Can MRI help assess aggressiveness of endometrial cancer?

AIM: To identify potential magnetic resonance imaging (MRI) biomarkers to predict the aggressiveness of endometrial cancer. MATERIALS AND METHODS: Seventy-one patients with endometrial cancer who underwent MRI staging were analysed retrospectively. The signal intensity (SI) of the tumours was assessed on sagittal T2-weighted imaging (WI) and sagittal T1WI sequences). The depth of myometrial invasion, tumour grade and subtype, lymphovascular invasion, and microsatellite stability status were assessed histopathologically, and these findings were compared with MRI findings using logistic regression. The log-rank test was used to assess differences in survival among groups defined by different MRI measurements. RESULTS: Tumours with qualitative higher signal than that of normal myometrium on the late T1WI DCE image sequences were more likely to have lymphovascular space invasion (p<0.001). Tumours that had a higher SI tumour ratio (T1 post-contrast arterial/T1 precontrast) had a higher chance of being microsatellite stable (odds ratio 2.36). The SI ratio of the tumour to the myometrium showed that lower T2 tumour/T2 myometrial ratio correlated with ≥50% depth of myometrial invasion as determined by imaging (p=0.006). Endometrial tumours showing a SI of >209 on delayed T1WI sequences had longer recurrence-free survival than those with tumours showing a SI ≤209 (p=0.014). Tumour subtype and grade were not associated with MRI findings. CONCLUSION: The SI of endometrial cancer on MRI may be used to predict the aggressiveness of the tumour and microsatellite stability status. Further studies are needed to confirm these findings.

Is MRI helpful in assessing the distance of the tumour from the internal os in patients with cervical cancer below FIGO Stage IB2?

AIM: To determine the ability of magnetic resonance imaging (MRI) in detecting tumour-free margins from the internal os (IO). MATERIALS AND METHODS: A database search yielded 79 women with early-stage cervical cancer who underwent radical hysterectomy and preoperative MRI. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of MRI in assessment of ≤5 and >5 mm IO involvement were calculated with histopathological surgical specimen findings considered to be the reference standard. A main and subset analysis was performed. The subset analysis included only those patients who would have been considered for radical trachelectomy. RESULTS: For predicting a distance between the tumour and the IO of ≤5 mm, MRI had a sensitivity of 73%, a specificity of 98.3%, a PPV of 95%, a NPV of 88.1%, and an accuracy of 89.8% for the main analysis, and sensitivity of 81.8%, a specificity of 93.2% a PPV of 69.2% a NPV of 96.5% and an accuracy of 91.4% for the subset analysis. CONCLUSION: MRI has high specificity, NPV, and accuracy in detecting tumour from the IO, making MRI suitable for treatment planning in patients desiring trachelectomy to preserve fertility.

Utility of lymphangiography in the prediction of lymph node metastases in patients with cervical cancer.

Our objective was to assess the value of lymphangiography in selecting patients for surgical staging of locally advanced cervical cancer. We reviewed our computerized database to identify patients with cervical cancer who had abnormal findings on lymphangiography and underwent retroperitoneal lymph node dissection between September 1991 and January 1996. The records of these patients were retrospectively reviewed, and the following data were retrieved: clinical tumor stage and findings on lymphangiography at surgery, and on pathologic examination of resected lymph nodes. The lymphangiograms were reviewed and reinterpreted in blinded fashion by two of the authors. The positive and negative predictive values of lymphangiography for the presence of lymph node metastases were calculated, with findings on pathologic examination of lymph nodes used as the gold standard. The positive and negative predictive values of surgeons' clinical assessments at surgery were also calculated. Fifty patients met the selection criteria and constituted the study population. Fourteen patients (28%) had histologically negative nodes, and 36 patients (72%) had lymph node metastases. Thirty-three patients had metastases to pelvic nodes, 1515 patients had metastases to common iliac nodes, and 1616 patients had metastases to para-aortic nodes. The positive predictive value of lymphangiography for lymph node metastases was 74% for pelvic nodes, 73% for common iliac nodes, and 88% for para-aortic nodes. The negative predictive value of lymphangiography for lymph node metastasis was 76% for common iliac nodes and 77% for para-aortic nodes. Overall, 46% of the patients selected for surgical exploration had histologic findings of either common iliac or para-aortic lymph node metastases; these findings led clinicians to extend radiation fields to cover the para-aortic lymph nodes. Lymphangiography is helpful in selecting patients with cervical cancer who have a high risk of common iliac or para-aortic lymph node metastasis. However, more accurate and more readily available noninvasive methods of evaluating cervical patients for the presence of regional disease continue to be needed.

Metastases to the pancreas from renal cell carcinoma: findings on three-phase contrast-enhanced helical CT.

OBJECTIVE: Our goal was to define the lesion enhancement characteristics of renal cell carcinoma metastases to the pancreas using three-phase helical CT. MATERIALS AND METHODS: Thin-section three-phase contrast-enhanced CT scans of nine patients with renal cell carcinoma metastases to the pancreas were evaluated. The helical CT protocol included 3-mm collimation and a 2:1 pitch. Scans through the pancreas were obtained in three series beginning 25, 60, and 120 sec after the start of administration of i.v. contrast material delivered at 3 ml/sec. The Hounsfield densities of the pancreatic lesions and normal pancreatic parenchyma during each of the enhancement phases were recorded and compared. RESULTS: The enhancement patterns of the metastatic deposits and the normal pancreas differed. Thirty-four lesions ranging in size from 6 to 110 mm were identified. All metastases showed rapid enhancement during the early (arterial and portal) phases, resulting in differential attenuations (compared with normal pancreatic parenchyma) of approximately 50-100 H. The differential attenuations were approximately 5-45 H on delayed-phase scans, resulting in poorer conspicuity of the lesions. Multifocal metastases were clearly identified on the early-phase scans in seven patients. CONCLUSION: Renal cell carcinoma metastases to the pancreas enhance most conspicuously during the early phases of helical CT. Such metastases may fail to be appreciated in the delayed phase. In patients with suspected renal cell carcinoma metastases to the pancreas, early-phase scanning after i.v. contrast administration should be performed.

Subtraction CT colonography: feasibility in an animal model.

AIM: To determine, in an in vitro animal model, the feasibility of subtracting residual faecal material, during virtual colonoscopy, by uniform mixing of the colonic contents with barium. MATERIALS AND METHODS: Segments of animal colon containing simulated soft-tissue polyps, measuring 3-10 mm, were filled with a faecal substitute consisting of a barium and peanut butter mix that had an attenuation value greater than 200 Hounsfield units. The colonic segments were then examined by CT using 3-10 mm beam collimations, and at pitch factors of 1 and 2. Using subtraction cut-off levels varying from 100-250 Hounsfield units, the barium and peanut butter mix was then subtracted to reveal the underlying polyps. RESULTS: Our optimal technical parameters required 3-mm beam collimation, a helical pitch factor of 2, reconstruction intervals of 3 mm, and a subtraction cut-off level of 150 Hounsfield units. The subtraction technique, in this animal model, had a sensitivity of 94% and a specificity of 80% for polyps measuring greater than 3 mm. CONCLUSION: In this limited animal model, the subtraction technique utilized was technically feasible and had an acceptable sensitivity.

Brachial plexus: demonstration at US.

Five healthy volunteers underwent ultrasonography (US) to determine the feasibility of visualizing the brachial plexus. The roots, trunks, and cords could be identified in the supraclavicular and infraclavicular regions. The roots within the neural foramina and the epidural space could not be evaluated. US may play a complementary role in the evaluation of patients with brachial plexopathy.

Relative value of physical examination, mammography, and breast sonography in evaluating the size of the primary tumor and regional lymph node metastases in women receiving neoadjuvant chemotherapy for locally advanced breast carcinoma.

The purpose of this study was to correlate physical examination and sonographic and mammographic measurements of breast tumors and regional lymph nodes with pathological findings and to evaluate the effect of neoadjuvant chemotherapy on clinical Tumor-Node-Metastasis stage by noninvasive methods. This was a retrospective analysis of 100 patients with locally advanced breast cancer registered and treated in prospective trials of neoadjuvant chemotherapy. All patients received four cycles of a doxorubicin-containing regimen and had noninvasive evaluation of the primary tumor and regional lymph nodes before and after neoadjuvant chemotherapy by physical examination, sonography, and mammography and underwent breast surgery and axillary dissection within 5 weeks after completion of neoadjuvant chemotherapy. The correlations between clinical and pathological measurements were determined by Spearman rank correlation analysis. A proportional odds model was used to examine predictive values. Eighty-three patients had both a clinically detectable primary tumor and lymph node metastases. Sixty-four patients had a decrease in Tumor-Node-Metastasis stage after chemotherapy. For 54% of patients, there was concordance in clinical response between the primary tumor and lymph node compartment; for the rest, results were discordant. Physical examination correlated best with pathological findings in the measurement of the primary tumor (P = 0.0003), whereas sonography was the most accurate predictor of size for axillary lymph nodes (P = 0.0005). The combination of physical examination and mammography worked best for assessment of the primary tumor (P = 0.003), whereas combining physical examination with sonography gave optimal evaluation of regional lymph nodes (P = 0.0001). In conclusion, physical examination is the best noninvasive predictor of the real size of locally advanced primary breast cancer, whereas sonography correlates better with the real dimensions of axillary lymph nodes. The combination of physical examination with either mammography or sonography significantly improves the accuracy of noninvasive assessment of tumor dimensions.

Decreased 3 alpha-hydroxysteroid dehydrogenase activity in peripheral blood lymphocytes from patients with primary open angle glaucoma.

The purpose of the present study was to determine whether peripheral blood lymphocytes (PBL) from primary open angle glaucoma (POAG) patients have reduced 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity as was previously found in POAG-derived cultured trabecular meshwork cells. The availability of PBL from both POAG and control patients makes this a useful system for studying the association of decreased 3 alpha-HSD activity with POAG. PBL were isolated from the venous blood of 17 POAG patients and 22 non-glaucoma controls and assayed for 3 alpha-HSD activity with tritiated 5 beta-dihydrocortisol as a substrate. The mean 3 alpha-HSD activity +/- S.E.M., expressed in comparable units of specific activity, of the POAG derived PBL was 13.8 +/- 1.3 U as compared to 32.8 +/- 2.0 U for control cells. This reduction (> 50%) was statistically significant (P < 0.001). Quantitative immunoblot analysis of PBL indicated that the POAG and control cells, despite their difference in 3 alpha-HSD activity, had nearly identical amounts of 3 alpha-HSD protein. The molecular weight of PBL 3 alpha-HSD from both groups of patients was 38,000, the same as previously reported for human liver. The results of this study show an association of decreased PBL 3 alpha-HSD activity and POAG which was not related to antiglaucoma therapy. The reduced levels of 3 alpha-HSD activity in the readily obtainable PBL may serve as a marker for POAG or those at risk for developing the disease.

Radiographic demonstration of intercostal lymphatics and lymph nodes.

The anatomy of the posterior intercostal lymphatics and lymph nodes is reviewed. These lymph nodes are occasionally visualized by bipedal conventional lymphography. Opacified and/or enlarged posterior intercostal lymph nodes may also be identified with computed tomography of the chest. Familiarity with the lymphatic drainage patterns of the intercostal spaces and recognition of abnormal intercostal lymph nodes may provide additional information regarding disease status in patients with inflammatory or malignant disease of the thorax.

Purification and properties of human hepatic 3 alpha-hydroxysteroid dehydrogenase.

3 alpha-Hydroxysteroid dehydrogenase (3 alpha-HSD) was purified greater than 500-fold from human liver cytosol. The purification was monitored using 5 beta-[3H]dihydrocortisol (5 beta-DHF) as substrate. Electrophoretically homogeneous enzyme was obtained using a procedure that involved ammonium sulfate precipitation and three successive column chromatography steps: DEAE-cellulose, hydroxylapatite and Blue-Sepharose. The enzyme is a monomer since the native molecular weight was found to be 37,000, using a calibrated Sephadex G-75 column, and the denatured subunit molecular weight was determined to be 38,500, by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. The enzyme had a pI of 5.6-5.9. The 3-ketosteroids: cortisol, testosterone, progesterone and androstenedione, were not substrates for 3 alpha-HSD indicating that a saturated 4,5 double bond was required for substrate activity. The conformation at the 5 position, however, did not influence substrate activity since 5 alpha- and 5 beta-DHF and 5 alpha-dihydrotestosterone were all reduced at similar rates. The purified enzyme preferred NADPH to NADH as a cofactor and showed a broad peak of activity in the pH range of 6.8-7.4. The apparent Km for 5 beta-DHF was 18 microM. The enzyme was markedly stabilized by 50 mM phosphate buffer containing 10 to 20% glycerol at 4 degrees C. Freezing and thawing of the enzyme resulted in a large loss of activity during early stages of the purification. This is the first report of the purification to homogeneity of 3 alpha-HSD from human tissue.

Human hepatic 3 alpha-hydroxysteroid dehydrogenase: possible identity with human hepatic chlordecone reductase.

3 alpha-Hydroxysteroid dehydrogenase is a cytosolic, monomeric, NADPH-dependent oxidoreductase which reduces 3-keto-5-dihydrosteroids to their tetrahydro products. We present here the first partial amino acid sequence data for the human liver enzyme and show these sequences to be identical to the deduced amino acid sequence for human hepatic chlordecone reductase. In addition, these two enzymes exhibit similar substrate and cofactor specificities and immunological reactivity. The results suggest that the natural substrates for chlordecone reductase are 3-keto-5-dihydrosteroids and that these two proteins may be identical.

Human hepatic cortisol reductase activities: enzymatic properties and substrate specificities of cytosolic cortisol delta 4-5 beta-reductase and dihydrocortisol-3 alpha-oxidoreductase(s).

The metabolism of cortisol by human liver homogenates has been studied. Cortisol delta 4-reductase and dihydrocortisol-3-oxidoreductase activities were distributed in all subcellular fractions. The products of the soluble enzymes were identified. Cortisol and 5 beta-dihydrocortisol were reduced to 3 alpha,5 beta-tetrahydrocortisol, and 5 alpha-dihydrocortisol was reduced to 3 alpha,5 alpha-tetrahydrocortisol. The soluble enzymes showed a wide range of substrate specificity. The 21 substituted cortisol derivatives were not metabolized. The apparent Km values of cortisol delta 4-5 beta-reductase and dihydrocortisol-3 alpha-oxidoreductase for their substrates (cortisol, 5 alpha-dihydrocortisol, and 5 beta-dihydrocortisol) all ranged from 18 to 27 microM. Dexamethasone inhibited the reduction of all of these substrates and the inhibition was abolished by 21 substitution of the dexamethasone. Testosterone was a competitive inhibitor of the reduction of cortisol, 5 alpha-dihydrocortisol, and 5 beta-dihydrocortisol with a Ki ranging from 11 to 32 microM. NADPH was the preferred cofactor for the cortisol delta 4-5 beta-reductase and dihydrocortisol-3 alpha-oxidoreductase. No end product inhibition was observed.

The stimulation by adrenocorticotropin of the phosphorylation of adrenal inhibitor-1: a possible role in steroidogenesis.

Adrenocorticotropin (ACTH) acts via protein kinase A and the putative phosphorylation of a regulatory protein(s). We have examined a role in this process for inhibitor-1 which, following phosphorylation by protein kinase A, inhibits a phosphoprotein phosphatase activity. In the tissues we have examined inhibitor-1 was found primarily in the cytosol (90%) with the rest in the mitochondrial pellet. The highest concentration was in the adrenal cortex. Using adrenal cortex slices, the stimulation of steroidogenesis by ACTH and dibutyryl cAMP is paralleled by a corresponding increase in the phosphorylation of inhibitor-1 and this is not affected by inhibitors of protein synthesis which inhibit the steroidogenic response. The increase in the phosphorylation of inhibitor-1 occurs in the cytosol, while that in the mitochondrial pellet is not affected. Exogenous phosphorylated inhibitor-1, however, was found to inhibit phosphoprotein phosphatase activity in the mitochondrial pellet. The results suggest that the ACTH-induced increase in phosphorylated inhibitor-1 in the cytosol can affect susceptible phosphoprotein phosphatase activity both in the cytosol and the mitochondrial pellet and, hence, the level of phosphorylation of regulatory protein(s) involved in steroidogenesis.

A regulation of the level of phosphorylated phospholamban by inhibitor-1 in rat heart preparations in vitro.

Inhibitor-1 following phosphorylation by protein kinase A inhibits phosphoprotein phosphatase-1. We have found that in the rat heart inhibitor-1 is present only in the cytosolic fraction and that its phosphorylation in ventricular slices was increased by isoproterenol but not by isoproterenol and propranolol together. Cardiac microsomal phosphoprotein phosphatase activity, with added phosphorylase a as the substrate, was inhibited 33% by phosphorylated inhibitor-1. Phosphorylated inhibitor-1 decreased the dephosphorylation by exogenous phosphoprotein phosphatase-1 of phospholamban present in the sarcoplasmic reticulum membranes. These results suggest an interaction of cytoplasmic inhibitor-1 with either cytoplasmic or membrane-bound phosphoprotein phosphatase-1 with a subsequent effect on the level of phosphorylated phospholamban and the probable involvement of this interaction in the cardiac response to beta-adrenergic hormones.