Combined pathologic-genomic algorithm for early-stage breast cancer improves cost-effective use of the 21-gene recurrence score assay.

Background: The 21-gene recurrence score (RS) (Oncotype DX®; Genomic Health, Redwood City, CA) partitions hormone receptor positive, node negative breast cancers into three risk groups for recurrence. The Anne Arundel Medical Center (AAMC) model has previously been shown to accurately predict RS risk categories using standard pathology data. A pathologic-genomic (P-G) algorithm then is presented using the AAMC model and reserving the RS assay only for AAMC intermediate-risk patients. Patients and methods: A survival analysis was done using a prospectively collected institutional database of newly diagnosed invasive breast cancers that underwent RS assay testing from February 2005 to May 2015. Patients were assigned to risk categories based on the AAMC model. Using Kaplan-Meier methods, 5-year distant recurrence rates (DRR) were evaluated within each risk group and compared between AAMC and RS-defined risk groups. Five-year DRR were calculated for the P-G algorithm and compared with DRR for RS risk groups and the AAMC model's risk groups. Results: A total of 1268 cases were included. Five-year DRR were similar between the AAMC low-risk group (2.7%, n = 322) and the RS < 18 low-risk group (3.4%, n = 703), as well as between the AAMC high-risk group (22.8%, n = 230) and the RS > 30 high-risk group (23.0%, n = 141). Using the P-G algorithm, more patients were categorized as either low or high risk and the distant metastasis rate was 3.3% for the low-risk group (n = 739) and 24.2% for the high-risk group (n = 272). Using the P-G algorithm, 44% (552/1268) of patients would have avoided RS testing. Conclusions: AAMC model is capable of predicting 5-year recurrences in high- and low-risk groups similar to RS. Further, using the P-G algorithm, reserving RS for AAMC intermediate cases, results in larger low- and high-risk groups with similar prognostic accuracy. Thus, the P-G algorithm reliably identifies a significant portion of patients unlikely to benefit from RS assay and with improved ability to categorize risk.

Determining the treatment strategy for colorectal neoplastic lesions: endoscopic assessment or the non-lifting sign for diagnosing invasion depth?

BACKGROUND AND STUDY AIMS: Assessment of the invasion depth of colorectal neoplasia is important in deciding between endoscopic and surgical resection treatment methods. Prior to attempting endoscopic resection, the lesion is lifted by submucosal injection, and a positive "non-lifting sign" is usually considered to indicate deeper submucosal infiltration. The purpose of this prospective multicenter study was to assess the predictive value of the non-lifting sign for differentiating between adenoma and early cancer (up to discrete submucosal infiltration [sm1]) and cancer with deeper infiltration (sm2). PATIENTS AND METHODS: During an 11-month period, a total of 271 colorectal neoplastic lesions in 239 patients were included in the study. Apart from the location, size, and macroscopic type of the lesion, the presence or absence of the non-lifting sign was recorded and compared with the endoscopic assessment of invasion depth. RESULTS: The non-lifting sign had a sensitivity of 61.5 %, a specificity of 98.4 %, a positive predictive value of 80.0 %, a negative predictive value of 96.0 %, and an accuracy of 94.8 %. Endoscopic diagnosis of deeper infiltration had a sensitivity of 84.6 %, a specificity of 98.8 %, a positive predictive value of 88.0 %, a negative predictive value of 98.4 %, and an accuracy of 97.4 %. Statistically significant differences were found in terms of sensitivity and accuracy. CONCLUSION: Because of its lower sensitivity and accuracy, the non-lifting sign will not replace endoscopic assessment. If a lesion does not lift, this can make resection technically difficult, but does not reliably predict deeper cancerous invasion.

Sonographic assessment of the cervix before, during and after a uterine contraction is effective in predicting the course of labor.

OBJECTIVE: To investigate whether the degree of change in cervical length during a uterine contraction is predictive of subsequent progression of labor. METHODS: The subjects were 73 uncomplicated parturient women at term. We observed the cervix before, during and after a uterine contraction by transvaginal ultrasound in the first stage of labor and determined the degree of cervical shortening during the contraction relative to the cervical length before contraction. We related the degree of cervical shortening to labor patterns at the time of the ultrasound examination, which were retrospectively determined by reviewing the partogram. RESULTS: The cervix was shortened in length by about 50% on average during a uterine contraction in the normal course of labor. The degree of cervical shortening was significantly greater in the normal latent and active phases than it was in the prolonged latent phase, protracted active phase and false labor, whereas there were no differences between the former two phases nor between the latter three phases. Nulliparous and parous women exhibited almost the same degree of shortening in the normal latent and active phases. CONCLUSIONS: Real-time ultrasound observation of the cervix during uterine contraction could help differentiate inefficient uterine contractions from normal ones and thus predict the subsequent course of labor.

Endoscopic mucosal resection.

We are now finding more malignancies in their early stages than previously. Attempts to ablate these lesions are difficult and do not provide the histological information required to decide on further treatment. Surgery is difficult to justify, as only a minority of lesions are associated with lymph node metastases and lesions may not become clinically relevant within the lifetime of an elderly patient. Endoscopic mucosal resection allows cancers to be resected at minimal cost, morbidity and mortality. It is also the most reliable investigation when assessing lesions which are suspicious for containing early cancer. After endoscopic removal, histological assessment of depth of penetration and a search for invasion into lymphatics or venules allows the risk of microscopic lymph node metastases to be predicted. The risk of developing metastatic disease can then be balanced against the risks of surgery in view of the patient's age and health.

Assessment of colorectal lesions using magnifying colonoscopy and mucosal dye spraying: can significant lesions be distinguished?

BACKGROUND AND STUDY AIMS: Assessing the nature of lesions at the time of colonoscopy is important, and magnifying colonoscopy allows examination of mucosal crypt patterns. In this study, we assessed mucosal crypt patterns to see whether we could predict the histological findings. PATIENTS AND METHODS: This retrospective study of total colonoscopy using magnifying colonoscopy involved 4445 patients between December 1993 and July 1998 at the National Cancer Center Hospital East. The mucosal crypt patterns of 3438 lesions were observed under magnifying colonoscopy with 0.2% indigo carmine solution, and classified according to a modified Kudo classification (type I to V). After endoscopic or surgical resection (3291 cases and 147 cases, respectively), histopathological examination was performed. RESULTS: The diagnostic accuracy of magnifying endoscopy for non-neoplastic lesions was 75% (117/157), for adenomatous polyps it was 94% (3006/3186), and for invasive carcinomas it was 85 % (81/95). CONCLUSIONS: The combination of magnifying colonoscopy and dye spraying is helpful in determining the nature of colonic lesions as non-neoplastic, adenomas, or invasive carcinomas. Therefore it may be possible to determine, at the time of colonoscopy, which lesions require no treatment, which can be removed endoscopically, and which should be removed by surgery.

Assessment of liver function in chronic liver diseases and regional function of irradiated liver by means of 99mTc-galactosyl-human serum albumin liver scintigraphy and quantitative spectral analysis.

Scintigraphy with 99mTc-diethylenetriamine pentaacetic acid galactosyl human serum albumin (99mTc-GSA) was performed on 102 patients, then the hepatic extraction fraction (HEF), the rate constant for liver uptake of the tracer from the blood (K1) and the hepatic blood flow index (HBFI) were determined by spectral analysis. The HEF, K1 and HBFI values correlated moderately or closely with various indices of hepatic function, and the HEF and K1 values decreased according to the stage of liver dysfunction. The HEF and K1 values linearly and nonlinearly correlated with HH15 and LHL15, respectively. The HEF, K1 and HBFI values for the irradiated portion of 20 patients before and alter irradiation were compared. The HEF value in patients with a cirrhotic liver significantly (p < 0.002) decreased compared with that in patients with a normal liver at a dose of less than 40 Gy, whereas the HBFI value in patients with a normal liver significantly (p < 0.05) decreased compared with that in patients with a cirrhotic liver at a dose of 40 Gy or greater. This method appears to be a simple, non-invasive and useful tool with which to quantitatively evaluate liver function and it also helps clarify changes in regional function of the irradiated liver.

Serial scintigraphic assessment of iodine-123 metaiodobenzylguanidine lung uptake in a patient with high-altitude pulmonary edema.

Iodine-123 metaiodobenzylguanidine ((123)I-MIBG) can be considered an indicator of pulmonary endothelial cell function. Serial (123)I-MIBG images of the chest were acquired in a patient with high altitude pulmonary edema (HAPE). The initial evaluation was performed 7 days after admission. The lung to upper mediastinum ratios (LMRs) of (123)I-MIBG uptake were 1.33 (for the right lung) and 1.12 (for the left lung). The second examination of (123)I-MIBG lung uptake, which was performed 2 months later, showed LMRs of 1.39 (right lung) and 1.33 (left lung). We speculated that the decreased lung uptake of (123)I-MIBG at the early recovery stage could reflect an impairment in pulmonary endothelial cell metabolic function in the development of HAPE.

Quantitative assessment of human leukocyte antigen-G protein in amniotic fluid by a double-determinant enzyme-linked immunosorbent assay using anti-human leukocyte antigen-G-specific antibody '87G'.

PROBLEM: The objective of this study was to establish an enzyme-linked immunosorbent assay (ELISA) system, in an attempt to quantify the amount of human leukocyte antigen (HLA)-G protein in amniotic fluid. METHOD OF STUDY: We established a double-determinant ELISA system using the anti-HLA-G specific mouse monoclonal antibody '87G' as a capture antibody and the horseradish-peroxidase labeled rabbit anti-human beta2-microglobulin antibody as a detection antibody. We then measured the concentration of HLA-G protein in amniotic fluid samples from nine normal second-trimester pregnant women and in serum samples from eight normal males. RESULTS AND CONCLUSION: HLA-G protein was detected in amniotic fluid at a concentration of 275 ng/ml (197-343 ng/ml) (median value and 95% confident range), whereas the concentration of HLA-G protein in male serum was below the minimum detection level.

Iodine-123 metaiodobenzylguanidine scintigraphic assessment of myocardial sympathetic innervation in patients with familial amyloid polyneuropathy.

OBJECTIVES: This study attempted to assess myocardial sympathetic innervation using iodine-123 (I-123) metaidobenzylguanidine (MIBG) imaging in patients with familial amyloid polyneuropathy. BACKGROUND: Signs and symptoms of cardiac autonomic dysfunction are commonly seen in patients with cardiac amyloidosis. However, the incidence and magnitude of abnormalities in myocardial sympathetic nerve function by means of I-123 MIBG imaging and their relation to clinical findings, cardiac function and the results of thallium-201 (Tl-201) and technetium-99m pyrophosphate (Tc-99m PYP) myocardial scanning have not yet been clarified. METHODS: We performed M-mode, two-dimensional and Doppler echocardiography and I-123 MIBG, Tl-201 and Tc-99m PYP imaging of the heart in 12 patients with familial amyloid polyneuropathy and biopsy-proved cardiac amyloidosis. RESULTS: Ten of 12 patients had no clinical evidence of overt heart disease, but left ventricular (LV) wall thickening was observed in 4 of these 10. Left ventricular percent fractional shortening and Doppler transmitral flow velocity patterns were found to be normal in all 12 patients. Eight of 12 patients showed no myocardial MIBG accumulation, with limited uptake in the remaining 4 demonstrated only in the LV anterior wall. Diffuse but mild myocardial uptake of Tc-99m PYP occurred in only 4 of 12 patients, and all 12 had normal results on Tl-201 myocardial scanning. Complete defects on myocardial MIBG scans were found in five of eight patients with negative findings on Tc-99m PYP myocardial scanning. The incidence and magnitude of myocardial uptake of MIBG were independent of clinical findings, extent of endomyocardial amyloid deposition, electrocardiographic QRS voltage and ventricular wall thickness. CONCLUSIONS: Patients with familial amyloid polyneuropathy show a high incidence of myocardial adrenergic denervation with viable myocardium that can be identified very early in cardiac amyloidosis, before the development of clinically apparent heart disease, ventricular wall thickening, significant LV systolic and diastolic dysfunction and positive findings on Tc-99m PYP myocardial scanning.

Regional diastolic function in effort angina pectoris: assessment with biplane left ventriculography.

To investigate left ventricular (LV) regional diastolic function in effort angina pectoris (AP), we performed left ventriculography in 14 patients with AP and isolated left anterior descending artery disease and in 9 normal subjects (N). LV volume (V), regional area (S) [anterior, apex, and inferior], and the first derivative of V and S (dV/dt, dS/dt) were derived from analysis of the left ventriculogram. Normalized peak filling rate (nPFR) and peak atrial filling rate (nPAFR) were derived from dV/dt. The ratio of filling volume to stroke volume during rapid filling and atrial contraction were defined as rapid filling fraction (RFF) and atrial filling fraction (AFF). Similarly, peak area changing rate (PACR), peak area changing rate during atrial contraction (PACRac), rapid area changing fraction (RACF), and atrial area changing fraction (AACF) were derived from S and dS/dt. We also calculated the time constant of LV relaxation (T), and LV global and regional compliance during atrial contraction [(dV/VdP)ac, (dS/SdP)ac]. The LV global diastolic function (T increases, nPFR decreases) was impaired in the angina patients. LV regional diastolic function (nPACR decreases, RACF decreases) was also impaired in the affected region of the AP group. While their rapid filling was impaired, nPACRac was maintained and AACF was increased in the affected region. Furthermore, nPACR and RACF each showed a significant inverse correlation with AACF in the anterior region [r = -0.57 (P < 0.01), r = -0.92 (P < 0.001)]. In the affected region of the patients with AP, (dS/SdP)ac was increased, but not significantly. Thus, LV global and regional diastolic functions were simultaneously impaired in patients with isolated left anterior descending artery disease.(ABSTRACT TRUNCATED AT 250 WORDS)

[Integrative assessment of the developmental pharmacology and developmental toxicology, with special reference to the brain].

Increasing numbers of neurotoxins or therapeutic agents that have specific target cells or receptors can be used to assess the developmental correlation between the structure and function of various organs including the brain. Patients with chronic diseases are now able to maintain their social activities but still must be medicated for a long period of their life. This might increase the potential hazard of prenatal drug exposure in the progeny. Functional teratology is quite a new concept in neuroscience. Recent observations of our laboratory and those of others suggest that the sensitive period for functional teratology might encompass the whole stage of fetal life in animals and humans. The shortage of precise information on the developmental integration of the structure and function of the neurons with different properties is a problem to be solved for the further progress of developmental pharmacology and toxicology. Single exposures to drugs at a different stage during the gestational period of rats or mice might provide more useful information on the relationship between the lesioned area and related functional disorders manifested postnatally. This paper reviews recent advances in developmental neuropharmacology and functional neuroteratology including beneficial points of the short-term exposures to drugs.

[A decrease in the wet-dog shakes response to the second administration of kainic acid in juvenile rats].

The effect of an intermittent administration of kainic acid on the KA-induced behavior, scratching, wet-dog shakes and limbic seizures was studied in the rat. Nine mg/kg kainic acid was injected i.p. at 3, 7, 14 or 21 days after the priming with the same dose of kainic acid at 25 days of age. There was no significant effect of KA-priming on the onset time of scratching. The frequency of wet-dog shakes decreased significantly in all the KA-primed rats. Fourteen day-priming of kainic acid was most effective for reducing the wet-dog shakes response. The onset time of limbic seizures tended to be shorter in all the KA-primed groups; seven day-priming resulted in a significant decrease. Histological findings showed a delay in the formation of dendritic processes of pyramidal cells in the CA3 area of the hippocampus. The results indicated that an intermittent administration of kainic acid with an interval of 3 to 21 days induces a marked tolerance in the wet-dog shakes response to kainic acid in juvenile rats, while no change in the scratching and an acceleration of the onset of limbic seizures were shown, implying that different neuronal systems are involved in these three behaviors induced by kainic acid.

Radionuclide angiographic assessment of left ventricular diastolic filling in amyloid heart disease: a study of patients with familial amyloid polyneuropathy.

To assess left ventricular diastolic filling in amyloid heart disease, 17 patients with familial amyloid polyneuropathy and 20 normal subjects were examined by radionuclide angiography. None of the patients showed clinical evidence of restrictive cardiomyopathy. All but two patients had normal left ventricular ejection fraction. Peak filling rate was significantly lower and time to peak filling rate was significantly greater in patients than in normal subjects (2.60 +/- 0.52 versus 3.10 +/- 0.44 EDV/s, p less than 0.001, and 215 +/- 53 versus 147 +/- 18 ms, p less than 0.001, respectively). The mean left ventricular filling volume during rapid diastolic filling and atrial systole in patients was 54.5 +/- 19.5% and 44.2 +/- 21.6% of the stroke volume, respectively, compared with 83.8 +/- 6.6% (p less than 0.001) and 20.0 +/- 6.0% (p less than 0.001), respectively, in normal subjects. Although 10 of the 14 patients without clinical evidence of overt heart disease had normal ventricular wall thickness as well as normal ejection fraction, 8 of the 10 showed abnormal diastolic filling. In patients with familial amyloid polyneuropathy, indexes of diastolic filling were significantly related to ventricular wall thickness alone. The incidence and magnitude of abnormalities in time to peak filling rate and contribution of rapid filling as well as atrial systole to ventricular filling increased with age and duration of illness. Thus, abnormal diastolic filling can be seen even in the early stage of familial amyloid polyneuropathy and may be related to myocardial amyloid deposition as well as to fibrosis. Careful consideration should be given to age and duration of illness when diastolic filling is assessed in this disorder.

[Left ventricular end-systolic pressure and wall thickness relation for the assessment of regional myocardial contractility in man (author's transl)].

In 28 patients (pts) (5 normal subjects (N), 12 pts with valvular heart disease, 6 with cardiomyopathy, and 5 with ischemic heart disease), left ventricular (LV) pressure was measured using Millar's catheter tip transducer simultaneously with LV posterior wall thickness (W) by echocardiography. After the control recording, LV peak systolic pressure was altered by about 30 mmHg from the control level by angiotensin (20 ng/kg/min) or nitroprusside (1 gamma/kg/min) to attain two (18 pts) or three (10 pts) different end-systolic pressure points, determined after the steady state was achieved. LV end-systolic pressure and wall thickness (P-W) relation a the three different end-systolic pressure points was found to be linear (r = 0.996) in each of the 10 pts, suggesting that end-systolic P-W relation is independent of afterload. Isoproterenol infused in 4 pts, which led to an increase in peak positive (+) dp/dt by a mean of 28%, increased the slope of the P-W relation by 43.4% of the control value (P less than 0.001), while propranolol, which led to a decrease in peak (+) dp/dt by a mean of 16.7%, reduced the slope by 27.3% (p less than 0.001). This indicates the sensitiveness of the slope of P-W relation to the inotropic change of the myocardium. In N, the slope of the P-W relation was -29.7 +/0 6.0 mmHg/mm (mean +/- SD), while the value in 4 pts with decreased functional capacity (NYHA III or IV) was significantly lower (-13.7 +/- 2.9 mmHg/mm; p less than 0.001). Thus, the present study suggests that the slope of the end-systolic P-W relation is useful in assessing regional myocardial contractility in man.