Biomedical subjects
Publications and source records attributed to R Romagnoli.
We report the synthesis of a new hybrid 13 which is a combination of the naturally occurring antitumor agent distamycin A 1 and the pyrrolo[2,1-c][1,4]benzodiazepine 11, related to the naturally occurring anthramycin 2. The antitumor activity of the hybrid 13 was tested in vitro and compared to the natural product distamycin 1 and the PBD 11.
A new series of 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-beta-D-ribofuranuronamide++ +-b earing N-arylureas or N-arylcarboxamido groups at the purine 6 position and N-arylureas combined with halogens or alkynyl chains at the 2 position have been synthesized and tested for affinity at A1 and A2A adenosine receptors in rat brain membranes and at cloned rat A3 receptors expressed in CHO cells. The derivatives contained the 5' substituent found in the potent, nonselective agonist 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-beta-D-ribofuranuronamide++ + (NECA). While the carboxamido derivatives (9-13) showed affinity for A1 receptors, the urea derivatives (30-45) showed different degrees of affinity and selectivity for the A3 adenosine receptor subtype. In particular the derivative bearing a p-sulfonamidophenyl-urea at the 6 position, 31 showed a high affinity (Ki = 9 nM) and selectivity for the A3 receptors compared to that of the reference compound 1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-be ta-D-ribofuranuronamide (IB-MECA). Furthermore, the importance of the stereochemistry in the interaction of these ligands at the rat A3 adenosine receptors has been evaluated by introducing a chiral chain at the 6 position. The introduction of halogens or alkynyl chains at the purine 2 position of selected ureas did not give the expected enhancement of potency at A2A and/or A3 receptors but rather showed a dramatic reduction of A2A affinity, resulting in compounds with good A2A/A3 selectivity. For example, the 2-(3-hydroxy-3-phenyl-1-propyn-1-yl)-6-(4-methoxyphenylurea) derivative 61 showed the capability to bind simultaneously to A1 and A3 receptor subtypes, excluding the A2A receptor. Compound 31 was shown to be an agonist, 9-fold more potent than NECA, at A3 receptors in rat RBL-2H3 mast cell membranes through stimulation of binding of [35S]GTP-gamma-S.
BACKGROUND: The classic manual end-to-side technique of esophagogastrostomy after gastric pull-up to the neck carries a rather high risk of fistula and stricture. METHODS: A terminalized semimechanical side-to-side technique of cervical esophagogastrostomy was performed in 16 patients by the application of an Endo-GIA stapler across the gastric and esophageal walls placed side by side, so as to create a V-shaped posterior opening between the two lumina. The anterior aspect of the anastomosis was hand-sewn using a classic running suture. The cross-sectional area of the semimechanical anastomoses was estimated by barium swallow study 2 months after operation and compared with that of 24 manual end-to-side esophagogastrostomies. RESULTS: The cross-sectional area was 225 +/- 15.7 mm2 (mean +/- standard error of the mean) for the 16 semimechanical anastomoses versus 136 +/- 15 mm2 for the 24 manual anastomoses (p = 0.0001). The anastomotic area decreased from 206.6 +/- 13.5 mm2 in 29 patients without dysphagia to 107.5 +/- 4.7 mm2 in 7 patients with moderate dysphagia for solids that did not require endoscopic dilation and to 55.7 +/- 16 mm2 in 4 patients with severe dysphagia that required dilation (p = 0). The anastomotic area in 6 of the 7 patients with initial moderate dysphagia for solids increased spontaneously with time from 107.3 +/- 5.5 mm2 to 174.6 +/- 8.1 mm2, with concomitant symptomatic relief (p = 0.0277). CONCLUSIONS: The terminalized semimechanical side-to-side suture technique produces a larger anastomosis than the classic end-to-side esophagogastrostomy technique. Inflammatory changes related to the operation may cause transient narrowing of a cervical esophagogastrostomy.
This article focuses on major clinical and imaging features that are of practical interest in the diagnosis and management of osteosarcoma, a malignant tumor arising from the osteogenic matrix. The current histologic classification of this tumor is also reported. Different types of osteosarcoma are described, each of them with a definite clinical and radiographic pattern. Conventional radiography is the keystone to diagnosis because it allows analysis of the patterns relevant to the different lesions (location, site, bone destruction, periostal reaction, soft tissue masses). The most common type of osteosarcoma is defined classic or conventional high grade (75%) and it typically involves the medullary cavity. Radiographically, it may be predominantly osteosclerotic or osteolytic, but more frequently it has a mixed (osteoslerotic/osteolytic) pattern. The teleangiectatic osteosarcoma is an aggressive form (5%) characterized by marked vascularization with large blood-filled cystic cavities; its typical radiographic pattern is purely osteolytic. Juxtacortical osteosarcoma (8-10%) indicates a group of osteosarcomas apparently arising on bone surface. The most common type is parosteal osteosarcoma which affects older subjects and has a better prognosis than the classic type. Radiography shows a heavily ossified mass with a broad base attached to the underlying cortex. CT and MRI are useful in the differential diagnosis of osteosarcoma and myositis ossificans or osteocondroma. Rare types of osteosarcoma include the periosteal and high-grade surface variants, as well as secondary and multifocal osteosarcoma (osteosarcomatosis). CT and MRI are the imaging procedures of choice in locoregional staging (intraosseous and extraosseous spread, skip metastases, growth plate and articular involvement). CT of the chest is a useful tool for detecting lung metastases. Also MRI has a role in monitoring the response to chemotherapy and in detecting recurrence. It permits a more accurate study of the tumor volume than other imaging techniques and clinical examination. MRI becomes even more useful when paramagnetic contrast agents are administered because dynamic MRI with contrast enhancement help differentiate postchemotherapy changes from viable tumor--the latter enhancing rapidly and the former slowly. Thus, dynamic MRI allows a precise mapping of any residual tumor activity.
OBJECTIVE: To determine whether the denervated stomach as an esophageal substitute is an inert conduit or a contractile organ. SUMMARY BACKGROUND DATA: The motor response of gastric transplants to deglutition suggests that the stomach pulled up to the neck acts as an inert organ. METHODS: The gastric motility of 11 healthy volunteers and 33 patients having either a gastric tube (GT) (n = 10) or their whole stomach (WS) (n = 23) as esophageal replacement was studied with perfused catheters during the fasting state, after a meal, and after intravenous administration of erythromycin lactobionate. A motility index was established for each period of recording by dividing the sum of the areas under the curves of all contractions of >9 mmHg by the time of recording. RESULTS: Over years, the denervated stomach recovers more and more motor activity, even displaying a real phase 3 motor pattern in 6 of the 10 WS patients and 1 of the 7 GT patients with >3 years of follow-up. Erythromycin lactobionate generates a phase 3-like motor pattern regardless of the length of follow-up. Extrinsic denervation of the whole stomach does not significantly modify the fasting motility index established >3 years after surgery (+17% on average, p > 0.05), but it reduces that in the fed period by an average of 62% (p = 0.0016). Tubulization of the denervated whole stomach lowers the fasting motility index by an average of 60% (p = 0.0248) and further impairs that in the fed period by an average of 67% (p = 0.0388). CONCLUSIONS: The denervated stomach as an esophageal substitute is a contractile organ that may even generate complete migrating motor complexes. Motor recovery is better in the fasting than in the fed period, and it is more marked in WS patients than in GT patients.
OBJECTIVE: Dipyridamole is a vasodilator that inhibits the cellular uptake of adenosine, which physiologically reduces the resistance to hepatic arterial flow inside the liver. This study aims at assessing the acute effect of dipyridamole on functional liver plasma flow (measured as the extrarenal sorbitol clearance) and on the Doppler US Congestion Index of the portal vein (the ratio between the cross-sectional area of this vein and the mean velocity of portal flow), which correlates with the severity of portal hypertension. METHODS: We have determined the extrarenal sorbitol clearance (14 cases) and the Congestion Index (seven cases) before and at 30, 60, and 90 min after the oral administration of 25 mg dipyridamole in patients with liver cirrhosis. We also measured the effect of dipyridamole on functional liver plasma flow in six healthy subjects. RESULTS: Dipyridamole increased the extrarenal sorbitol clearance in controls (+17%, p < 0.01) and in cirrhotic patients (+15%, p < 0.01). The drug decreased the portal Congestion Index in all patients, averaging -24% (p < 0.05) 90 min after its oral administration. CONCLUSIONS: This result was due both to a mean decrease of the portal sectional area and to a mean increase in portal flow velocity. In conclusion, these data suggest that dipyridamole should decrease the vascular resistance to portal flow in cirrhosis; this effect may be mediated by an adenosine-dependent vasodilation in the intrahepatic site or along the portosystemic collaterals.
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It is generally accepted that neoplastic transformation is related to genes alteration or oncogene activation. In particular, DNA minor groove binding drugs have been extensively studied through the years in order to influence the regulation of gene expression by means of specific interactions with DNA bases moieties. Pyrrolo[2,1-c],[1,4].benzodiazepines (PBDs), CC-1065 and distamycins are three classes of minor groove binders which showed interesting cytotoxicity profiles, refined through already reviewed processes of SAR studies. Among the modifications to the three families of antitumor compounds, heterocyclic substitutions have been extensively applied by many groups in order to either modify the reactivity profile or introduce extra interactions within the minor groove, thus changing the binding site or modulating the binding sequence. The updated material related to these modifications has been rationalised and ordered to offer an overview of the argument.
BACKGROUND: The surgical technique proposed by Caldwell and Luc more than a century ago has been applied in over a million cases to treat maxillary sinusitis. A critical re-evaluation of the method has been in progress for several years, in the light of the results that can be achieved with endoscopic functional surgery. METHODS: In a retrospective study, operations performed according to the Caldwell-Luc technique on 40 patients, mean age 45 years, between 1992 and 1996, were evaluated critically to determine the efficacy of this approach in treating maxillary sinusitis, with particular emphasis on the incidence of immediate or delayed complications. Initially, clinical and radiological data concerning each patient where considered with particular reference to the subjective and objective symptomatology, preoperative radiological diagnosis and etiology of the sinusitis. RESULTS: Having completed the analysis of the documentation available, some of the patients were recalled and subjected to an in-depth instrumental diagnosis through traditional and CT radiography. CONCLUSIONS: It was concluded that, in consideration of the marked incidence of complications, the Caldwell-Luc procedure may be defined as a non-obligatory therapeutic option even in chronic maxillary sinusitis. The use of this surgical procedure is rational in cases of antral tumour, trauma, very serious mycotic or septic factors, or when a surgical approach to the pterigo-maxillary fossa is necessary. In all other cases, the preferred treatment must now be endoscopy.
BACKGROUND: Investigative sinus endoscopy for purely diagnostic purposes has become an important therapeutic tool for disorders of the paranasal system thanks to the enormous technological developments of the last twenty years. METHODS: In a retrospective study, sinus endoscopies carried out between 1990 and 1994 on 57 patients, mean age 43 years, were subjected to critical re-evaluation, with the aim of evaluating the efficacy of endoscopic treatment. In the first phase, the documentation available for each patient was examined; it included clinical data, preoperative traditional and CT radiographs, rhinoscopic and sinus endoscopic findings. Once the analysis of the available documentation had been completed the patients were recalled and subjected to clinical and radiological evaluation. Radiographic examination was carried out by traditional radiography. RESULTS: CT scanning was only performed for those patients in whom the clinical findings indicated a possible relapse. Immediate and delayed complications occurring after the endoscopic sinus surgery were taken into consideration. CONCLUSIONS: In conclusion, sinus endoscopy is a fundamental instrumental investigation in the diagnosis of rhinosinusopathies. It can no longer be considered as only a diagnostic investigation able to provide clear visual images, it also allows specimens to be taken for bacteriological, micological, cytological and histological analysis. Furthermore, endoscopic surgery can treat pathologies for which, until a few years ago, operations were necessary which respected the physiology of the paranasal system to a much lesser extent (Denker-Caldwell-Luc).
Opinion is divided regarding the influence of iodized oil on MRI signal intensity of hepatic tumours treated with transcatheter arterial chemoembolization (TACE), in which lipiodol deposits. The aim of our study was to ascertain whether or not lipiodol directly influences the MRI signal intensity of hepatocellular carcinoma (HCC) treated by TACE and that of the surrounding liver. Thirteen patients with HCC were studied retrospectively. CT and MRI scans were performed both before and 3 months after TACE. The CT scan was performed to check whether embolized nodules contained lipiodol and how lipiodol was distributed within them. In addition, eight patients were examined prospectively within 7 days after TACE. In these patients a CT scan was performed to see how lipiodol was distributed in the neoplastic nodules and in normal hepatic parenchyma. In the first group of patients the contrast-to-noise (C/N) ratio on T1-weighted (T1W) images and the T2 relaxation time on T2-weighted (T2W) images were calculated for both neoplasm and surrounding liver. In the second group of patients we also measured the signal intensity of non-neoplastic liver that was either permeated or not permeated by lipiodol. The data were analysed with Wilcoxon's test. On T1W images we observed that the retention of lipiodol increased the C/N ratio in all the tumours studied within 1 week after TACE. In the patients studied 3 months after TACE the C/N ratio was not significantly increased. On T2W images lipiodol retention did not change tumour signal intensity. The iodized oil did not change the signal intensity of the liver surrounding the tumour, in comparison with the liver not permeated by lipiodol, on either T1W or T2W images. The results indicate that lipiodol does not modify the signal intensity in non-neoplastic hepatic parenchyma in which it is deposited; after 3 months it does not significantly affect the signal of the tumours that accumulated it. Lipiodol produces a high signal on T1W images over the first few days following TACE in those tumours in which it is deposited.
BACKGROUND: Esophagectomy with extensive lymph node dissection is the best way to give Barrett's patients with locally advanced adenocarcinoma a good chance of cure. MATERIAL AND METHODS: Fifty-five patients underwent subtotal (n = 47) or distal (n = 8) esophagectomy for Barrett's adenocarcinoma (n = 43) or high-grade dysplasia (HGD) (n = 12). Thirteen patients (23.6%) never had had any reflux symptom before disclosure of the neoplastic lesion, and 20 patients (36.4%) had esophageal shortening. Ro resections (n = 50) included removal of the esophageal tube en bloc with the locoregional lymph nodes. RESULTS: An invasive carcinoma was found in the resected specimen of 4 of the 12 patients operated on for HGD. Two of the 5 patients whose metaplasia was surveyed endoscopically were operated on for an advanced lesion (T2N1, T3N1) because they had not strictly complied with the proposed schedule. One of the 4 patients whose HGD was followed up endoscopically until disclosure of deeper mucosal invasion had positive lymph nodes at operation. The prevalence of early lesions (Tis, T1, T2, No) was 7.4% in patients with tumor-related symptoms versus 85.7% in those having unrelated symptoms (P = 0.0000), which resulted in a 5-year survival rate of 33.8% and 82.4%, respectively (P = 0.0012). Five-year survival rate after Ro resection made for invasive carcinoma was 59.3% (all cases), 73.1% (No), 61.5% (< or =5 positive lymph nodes), and 0% (>5 positive lymph nodes). CONCLUSIONS: High-grade dysplasia is an indication for esophageal resection. Early detection of the neoplastic transformation of Barrett's metaplasia prior to the onset of obstructive symptoms gives the best chance of cure. Esophagectomy with radical lymph node clearance is capable of curing a large proportion of the patients having no or a limited number of metastatic lymph nodes.
AIM AND METHODS: This prospective study was carried on 20 patients (10 with liver cirrhosis and 10 with myelo-lymphoproliferative disorders), consecutively admitted to our ward for splenomegaly and thrombocytopenia, with the aim of evaluating the ability of Duplex-Doppler ultrasonography (DDUS) to discriminate between congestive splenomegaly and enlarged spleen caused by haematological disorders. RESULTS: Comparing the clinical/laboratory and DDUS findings for the two groups, it emerged that maximum-portal flow velocity (PFV) values revealed the most statistically significant differences: 17.31 SD 2.48 vs. 28.27 SD 3.53 (cm/s, P < 0.001). Discriminant analysis showed that max-PFV is the variable which by itself maximizes the separation between the two groups (F = 71.56; P < 0.0001). The patients with congestive splenomegaly exhibited lower max-PFV than the controls (17.31 SD 2.48 vs. 26.29 SD 2.38 cm/s, P < 0.001), unlike those with haematological diseases, whose max-PFV values were greater, albeit not significantly so (28.27 SD 3.53 vs. 26.29 SD 2.38 cm/s, P = 0.161). CONCLUSIONS: DDUS assessment of portal haemodynamics thus proved useful in the differential diagnosis of splenomegaly in asymptomatic patients since it distinguishes rapidly and non-invasively between congestive and haemotological splenomegaly. A lower-than-normal max-PFV value indicates congestive splenomegaly; a highish value, on the other hand, suggests a splenomegaly of haematological origin.
PROBLEM: Type-I interferon (IFN) is the protein recognizing pregnancy in ruminants. Although IFN is secreted in early pregnancy, its role is not still clear in other species. Like other cytokines, IFN exerts its biological functions through specific membrane receptors. We have investigated the potential action of IFN in human pregnancy by studying the distribution of the receptors in the human placenta. METHOD: Reactivity to monoclonal antibodies (mAbs) to the type-I IFN-receptor (R) was analyzed by immunohistochemistry in human placental tissues and in cytospins of first trimester trophoblast cells. RESULTS: Type-I IFN-R immunoreactivity was observed mostly in first trimester villous cytotrophoblasts and in the cytotrophoblast cell columns. Trophoblast in the decidua, the epithelium of the uterine glands, and most of the isolated trophoblast cells were also immunoreactive. CONCLUSION: The expression of type-I IFN-R in the highly proliferating and migrating trophoblast suggests that this cytokine has a role in trophoblast growth and invasion.
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Two pyrazole analogs structurally related to the antitumor agents adozelesin and U-71,184 respectively were synthesized. By using a polymerase chain reaction approach, both compounds show selective binding to A + T rich sequences exactly as reference compound U-71,184. In in vitro assays, against L1210 cell lines, both derivatives showed cytotoxicity in the pM range, values comparable with the natural target compound (+)-CC-1065. The most active compound showed very high antitumor activity in mice implanted with L1210 cells (ILS% 363).
Three simplified pyrazole analogs (7-9) of the antitumor agents CC-1065, were synthesized. In in vitro assays, against L1210 cell lines all derivatives showed a cytotoxicity in a pM range, values close to the natural target compound (+)-CC-1065. In in vivo tests, against disseminate L1210 leukemia cells, synthesized compounds showed a good potency (O.D. 300 micrograms/Kg) but no activity. These observations further validate the effect of the hydrophilic and/or hydrophobic characteristics of the substituents present on the molecules, confirming the relevance of this phenomena on in vivo activity. In fact in this case the increase of hydrophobic characteristics of the molecules produce the loss of activity, probably due to a worse bioavailability of the drugs in animals.
The synthesis and the comparative preliminary biological evaluation of a new pyrazole analog (16) of the CC-1065 alkylating unit (CPI) are described. This new derivative showed low cytotoxicity against L1210 murine leukemia (IC50 3064 nM) with respect to reference compound, but contrarily to literature data, was found to be more stable to solvolysis than the natural derivative (+/-)-N-Boc-CPI (pH 3, t1/2 = 212 h vs. 37 h). The results of such investigation showed that alkylation of the pyrazole nitrogen caused a loss of cytotoxic activity in vitro against tumor cells. This experimental observation allowed us to confirm the importance of free N-H for the anticellular activity.