnosed as Stage 0 or I was 51.2%, compared with 55.9% of patients from the other income zip codes. Of patients from lower income zip codes, 12.1% were reported to have Stage III or IV disease, compared with 10.0% of patients from other income zip codes. Patients from low income zip codes received less tissue-sparing surgery. Of patients from low income zip codes, 14.9% received partial mastectomy with or without radiation or systemic therapy, compared with 18.3% of patients from other income zip codes. The percentage of patients from low income zip codes who received a partial mastectomy with axillary lymph node dissection was 23.3% for patients from other income zip codes, the percentage was 30.5%. Conversely, 49.8% of patients from lower income zip codes received a modified radical mastectomy, compared with 40.5% of patients from other income zip codes. CONCLUSIONS: Further improvements in the early diagnosis and surgical treatment of low income patients can probably be achieved. Programmatic activities that further explain or reduce the apparent nonpreferred treatment of some low income patients should be encouraged.

The NCCN/American Cancer Society partnership.

The National Comprehensive Cancer Network (NCCN) partnered with the American Cancer Society two years ago in an effort to translate the NCCN Practice Guidelines for professionals into guidelines for patients. The response from patients to the first two guidelines was overwhelmingly positive. The following panel discussion provides some background information on this alliance and discusses the development and highlights of their latest collaboration, the Colorectal Cancer Patient Guidelines.

Targeted disruption of mouse Yin Yang 1 transcription factor results in peri-implantation lethality.

Yin Yang 1 (YY1) is a zinc finger-containing transcription factor and a target of viral oncoproteins. To determine the biological role of YY1 in mammalian development, we generated mice deficient for YY1 by gene targeting. Homozygosity for the mutated YY1 allele results in embryonic lethality in the mouse. YY1 mutants undergo implantation and induce uterine decidualization but rapidly degenerate around the time of implantation. A subset of YY1 heterozygote embryos are developmentally retarded and exhibit neurulation defects, suggesting that YY1 may have additional roles during later stages of mouse embryogenesis. Our studies demonstrate an essential function for YY1 in the development of the mouse embryo.

Clinical highlights from the National Cancer Data Base, 1999.

The National Cancer Data Base (NCDB), a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society, collects and analyzes data from a wide variety of sources throughout the United States, including small community hospitals. Due to this unique reporting system, individual facilities can compare their own data with the aggregate data from the NCDB, using their findings to evaluate local patient care practices. This article highlights the principal findings of the NCDB and Patient Care Evaluation articles published in 1998 on breast, prostate, cervical, endometrial, gallbladder, head and neck, nasopharyngeal, rectal, thyroid, and vaginal cancers, as well as on melanoma, brain tumors, and Hodgkin's disease. With more than five million cancer cases in the NCDB for the years between 1985 and 1995, sufficient numbers of even rare cancers have been accrued to permit some types of epidemiologic and clinical assessments.