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PubMed2025

Recent Advances in nccRCC Classification and Therapeutic Approaches.

Non-clear cell renal cell carcinoma (nccRCC) constitutes a biologically diverse category of renal malignancies. The 2022 WHO classification framework has significantly evolved to incorporate molecularly defined entities alongside traditional histologic subtypes, reflecting the growing recognition of distinct pathogenic drivers. Current therapeutic paradigms for advanced disease remain suboptimal, with treatment strategies often extrapolated from clear cell renal cell carcinoma (ccRCC). In this review, we highlight transformative multi-omics approaches to address nccRCC's profound heterogeneity, which enables molecular stratification beyond conventional pathology, identifying novel subtypes characterized by unique immune microenvironment features, metabolic profiles, and genomic instability patterns. This molecular reclassification provides a foundational framework for precision oncology, facilitating patient selection for targeted therapies and immunomodulatory strategies. Advancements in multi-omics subtyping represent a pivotal shift toward biologically guided clinical management and underscore the imperative for biomarker-driven therapeutic development in nccRCC.

Humans↗
PubMed2000

p53 accumulation confers prognostic information in resectable adenocarcinomas with ductal but not with intestinal differentiation in the pancreatic head.

The aim of the study was to examine the relation between p53 protein accumulation, clinicopathological variables and prognosis in resectable adenocarcinomas of the pancreatic head. The clinical records and tissue specimens of 82 consecutive patients resected for adenocarcinomas located in the head of the pancreas were reviewed retrospectively. Formalin-fixed and paraffin-embedded specimens from each tumour were stained with the monoclonal antibody DO7, and the nuclear p53 positivity within each tumour was assessed. Histopathological reclassification showed that 60 tumours exhibited ductal differentiation and 22 tumours intestinal differentiation. Twenty-five percent (15/60) of the ductal tumours and 50% (11/22) of the intestinal tumours were positive for p53 accumulation. p53 immunoreactivity was significantly correlated to a worse prognosis in the tumours of ductal differentiation, with median survival 0.76 years for p53 positive and 1.44 years for p53 negative patients. The p53 positivity of tumours with intestinal differentiation showed no such correlation. No correlation was found between p53 accumulation and other known prognostic factors in either the ductal or the intestinal type of tumours. Our results indicate that the tumour biology of ductal adenocarcinomas differs significantly from that of adenocarcinomas of the intestinal type located in the pancreatic head, and that p53 accumulation confers a worse prognosis only of ductal tumours. Subclassification of these tumours based on type of differentiation is therefore suggested since periampullary tumours include ductally as well as intestinally differentiated adenocarcinomas.

Adenocarcinoma↗
PubMed1992

A new scale for the clinical assessment of spinal cord function.

The systems currently used for grading the severity of neurologic injuries have serious limitations. The authors have developed a neurologic grading system to assess spinal cord function. This is a new, functionally oriented scale which can be used at the bedside and requires no special tests other than those done in a routine clinical neurological examination. This scale includes assessment of motor and sensory function, rectal tone, and bladder control. A major advantage of this scale is that motor function is assessed on a functional rating system. To evaluate the usefulness of this scheme, patients who have been previously entered into a prospective study on the surgical treatment of burst fractures were re-evaluated. A significant number of patients under our new reclassification system were noted to have had significant improvement which had been overlooked using the Frankel Grade system. The authors conclude that their new spinal cord assessment technique has many advantages and suggest that it be used by spinal cord injury centers.

Anal Canal↗
PubMed2005

[Development of clinical performance indicators for establishing a connecting system between hospital performance management and quality improvement].

PURPOSE: This study aimed at developing integrated clinical performance indicators(CPIs) through the analysis of quality improvement(QI) activities of a hospital and literature review about performance measures. METHOD: The CPIs were developed through the following three stages; 1)Identifying preliminary CPIs 2)A staff validity test in preliminary CPIs 3)Developing final CPIs. RESULT: One hundred twenty-three preliminary CPIs were developed through QI activities of the target hospital for 8 years and literature review. The results of the validity test for the preliminary CPIs supported ninety-one items. Sixty-two CPIs were selected through integration, reclassification and renaming. Then, eighteen items were deleted on account of an imprecise calculation method. Finally, forty-four CPIs were confirmed. They consisted of twenty-six items at the hospital level and eighteen items at the department level. CONCLUSION: CPIs can be used as criteria to evaluate the performance of healthcare organizations, and to decide the quality of healthcare for customers. This study may contribute to establishing an integrated system between QI activities and performance measurement of healthcare organizations.

Adult↗
PubMed2002

Primer on medical genomics. Part III: Microarray experiments and data analysis.

Genomics has been defined as the comprehensive study of whole sets of genes, gene products, and their interactions as opposed to the study of single genes or proteins. Microarray technology is one of many novel tools that are allowing global and high-throughput analysis of genes and gene products. In addition to an introduction on underlying principles, the current review focuses on the use of both complementary DNA and oligodeoxynucleotide microarrays in gene expression analysis. Genome-wide experiments generate a massive amount of data points that require systematic methods of analysis to extract biologically useful information. Accordingly, the current educational communication discusses different methods of data analysis, including supervised and unsupervised clustering algorithms. Illustrative clinical examples show clinical applications, including (1) identification of candidate genes or pathological pathways (ie, elucidation of pathogenesis); (2) identification of "new" molecular classes of diseases that may be relevant in disease reclassification, prognostication, and treatment selection (ie, class discovery); and (3) use of expression profiles of known disease classes to predict diagnosis and classification of unknown samples (ie, class prediction). The current review should serve as an introduction to the subject for clinician investigators, physicians and medical scientists in training, practicing clinicians, and other students of medicine.

Breast Neoplasms↗
PubMed2005

Detection of antifungal properties in Lactobacillus paracasei subsp. paracasei SM20, SM29, and SM63 and molecular typing of the strains.

Lactobacilli isolated from different food and feed samples such as raw milk, cheese, yoghurt, olives, sour dough, as well as corn and grass silage, were screened for their antifungal activities. Out of 1,424 isolates tested, 82 were shown to be inhibitory to different yeasts (Candida spp. and Zygosaccharomyces bailii) and a Penicillium sp., which were previously isolated from spoiled yoghurt and fruits. Carbohydrate fermentation patterns suggested that a substantial portion, 25%, belonged to the Lactobacillus casei group, including L. casei, L. paracasei, and L. rhamnosus. The isolates SM20 (DSM14514), SM29 (DSM14515), and SM63 (DSM14516) were classified by PCR using species-specific primers to target the corresponding type strains (L. casei, L. paracasei, and L. rhamnosus) as controls. Further molecular typing methods such as randomly amplified polymorphic DNA, pulsed-field gel electrophoresis, and sequencing analysis of the 16S rRNA gene allowed classifying strains SM20, SM29, and SM63 as L. paracasei subsp. paracasei in accordance with the new reclassification of the L. casei group proposed by Collins et al.

Animal Feed↗
PubMed2005

Frozen section diagnosis in pediatric surgical pathology: a decade's experience in a children's hospital.

CONTEXT: Intraoperative consultations, including frozen sections (FSs), are essential for patient care and are a key quality component in anatomic pathology. Little data exists about the use, frequency, and type of discrepancies and deferral rates of FS diagnoses in pediatric and adolescent surgical pathology. OBJECTIVE: The purpose of this study was to analyze indications, discrepancies, and deferrals for all FSs performed at a children's hospital during a 10-year period. DESIGN: All FSs for 1995-2004 were reviewed for indications, discrepancies, deferred diagnoses, and turnaround time. Discrepancies were categorized into major and minor subtypes according to potential impact on patient care. RESULTS: A total of 35,611 surgical pathology cases were accessioned, with 2839 intraoperative consultations, which included 2783 FSs and 56 nonmicroscopic consultations. Most frequent indications included questions related to neoplasms (tumor detection, specimen adequacy, triage, classification, and margins) and suspected Hirschsprung disease. In these consultations, 115 discrepancies (4%) were identified, of which 7 (0.2%) were major, with potentially significant clinical impact, and 108 (3.9%) were minor. The major discrepancies included tumor, ganglion cell, or organism detection. The minor discrepancies involved sampling error, reclassification of benign or malignant neoplasms without clinical consequences, tumor typing or grading, and ganglion cell identification without clinical impact. Deferrals in 718 FSs (25% deferral rate) included tumor classification from generic to specific, identification of organisms, and evaluation of lymph node biopsies for lymphoma. Turnaround time exceeded 20 minutes in 403 cases (14%). CONCLUSIONS: The FS rate of 7.8% overall and 5% of surgical pathology cases is similar in children's and general hospitals. The major discrepancy (discordance) rate is lower, which may reflect the different indications for FS in children and adolescents. Evaluation of colonic biopsies for ganglion cells is a diagnostic pitfall. The deferral rate of 25% reflects the definition of a deferred diagnosis. Traditional definitions of deferred and discordant FS diagnoses should be refined to reflect the increasing use of adjunct techniques, especially in tumor classification. These findings emphasize that, in children and adolescents, most FSs are performed for tumor classification, triage, detection, and specimen adequacy, and for possible Hirschsprung disease. In children and adolescents, FSs are used infrequently to identify normal or unknown tissue, to analyze a lesion in a radiographically directed specimen, or to detect lymph node metastases. The differences in pediatric and adolescent FS indications and use underscore the importance of focused education in pediatric surgical pathology.

Frozen Sections↗
PubMed2025

A Prospective Validation of the Decipher Genomic Classifier in Men With Early Localized Prostate Cancer: The VANDAAM Study.

BACKGROUND: The emergence of genomic precision oncology has advanced personalized care for some patients with prostate cancer (PCa), while threatening to widen existing disparities due to the historically low recruitment of African American men (AAM), who have the highest disease burden. Here, we report the first prospective validation of a genomic classifier (GC) to predict rapid-onset biochemical recurrence (BCR) in AAM. METHODS: Between 2016 and 2021, this multicenter prospective validation study recruited 243 patients with low- or intermediate-risk PCa who received treatment for their disease. Patients were recruited on a 1:1 basis (AAM:White) and matched by CAPRA score. Patients who elected active surveillance were ineligible for participation. Decipher GC testing was ordered for all patients using their biopsy and/or radical prostatectomy (RP) tumor tissue. The primary outcome was to determine whether the GC could predict 2-year BCR rates-used as a surrogate for disease aggressiveness-following standard treatment. The secondary outcome evaluated the concordance between biopsy- and RP-derived GC risk scores for treatment recommendations. RESULTS: The final analytical cohort included 226 matched patients with genomic information, and 207 evaluable cases (104 AAM, 103 White) with both genomic and complete clinical outcome data. Overall, a high genomic-risk GC score was associated with a 5.25-fold increase in the odds of rapid-onset 2-year BCR compared with the low-risk group (odds ratio, 5.25 [95% CI, 1.27-21.66]; P=.021). In a subset of the surgical cohort (n=74), biopsy- and RP-derived GC scores exhibited a 77% concordance rate, defined as no reclassification in GC risk-based categories. CONCLUSIONS: This study represents the first prospective validation of GC performance in predicting early 2-year BCR in both AAM and White men. The findings provide strong evidence supporting the integration of the GC into clinical practice guidelines to improve risk stratification and management of AAM with early-stage PCa. CLINICALTRIALS: gov identifier: NCT02723734.

Aged↗
PubMed2026

Large-scale functional annotation establishes a reference framework for human LRRK2 variants.

Pathogenic variants in leucine-rich repeat kinase 2 (LRRK2)1are among the most frequent monogenic causes of Parkinson's disease (PD)2 and act through a gain-of-function mechanism of increased kinase activity. LRRK2-targeted therapies are in clinical development, but interpretation of the rapidly expanding catalogue of rare LRRK2 variants remains a barrier to translation. Here, we present functionally annotated data on >350 LRRK2 coding variants using a standardized cellular assay with Rab10 phosphorylation as a readout of kinase activity and integrated these data with curated genetic and clinical annotations from the Movement Disorders Society Genetic Mutation Database (MDSGene). Variants differed in activation magnitude, ranging from modest increases (e.g., p.G2019S) to strongly activating substitutions such as p.Y1699C or p.L1795F. Activating variants occurred across the full length of LRRK2, although the largest effects clustered within the ROC-COR regulatory hub, where structural analysis identified subdomains forming an allosteric scaffold controlling kinase output. All known/established pathogenic variants showed increased activity, whereas benign and likely benign variants remained within the wild-type range. Functional effect sizes correlated with pathway activation in patient-derived immune cells, altogether providing a framework for ACMG-based variant interpretation in which kinase activation can support PS3 functional evidence for reclassification of variants.

Protein phosphorylation↗
PubMed1994

Exercise tomographic thallium-201 imaging in patients with severe coronary artery disease and normal electrocardiograms.

OBJECTIVE: To assess the incremental value and cost-effectiveness of exercise tomographic thallium-201 imaging compared with clinical and exercise electrocardiographic variables for detecting three-vessel or left main coronary artery disease in patients with normal at-rest electrocardiograms. DESIGN: Prospective cohort study. PARTICIPANTS: 411 patients (77 [19%] had three-vessel or left main disease) with normal at-rest electrocardiograms who underwent exercise tomographic thallium-201 studies and subsequently had coronary angiography. MEASUREMENTS: Clinical, exercise, and thallium-201 variables; univariate followed by multivariate logistic regression analysis to determine predictors of three-vessel or left main disease (clinical variables; clinical and exercise electrocardiographic variables; and clinical, exercise, and thallium-201 variables). Patients were classified by each of these models into low-, intermediate-, and high-risk groups. SETTING: A tertiary referral center. RESULTS: Among the clinical variables, diabetes mellitus, sex, age, and typical angina were independently associated with severe coronary disease (46% of patients were correctly classified into low- or high-risk groups). The peak exercise heart rate-blood pressure product and the magnitude of the exercise-induced ST depression added independent information to clinical variables. Among the thallium variables, the change in the global thallium-201 score (a measure of redistribution) added independent information to clinical and exercise variables, resulting in only 3% of the patients being reclassified regarding their predicted risk for severe coronary disease. The cost per additional reclassification was estimated to be $20,550. Twenty-one cardiac events occurred (7 cardiac deaths and 14 myocardial infarctions) after thallium study (follow-up, 2.8 +/- 1.0 years). Event-free survival was 94% to 97% regardless of the predicted probability of developing three-vessel or left main coronary artery disease by any model. CONCLUSIONS: When the at-rest electrocardiogram is normal, thallium-201 scintigraphy adds little information to clinical and exercise variables in identifying patients with severe coronary artery disease. The high cost of this information may not justify the routine use of sophisticated imaging for this purpose.

Coronary Angiography↗
PubMed1997

Medicinal applications of delta-9-tetrahydrocannabinol and marijuana.

The use of crude marijuana for herbal medicinal applications is now being widely discussed in both the medical and lay literature. Ballot initiatives in California and Arizona have recently made crude marijuana accessible to patients under certain circumstances. As medicinal applications of pure forms of delta-9-tetrahydrocannabinol (THC) and crude marijuana are being considered, the most promising uses of any form of THC are to counteract the nausea associated with cancer chemotherapy and to stimulate appetite. We evaluated the relevant research published between 1975 and 1996 on the medical applications, physical complications, and legal precedents for the use of pure THC or crude marijuana. Our review focused on the medical use of THC derivatives for nausea associated with cancer chemotherapy, glaucoma, stimulation of appetite, and spinal cord spasticity. Despite the toxicity of THC delivered in any form, evidence supports the selective use of pure THC preparations to treat nausea associated with cancer chemotherapy and to stimulate appetite. The evidence does not support the reclassification of crude marijuana as a prescribable medicine.

Appetite Stimulants↗
PubMed1997

Reliability of tuberculin skin test measurement.

BACKGROUND: Important management decisions depend on results of the tuberculin skin test. However, the test is subject to several potential errors, and its reliability has not been adequately studied. OBJECTIVE: To ascertain the reliability of tuberculin skin testing. DESIGN: Cross-sectional study. SETTING: University hospital. PARTICIPANTS: 96 persons who received a tuberculin skin test. MEASUREMENTS: Ballpoint-pen and palpation measures of induration. RESULTS: Global intra- and interobserver reliability coefficients of the ballpoint-pen technique were high. Five percent of the time, however, a second measurement by the same observer could be at least 2.7 mm less to 3.0 mm more than the first measurement and the measurement from the second observer could be at least 3.4 mm less to 3.7 mm more than the measurement from the first observer. This could lead to the reclassification of a positive test result as negative or vice versa. The area of imprecision was 38% less broad for the ballpoint-pen technique than for the palpation technique. CONCLUSION: Reading of tuberculin skin tests may frequently result in misclassifications when measurements are close to the cutoff point that separates negative from positive results.

Cross-Sectional Studies↗
PubMed2003

The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update.

BACKGROUND: The incidence of hepatocellular carcinoma was reported to be increasing in the United States. However, alternate explanations were diagnostic or reclassification bias and changes in the demographic features of the general population. OBJECTIVE: To examine the temporal trends in the incidence of hepatocellular carcinoma. DESIGN: Retrospective cohort study. SETTING: Information collected by population-based registries of the Surveillance, Epidemiology, and End Results (SEER) program. PATIENTS: Persons given a diagnosis of hepatocellular carcinoma between 1975 and 1998. MEASUREMENTS: Linear Poisson multivariate regression model, controlling for differences in age, sex, race or ethnicity, and geographic region among patients with hepatocellular carcinoma and in the underlying population. RESULTS: The overall age-adjusted incidence rates of hepatocellular carcinoma increased from 1.4 per 100 000 in 1975 to 1977 to 3.0 per 100 000 in 1996 to 1998. There was a 25% increase during the last 3 years of the study compared with the preceding 3 years (1993 to 1995). The increase affected most age groups above 40 years, with the greatest increase in the 45- to 49-year-old age group. White men had the greatest increase (31%) in the last time period (1996 to 1998) compared with 1993 to 1995. The Poisson regression model confirmed an almost 2-fold increase in the incidence rate ratio for hepatocellular carcinoma between 1975 to 1978 and 1996 to 1998. CONCLUSIONS: The incidence of hepatocellular carcinoma continues to increase rapidly in the United States, with rates increasing the fastest in white men 45 to 54 years of age. These findings are consistent with a true increase and could be explained by consequences of hepatitis C virus acquired during the 1960s and 1970s.

Adult↗
PubMed2000

[Syndromes of autonomic dysfunction associated with orthostatic intolerance].

Stimulated by the wide-spread use of tilt table testing, disorders of autonomic function with orthostatic hypotension have recently gained attention by clinical cardiologists. At the same time, improved characterization of the underlying circulatory responses have led to a reclassification of these syndromes. In particular, three subgroups of chronic primary dysautonomia have been defined: pure autonomic dysfunction, multiple system atrophy, and the postural orthostatic tachycardia syndrome. On the other hand, acute dysautonomias represent a rare yet clinically sometimes dramatic form of autonomic disorders. Several diseases as well as enzymatic disorders, and pharmacological drugs may cause secondary dysautonomia. The clinical correlate of all these forms of dysautonomia is orthostatic hypotension and syncope. Thus, a careful history forms the basis of a successful diagnostic workup of the underlying cause of syncope. This review summarizes the current knowledge of autonomic disorders, their classification and diagnostic and therapeutic strategies.

Autonomic Nervous System Diseases↗
PubMed1990

Medicare program; Geographical Classification Review Board; procedures and criteria--HCFA. Interim final rule with comment period.

This interim final rule with comment period implements provisions of the Omnibus Budget Reconciliation Act of 1989 establishing the Medicare Geographical Classification Review Board (MGCRB) and sets forth criteria for the MGCRB to use in issuing its decisions concerning the geographic reclassification of hospitals for purposes of payment under the prospective payment system.

Catchment Area, Health↗
PubMed1991

Medicare program; Medicare Geographic Classification Review Board--procedures and criteria--HCFA. Final rule with comment period.

This final rule with comment period responds to public comments on the September 6, 1990 interim final rule with comment period that established the Medicare Geographic Classification Review Board (MGCRB) and sets forth the criteria for the MGCRB to use in issuing its decisions concerning the geographic reclassification of hospitals for purposes of payment under the prospective payment system. In addition, this final rule with comment period implements provisions of the Omnibus Budget Reconciliation Act of 1990 concerning the MGCRB.

Catchment Area, Health↗
PubMed1992

Hospitals on the frontier.

The concept of a limited service rural hospital recently gained nationwide attention when Montana introduced the medical assistance facility (MAF) model, which allows a hospital to have a license under less stringent rules (rather than close completely). The MAF is a down-scaled, limited-service rural hospital that makes extensive use of midlevel practitioners and has flexible staffing requirements. MAFs restrict admission to patients with low-intensity, acute illnesses who typically require short-term hospitalization. Montana currently has four MAFs certified as Medicare and Medicaid providers under the terms of a waiver agreement with the Health Care Financing Administration (HCFA). MAFs are located in four "frontier" communities--counties or regions with fewer than six residents per square mile. A 96-hour cap on inpatient stay effectively guarantees that the MAF's scope of services will be circumscribed. However, the array of services that meet the definition of low intensity and short term is potentially broad. The flexibility--and thus the real strength--of the MAF model is in the licensure rules, which relax some of the requirements that the small rural hospital has difficulty meeting (such as those regarding staffing). The demonstration project is now entering its final two years. So far, it has gained widespread interest and support. The central question is whether HCFA will extend the waiver after 1993. Another possibility is the reclassification of MAFs to rural primary care hospitals, which do not require waiver coverage to receive Medicare and Medicaid reimbursement.

Health Services Accessibility↗
PubMed1992

Employee v. independent contractor: tax and other considerations for group practices.

The classification of physicians and associated health care professionals as employees or independent contractors in a group practice context is an important and frequently misunderstood issue, with many traps for the unwary. This article discusses the effect of classification on a group's responsibilities, the factors to consider in determining whether a health care professional should be classified as an employee of the group or an independent contractor, and the practical considerations involved in reclassification of an improperly classified worker.

Contract Services↗