ABSTRACT Surgical ablation of five-sixths renal mass in Munich-Wistar rats fed a high protein die... more ABSTRACT Surgical ablation of five-sixths renal mass in Munich-Wistar rats fed a high protein diet leads to focal sclerosis in the remnant kidney and progressive renal failure. Experimental data suggest that this injury results from intraglomerular hypertension and/or chronic glomerular hyperfiltration. Data in humans largely are limited to patients with unilateral renal agenesis or uninephrectomy, either for unilateral renal disease or for kidney transplant donation. Isolated case reports have documented focal sclerosis and progressive renal failure in two patients with a remnant kidney. To obtain data in humans with a remnant kidney, we surveyed more than 800 urologists and nephrologists in the United States and abroad. Criteria for inclusion in the study were (1) surgical resection (in one or more operations) resulting in the presence of a remnant kidney; and (2) an adequate period of follow-up, defined as 5 years or greater. A total of 13 patients were identified (from 13 different centers). Twelve patients had renal cancer and one had tuberculosis. Six patients were observed for 10 or more years postoperatively and all have stable serum creatinine levels of less than 270 mumol/L (3.0 mg/dL); two of these six patients are now more than 25 and 30 years postoperation. The other seven patients, observed for 5 to 7 years, have serum creatinine levels less than 270 mumol/L (3 mg/dL), while one has an increasing serum creatinine level. The two longest surviving patients both have undergone successful pregnancy with no overall change in serum creatinine. These observations demonstrate that it is possible for humans to survive more than 30 years with a stable serum creatinine, despite the presence of only a remnant kidney.
Ureteral obstruction is a seldom recognized complication of Crohn's disease and its incidence... more Ureteral obstruction is a seldom recognized complication of Crohn's disease and its incidence and natural history are unknown. The intravenous pyelogram findings in 5 cases of Crohn's disease are discussed and it is suggested that ureteral involvement signifies severe disease necessitating operation. The operative treatment of 1 of the cases by ureterolysis plus bowel excision is presented and discussed. Routine intravenous urography is recommended as part of the assessment of cases of Crohn's disease.
Interstitial cystitis (IC) is frequently a diagnosis of exclusion in patients with irritative voi... more Interstitial cystitis (IC) is frequently a diagnosis of exclusion in patients with irritative voiding symptons and negative urine cultures. The true incidence of IC is difficult to ascertain because of non-uniform clinical, endoscopic and histologie diagnostic criteria (Sant 1987). Oravisto estimated the incidence of IC in Finland to be 18 per 100 000 women (Oravisto 1975). However, a recent questionnaire survey estimated the prevalence of IC in the United States to be at least twice that in Finland (Held et al. 1987). Females are affected ten times more frequently than men. The condition is not common in blacks, children or adolescents (Geist and Antolak 1970).
ABSTRACT To study the presence of intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-s... more ABSTRACT To study the presence of intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin, as well as the cytoskeletal components talin and vinculin that bind to cellular adhesion molecules (CAMs), in bladder biopsies from patients with interstitial cystitis (IC) and controls. IC is a sterile, bladder disorder characterized by urinary frequency and pelvic floor pain. The pathologic bladder findings include defective urothelium, activated mast cells, and variable inflammation. Mast cells can induce the expression of CAMs necessary for initiation of inflammation. Fresh frozen biopsies were analyzed immunocytochemically from 2 female normal bladders, 10 female IC bladders, 1 clear margin of transitional cell carcinoma of female bladder, 1 normal foreskin, 1 transitional cell carcinoma of foreskin, and 1 inflamed male finger. Of the 10 IC samples, 9 were positive for ICAM-1, 6 for P-selectin, 6 for vinculin, 5 for talin, and 4 for E-selectin, all exclusively perivascular. Both normal bladders were negative for ICAM-1 and P-selectin and faintly positive for E-selectin, and one was weakly positive for talin and vinculin; the normal foreskin was negative. The "control" samples from the transitional cell carcinoma of the bladder and foreskin, as well as the inflamed finger skin, were positive only for ICAM-1. An increased number of activated mast cells associated with ICAM-1 was noted in IC. These results showed that ICAM-1 is expressed in IC, with variable expression of the other markers studied, supporting the different degrees of bladder inflammation noted in patients with IC.
Largely due to tumor heterogeneity, risk stratification of patients diagnosed with ductal carcino... more Largely due to tumor heterogeneity, risk stratification of patients diagnosed with ductal carcinoma in situ (DCIS) of the breast remains a significant challenge. Management of DCIS is also problematic as we wish to personalize treatment of a patient’s tumor in order to avoid overtreatment of lower-risk lesions or undertreatment of DCIS that may recur or progress into invasive cancer. Matching treatment to the underlying severity of the illness is key to practicing cost-effective cancer care in an era where this is a very large concern to society. The aim of this study was to analytically validate a precision risk-stratification tool based on phenotype, which is capable of predicting which patients will develop invasive cancer with greater than 80% sensitivity and specificity. Leveraging the novel capability to rapidly culture primary breast biopsy cells, we present a “biopsy-on-a-chip” microfluidic platform that quantifies dynamic and static phenotypic biomarkers via machine vision to generate predictive clinical scores via machine learning algorithms to determine if a DCIS patient will experience invasive cancer. 47 consecutive lumpectomy or mastectomy samples were collected and objectively analyzed in a blinded study, measuring 1000 phenotypic biomarkers with single-cell resolution using machine vision software. Biomarker measurements were input into machine learning algorithms to develop predictive statistical algorithms. Statistical algorithms were able to independently predict surgical adverse pathology features such as extranodal extension, grade, lymphovascular invasion, lymph invasion, lobular carcinoma in situ (LCIS), and DCIS with sensitivities and specificities greater than 90%. Additional machine learning based algorithms were able to predict if DCIS patients were more likely to develop subsequent metastasis as measured by lymphovascular invasion and/or lymphatic invasion with area under the curve (AUC) > 0.85. This study is the first study to demonstrate the prediction of breast cancer adverse pathology features from live primary biopsy cells and provides the basis to develop a powerful precision risk-stratification tool to risk-stratify DCIS. Furthermore, the methodology described and its ability to rapidly analyze primary breast biopsy tissue with single-cell resolution in a high-throughput manner engenders a powerful research tool to further understand tumor heterogeneity in breast cancer towards the development of personalized therapeutics. Applications of cost effectiveness analysis to our methodology will achieve the triple goal of providing cost-effective, patient-centered, and appropriate breast cancer and DCIS care. Note: This abstract was not presented at the conference. Citation Format: Ashok Chander, Michael Manak, Jonathan Varsanik, Brad Hogan, Grannum Sant, Kevin Knopf. Risk stratification of ductal carcinoma in situ: Analytical validation of a prognostic test analyzing live-primary cells via phenotypic biomarkers and machine learning at single-cell resolution [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A31.
ABSTRACT Surgical ablation of five-sixths renal mass in Munich-Wistar rats fed a high protein die... more ABSTRACT Surgical ablation of five-sixths renal mass in Munich-Wistar rats fed a high protein diet leads to focal sclerosis in the remnant kidney and progressive renal failure. Experimental data suggest that this injury results from intraglomerular hypertension and/or chronic glomerular hyperfiltration. Data in humans largely are limited to patients with unilateral renal agenesis or uninephrectomy, either for unilateral renal disease or for kidney transplant donation. Isolated case reports have documented focal sclerosis and progressive renal failure in two patients with a remnant kidney. To obtain data in humans with a remnant kidney, we surveyed more than 800 urologists and nephrologists in the United States and abroad. Criteria for inclusion in the study were (1) surgical resection (in one or more operations) resulting in the presence of a remnant kidney; and (2) an adequate period of follow-up, defined as 5 years or greater. A total of 13 patients were identified (from 13 different centers). Twelve patients had renal cancer and one had tuberculosis. Six patients were observed for 10 or more years postoperatively and all have stable serum creatinine levels of less than 270 mumol/L (3.0 mg/dL); two of these six patients are now more than 25 and 30 years postoperation. The other seven patients, observed for 5 to 7 years, have serum creatinine levels less than 270 mumol/L (3 mg/dL), while one has an increasing serum creatinine level. The two longest surviving patients both have undergone successful pregnancy with no overall change in serum creatinine. These observations demonstrate that it is possible for humans to survive more than 30 years with a stable serum creatinine, despite the presence of only a remnant kidney.
Ureteral obstruction is a seldom recognized complication of Crohn's disease and its incidence... more Ureteral obstruction is a seldom recognized complication of Crohn's disease and its incidence and natural history are unknown. The intravenous pyelogram findings in 5 cases of Crohn's disease are discussed and it is suggested that ureteral involvement signifies severe disease necessitating operation. The operative treatment of 1 of the cases by ureterolysis plus bowel excision is presented and discussed. Routine intravenous urography is recommended as part of the assessment of cases of Crohn's disease.
Interstitial cystitis (IC) is frequently a diagnosis of exclusion in patients with irritative voi... more Interstitial cystitis (IC) is frequently a diagnosis of exclusion in patients with irritative voiding symptons and negative urine cultures. The true incidence of IC is difficult to ascertain because of non-uniform clinical, endoscopic and histologie diagnostic criteria (Sant 1987). Oravisto estimated the incidence of IC in Finland to be 18 per 100 000 women (Oravisto 1975). However, a recent questionnaire survey estimated the prevalence of IC in the United States to be at least twice that in Finland (Held et al. 1987). Females are affected ten times more frequently than men. The condition is not common in blacks, children or adolescents (Geist and Antolak 1970).
ABSTRACT To study the presence of intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-s... more ABSTRACT To study the presence of intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin, as well as the cytoskeletal components talin and vinculin that bind to cellular adhesion molecules (CAMs), in bladder biopsies from patients with interstitial cystitis (IC) and controls. IC is a sterile, bladder disorder characterized by urinary frequency and pelvic floor pain. The pathologic bladder findings include defective urothelium, activated mast cells, and variable inflammation. Mast cells can induce the expression of CAMs necessary for initiation of inflammation. Fresh frozen biopsies were analyzed immunocytochemically from 2 female normal bladders, 10 female IC bladders, 1 clear margin of transitional cell carcinoma of female bladder, 1 normal foreskin, 1 transitional cell carcinoma of foreskin, and 1 inflamed male finger. Of the 10 IC samples, 9 were positive for ICAM-1, 6 for P-selectin, 6 for vinculin, 5 for talin, and 4 for E-selectin, all exclusively perivascular. Both normal bladders were negative for ICAM-1 and P-selectin and faintly positive for E-selectin, and one was weakly positive for talin and vinculin; the normal foreskin was negative. The "control" samples from the transitional cell carcinoma of the bladder and foreskin, as well as the inflamed finger skin, were positive only for ICAM-1. An increased number of activated mast cells associated with ICAM-1 was noted in IC. These results showed that ICAM-1 is expressed in IC, with variable expression of the other markers studied, supporting the different degrees of bladder inflammation noted in patients with IC.
Largely due to tumor heterogeneity, risk stratification of patients diagnosed with ductal carcino... more Largely due to tumor heterogeneity, risk stratification of patients diagnosed with ductal carcinoma in situ (DCIS) of the breast remains a significant challenge. Management of DCIS is also problematic as we wish to personalize treatment of a patient’s tumor in order to avoid overtreatment of lower-risk lesions or undertreatment of DCIS that may recur or progress into invasive cancer. Matching treatment to the underlying severity of the illness is key to practicing cost-effective cancer care in an era where this is a very large concern to society. The aim of this study was to analytically validate a precision risk-stratification tool based on phenotype, which is capable of predicting which patients will develop invasive cancer with greater than 80% sensitivity and specificity. Leveraging the novel capability to rapidly culture primary breast biopsy cells, we present a “biopsy-on-a-chip” microfluidic platform that quantifies dynamic and static phenotypic biomarkers via machine vision to generate predictive clinical scores via machine learning algorithms to determine if a DCIS patient will experience invasive cancer. 47 consecutive lumpectomy or mastectomy samples were collected and objectively analyzed in a blinded study, measuring 1000 phenotypic biomarkers with single-cell resolution using machine vision software. Biomarker measurements were input into machine learning algorithms to develop predictive statistical algorithms. Statistical algorithms were able to independently predict surgical adverse pathology features such as extranodal extension, grade, lymphovascular invasion, lymph invasion, lobular carcinoma in situ (LCIS), and DCIS with sensitivities and specificities greater than 90%. Additional machine learning based algorithms were able to predict if DCIS patients were more likely to develop subsequent metastasis as measured by lymphovascular invasion and/or lymphatic invasion with area under the curve (AUC) > 0.85. This study is the first study to demonstrate the prediction of breast cancer adverse pathology features from live primary biopsy cells and provides the basis to develop a powerful precision risk-stratification tool to risk-stratify DCIS. Furthermore, the methodology described and its ability to rapidly analyze primary breast biopsy tissue with single-cell resolution in a high-throughput manner engenders a powerful research tool to further understand tumor heterogeneity in breast cancer towards the development of personalized therapeutics. Applications of cost effectiveness analysis to our methodology will achieve the triple goal of providing cost-effective, patient-centered, and appropriate breast cancer and DCIS care. Note: This abstract was not presented at the conference. Citation Format: Ashok Chander, Michael Manak, Jonathan Varsanik, Brad Hogan, Grannum Sant, Kevin Knopf. Risk stratification of ductal carcinoma in situ: Analytical validation of a prognostic test analyzing live-primary cells via phenotypic biomarkers and machine learning at single-cell resolution [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A31.
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