Use of the ROLL technique for lumpectomy in non-palpable breast lesions. / Utilidad de la técnica ROLL en la exéresis de lesiones no palpables de mama.

OBJECTIVE: To evaluate the efficiency of radioguided occult lesion localising in non-palpable breast lesions (NPBL) compared to the surgical wire technique. METHOD: A prospective study was conducted on 161 women with NPBL, of whom 80 marked with the wire (group 1), whereas 81 women were marked with an intratumour injection of 99mTc-nanocoloid (group 2). The NPBL were located by ultrasound or stereotactic guidance. The lumpectomies were performed following the wire direction in group 1, and with the aid of a gamma-probe in group 2. Surgical margins were then checked, determining the need of extension if the margin was less than 5mm in the intra-surgical study, and less than 2mm in the deferred study. Data were collected on the mean number detected by surgery, surgical margins, number of extensions, presence of residual tumour in the extension, second surgeries, lumpectomy volume, as well as total resected volume, volume/tumour ratio, and complications. RESULTS: No significant differences were observed between the two groups in the mean number detected, surgical margins, number of extensions, presence of residual tumour in the extension, second surgeries, lumpectomy volume, total resected volume, volume/tumour ratio or complications. The multivariate analysis showed the determining factors of the resected volume were the radiological guidance technique, as well as the surgeon. CONCLUSIONS: The radioguided occult lesion localising technique helps in the detection and resection of NPBL with the same efficiency as the surgical wire, and adds the possibility of sentinel node detection in the same surgery. The determining factors of the resected volume were the radiological guidance technique and the surgeon.

Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats.

BACKGROUND: In experimental models of glioblastoma multiforme (GBM), irradiation (IR) induces local expression of the chemokine CXCL12/SDF-1, which promotes tumour recurrence. The role of CXCR7, the high-affinity receptor for CXCL12, in the tumour's response to IR has not been addressed. METHODS: We tested CXCR7 inhibitors for their effects on tumour growth and/or animal survival post IR in three rodent GBM models. We used immunohistochemistry to determine where CXCR7 protein is expressed in the tumours and in human GBM samples. We used neurosphere formation assays with human GBM xenografts to determine whether CXCR7 is required for cancer stem cell (CSC) activity in vitro. RESULTS: CXCR7 was detected on tumour cells and/or tumour-associated vasculature in the rodent models and in human GBM. In human GBM, CXCR7 expression increased with glioma grade and was spatially associated with CXCL12 and CXCL11/I-TAC. In the rodent GBM models, pharmacological inhibition of CXCR7 post IR caused tumour regression, blocked tumour recurrence, and/or substantially prolonged survival. CXCR7 expression levels on human GBM xenograft cells correlated with neurosphere-forming activity, and a CXCR7 inhibitor blocked sphere formation by sorted CSCs. CONCLUSIONS: These results indicate that CXCR7 inhibitors could block GBM tumour recurrence after IR, perhaps by interfering with CSCs.

Outcome and toxicity using helical tomotherapy for craniospinal irradiation in pediatric medulloblastoma.

PURPOSE: The objective of this study is to evaluate the tolerability and outcome of craniospinal irradiation (CSI) with helical tomotherapy (HT) in the treatment of medulloblastoma. METHODS: We evaluated 19 consecutive patients with primary medulloblastoma who were treated with HT from 2007 through 2010. HT regimens to the neuroaxis included: 23.4 Gy at 1.8 Gy/fraction (N = 10), 36 Gy at 1.8 Gy/fraction (N = 7), and 39 Gy bid at 1.3 Gy/fraction (N = 2). The tumor bed received 54-60 Gy. Potential associations between patient, treatment, and toxicity factors and overall survival (OS) were assessed in univariate analyses using the Cox proportional hazards model. Spearman's rank correlation coefficient was used to correlate potential risk factors with the grade of acute toxicity. RESULTS: The median age at diagnosis was 5 years (range 2-14) and the median follow-up for alive patients (N = 14) 40 months (range 10-62). Two- and three-year overall survival was 75 and 68 %, respectively. The most common acute toxicity was hematological (79 %), being grade 2 and grade 3 in 4 (21 %) and 11 (58 %) cases, respectively. No grade ≥2 late toxicities were observed. Higher grades of acute body toxicity were found in older children (P = 0.004). Longer time between diagnosis and radiation therapy was correlated with shorter OS (P = 0.03). In addition, higher grades of acute thrombocytopenia were associated with shorter OS (P = 0.03). CONCLUSIONS: CSI delivered with HT for medulloblastoma is well tolerated with low rates of severe acute toxicity. Further research is necessary to assess late toxicity with a longer follow-up.

Risk factors for local and regional recurrence in patients with resected N0-N1 non-small-cell lung cancer, with implications for patient selection for adjuvant radiation therapy.

BACKGROUND: The purpose of this study was to evaluate the actuarial risk of local and regional failure in patients with completely resected non-small-cell lung cancer (NSCLC), and to assess surgical and pathological factors affecting this risk. PATIENTS AND METHODS: Between January 1998 and December 2009, 1402 consecutive stage I-III (N0-N1) NSCLC patients underwent complete resection without adjuvant radiation therapy. The median follow-up was 42 months. RESULTS: Local-regional recurrence was identified in 9% of patients, with local failure alone in 3% of patients, regional failure alone in 4% of patients, and both local and regional failure simultaneously in 2% of patients. Patients who had local failure were found to be at increased risk of mortality. By multivariate analyses, three variables were shown to be independently significant risk factors for local [surgical procedure (single/multiple wedges+segmentectomy versus lobectomy+bilobectomy+pneumonectomy), tumor size>2.7 cm, and visceral pleural invasion] and regional (pathologic N1 stage, visceral pleural invasion, and lymphovascular space invasion, LVI) recurrence, respectively. CONCLUSION: Patients with N0-N1 disease have low rates of locoregional recurrence after surgical resection. However, several prognostic factors can be identified that increase this risk and identify patients who may benefit from adjuvant treatment.

Stereotactic ablative radiotherapy delivered by image-guided helical tomotherapy for extracranial oligometastases.

PURPOSE: To investigate the outcomes and risk factors of patients treated with stereotactic ablative radiotherapy (SABR) delivered by image-guided helical tomotherapy (HT) for extracranial oligometastases. METHODS: From August 2006 through July 2011, 42 consecutive patients (median age 69 years [range 16-87]) with oligometastases (≤3) received HT to all known cancer sites (lung, n = 28; liver, n = 12; adrenal, n = 2). Prognostic factors were assessed by Cox's proportional hazards regression analysis. RESULTS: A total of 60 lesions were treated with hypofractionated HT (median dose 39 Gy [range 36-72.5]; median dose per fraction 12 Gy [range 5-20]). Complete or partial response was observed in 40 (54 %) patients. With a median follow-up period of 15 months, 1- and 2-year overall survival (OS) was 84 and 63 %, respectively; and 1- and 2-year local control (LC) was 92 and 86 %, respectively. Four patients had pneumonitis Grade ≥2 and two patients had lower gastrointestinal toxicity Grade ≥2. Only the lack of complete/partial response was associated with higher risk of mortality on univariate (HR = 3.8, P = 0.04) and multivariate (HR = 6.6, P = 0.01) analyses. CONCLUSIONS: SABR delivered by image-guided HT is well tolerated and offers adequate LC with low acute morbidity in patients with extracranial oligometastatic disease. We found that the response to HT was the only predictor for OS.

Discovery of a novel series of inhibitors of human cytomegalovirus primase.

Infection by human cytomegalovirus (hCMV) remains a potent threat to susceptible people throughout the world. We have discovered a series of imidazolyl-pyrimidine compounds, which were found to be irreversible inhibitors of the hCMV UL70 primase based on results from radiolabeling and SAR studies. Two promising analogs are described that rival ganciclovir and cidofovir in antiviral potency and possess improved cytotoxicity profiles.

Hydrophilic, pro-drug analogues of T138067 are efficacious in controlling tumor growth in vivo and show a decreased ability to cross the blood brain barrier.

The novel anticancer compound T138067 is an irreversible inhibitor of tubulin polymerization. Amides 3-6 were synthesized using standard methodologies and determined to be significantly less lipophilic than T138067 based on logP calculations. Tubulin polymerization and [(3)H]-T138067 competition assays revealed that these amides are pro-drugs for parent aniline 2. Amides 3-5 showed no detectable signs of crossing the blood brain barrier, while amide 6 was found in extremely small amounts (12 ng/g of brain tissue). Aniline 2, which was formed in vivo from these amides, was found in significantly smaller amounts (approximately 20 to >5000 times) in the brain than when 2 was administered directly. The in vivo efficacy of amide 6 approached that of T138067 and was better tolerated when administered to athymic nude mice bearing MX-1 human mammary tumor xenografts.

[Extracranial meningioma presenting as a polyp of the outer ear canal]. / Meningioma extracraneal que se manifiesta como pólipo de conducto auditivo externo.

Meningiomas are the most frequent benign intracranial tumor. Up to 20% of these neoplasms may eventually extend beyond the skull, particularly when tumor spread affects the temporal bone. We report a clinicopathological observation of an extracranial meningothelial meningioma that was diagnosed morphologically using immunohistochemical techniques. The tumor presented as polyp in the ear canal of a 70-year-old woman who had a history of ear disease and seizures and was under medical treatment. The growth was associated with a right temporal lobe tumor involving the petrosal bone that had been detected 6 years earlier on computed axial tomography.

Novel halogenated sulfonamides inhibit the growth of multidrug resistant MCF-7/ADR cancer cells.

In this report, we describe the synthesis of halogenated benzenesulfonamide compounds and their ability to inhibit the growth of HeLa, MCF-7 and MCF-7/ADR tumor cells in vitro. The multidrug resistance (MDR) phenotype of certain cells does not affect their sensitivity to these compounds. These agents belong to a family of compounds previously shown to bind irreversibly to cysteine-239 of beta-tubulin. Consistent with this mechanism of action, the cytotoxicities of these compounds appear to correlate with their ability to undergo nucleophilic aromatic substitution.

Selective, covalent modification of beta-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors.

Microtubules are linear polymers of alpha- and beta-tubulin heterodimers and are the major constituents of mitotic spindles, which are essential for the separation of chromosomes during mitosis. Here we describe a synthetic compound, 2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene (T138067), which covalently and selectively modifies the beta1, beta2, and beta4 isotypes of beta-tubulin at a conserved cysteine residue, thereby disrupting microtubule polymerization. Cells exposed to T138067 become altered in shape, indicating a collapse of the cytoskeleton, and show an increase in chromosomal ploidy. Subsequently, these cells undergo apoptosis. Furthermore, T138067 exhibits cytotoxicity against tumor cell lines that exhibit substantial resistance to vinblastine, paclitaxel, doxorubicin, and actinomycin D. T138067 is also equally efficacious in inhibiting the growth of sensitive and multidrug-resistant human tumor xenografts in athymic nude mice. These observations suggest that T138067 may be clinically useful for the treatment of multidrug-resistant tumors.

Papillary thyroid carcinoma arising in the wall of a thyroglossal duct cyst.

The thyroglossal duct cyst is the most common anomaly in thyroid development. However, carcinomas arising in a thyroglossal duct cyst are rare entities. To date, approximately 125 cases have been reported, the majority being papillary thyroid carcinomas. In most cases the diagnosis is established only after excision of a clinically benign thyroglossal duct cyst. The etiology of such tumors remains unclear but de novo origin is generally proposed. Controversies exist in relation to a rational and effective therapeutic approach. A further case of thyroglossal duct papillary carcinoma affecting a 55 year-old Spanish man is presented to highlight the clinicopathological features of this condition. Preoperative computed tomography performed on our patient showed irregular calcium deposits adjacent to the hyoid bone. Cytohistological and immunohistochemical studies showed a papillary thyroid carcinoma with abundant psammoma bodies. Surgery consisted only of a Sistrunk procedure. In view of the prolonged course of papillary carcinoma, long-term follow-up is mandatory.

Novel antineoplastic agents with efficacy against multidrug resistant tumor cells.

A novel series of pentafluorobenzenesulfonamides has been shown to inhibit the growth of a variety of human tumor cell lines. Among the cell types against which these agents were evaluated were the multidrug resistant (MDR) cell lines MCF-7/ADR and P388/ADR. The cytotoxic activity of members of this series of compounds was not affected by the multidrug resistant pump in MCF-7/ADR or P388/ADR cells.

Kynurenic acid derivatives inhibit the binding of nerve growth factor (NGF) to the low-affinity p75 NGF receptor.

The ability of a series of substituted kynurenic acids, thienopyridinonecarboxylic acids, and related compounds to inhibit the binding of nerve growth factor (NGF) to the p75 NGF receptor (NGFR) was evaluated in a radioligand binding assay that utilized a biotinylated derivative of the extracellular domain of p75 NGFR (p75ext) fixed to streptavidin-coated plastic wells. Two compounds, 6-aminokynurenic acid (5h) and the 3-methyl ester of 4,7-dihydro-2-methyl-7-oxothieno[3,2-b]pyridine-3,5-dicarboxylic acid (16), were found to inhibit the binding of [125I]NGF to p75ext with IC50 values in the low micromolar range. Other amino-substituted kynurenic acids also possessed activity at slightly higher concentrations. Several structural features seem to be essential, including the carboxylic acid, a polar group on the benzene ring (or thiophene ring, in the case of analogues of 16), and the C-4 carbonyl group in the pyridinone ring. These compounds were also found to inhibit the binding of [125I]NGF to its receptors in membranes from PC12 cells (which express p75 as well as trka receptors for NGF) and DG44-CHO cells (transfected with full length p75 NGFR). The available data for 5h and 16 do not allow the determination of whether the effects of these compounds are mediated by their interaction with NGF or the NGF receptors.

Cholinergic therapies for Alzheimer's disease. Palliative or disease altering?

Loss of cholinergic function in the neocortex and hippocampus arising from death or atrophy of basal forebrain cholinergic neurons is a consistent feature of the Alzheimer brain at autopsy or biopsy. Replacement of lost cholinergic function, therefore, may be of therapeutic benefit to the Alzheimer's (AD) patients. This can be accomplished by enhancing endogenous levels of acetylcholine (ACh) through inhibition of its degradation by acetylcholinesterase on by directly mimicking its actions at postsynaptic muscarinic receptors. Initial efforts focused on inhibition of cholinesterase activity with tacrine (1,2,3,4-tetrahydroaminoacridine monochloride, CAS 1684-40-8, THA, Cognex). Tacrine is a mixed, reversible inhibitor of cholinesterase activity that binds near but not to the catalytically active serine in the active site of the enzyme. Through this action tacrine indirectly elevates ACh levels in the brains of animals and improves cognitive performance in rodents and monkeys. More importantly, tacrine has been shown to significantly improve several measures of cognitive performance in probable AD patients in well-controlled clinical trials, although not all patients respond to this agent. CI-979 ((E)-1,2,5,6-tetrahydro-1-methyl-3-pyridine-carboxyaldehyde-O-meth yl oxime, CAS 139886-04-7) is a non-subtype selective, partial muscarinic agonist that enhances cognitive performance and increases central cholinergic activity in rodents at doses below those required to increase peripheral cholinergic tone. In normal healthy volunteers, CI-979 is well tolerated at single and multiple doses (q 6 h) up to 1.0 mg. In normal healthy volunteers, CI-979 is well tolerated at single and multiple doses (q 6 h) up to 1.0 mg. Expected signs of mild to moderate peripheral cholinergic stimulation were noted at 0.5 to 1.0 mg doses (q 6 h).(ABSTRACT TRUNCATED AT 250 WORDS)

The discovery and structure-activity relationships of 1,2,3,6-tetrahydro-4-phenyl-1-[(arylcyclohexenyl)alkyl]pyridines. Dopamine autoreceptor agonists and potential antipsychotic agents.

A novel dopamine (DA) autoreceptor agonist, 1,2,3,6-tetrahydro-4-phenyl-1- [(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine (14), was identified. The structure-activity relationships surrounding this compound were studied by synthesis of analogues and evaluation of their dopaminergic activity. The cyclohexene substitution pattern was varied along with the length of the chain connecting the 1,2,3,6-tetrahydro-4-phenylpyridine to the cyclohexene. Compound 14, having the 1,3-substitution pattern and a single methylene chain, was the most potent. The 1,2,3,6-tetrahydro-4-phenylpyridine could be replaced by other aryl-cyclic amines with a slight loss in activity. The phenyl group on the cyclohexene ring could be para substituted; electron-donating groups were better tolerated than electron-withdrawing groups. Finally, the enantiomers of 14 were resolved via the 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate salts. Although both isomers were partial DA agonists, the (+)-enantiomer had higher intrinsic activity than the (-)-enantiomer. Syntheses were developed that allowed rapid preparation of analogues. An X-ray crystal structure determination of an intermediate identified the (+)-isomer of 14 as having R configuration. This compound, designated CI-1007 (PD 143188), was found to have antipsychotic-like activity in behavioral tests; in particular, it was orally active in the conditioned avoidance test in squirrel monkeys with an ED50 of 0.6 mg/kg. The overall profile suggests that (R)-(+)-14 may be a clinically useful antipsychotic agent.

Characterization of muscarinic agonists in recombinant cell lines.

Using recombinant CHO cells that express Hm1-Hm5 receptors, reference muscarinic agonists have been characterized with respect to their activity in receptor binding and second messenger assays. In whole cell [3H]-N-methyl scopolamine binding, no agonist was found to be truly subtype selective, although some showed marked differences between several of the subtypes (e.g. m1 vs. m2). As a functional index of receptor activation, phosphatidyl-inositol (PI) turnover was measured for m1, m3, and m5 receptors while inhibition of forskolin-stimulated cAMP accumulation was measured for m2 and m4 receptors. Both full and partial agonists were delineated in PI turnover, but all agonists showed similar responses on cAMP. Alkylation studies with propylbenzylcholine mustard showed that both efficacy and potency were markedly affected in the functional assays by the number of free receptors. Thus, receptor reserve appears to play a major role in the determination of subtype selectivity for agonists using functional measures. Even with these limitations, however, the use of transformed cell lines is playing a pivotal role in the discovery of selective agonists.

ProMACE-C-MOPP in aggressive non-Hodgkin's lymphoma. Long-term results in 45 patients treated in a single institution.

Forty-five previously untreated patients with intermediate or high-grade non-Hodgkin's lymphoma were treated with the Pro-MACE-C-MOPP regimen (flexitherapy). The median age of the patients was 51 years, 51% had constitutional symptoms, 78% were in Ann Arbor stage III-IV, 40% had two or more involved extranodal sites and 87% had serum lactate dehydrogenase (LDH) above 225 U/l. Twenty-two (49%) patients had immunoblastic lymphoma (Working Formulation). Overall, 40% of the patients attained complete response (CR) and there were no relapses. The dose-limiting toxicity was myelosuppression (69% of the patients with WBC less than 1.9 x 10(9)/l). Three deaths were attributed primarily to chemotherapy, but another two patients died of long-term complications of therapy. After a median follow-up of 50 months (18-80), 15 patients (33%) were alive without lymphoma. Only histologic subtype (intermediate vs. high) and abdominal involvement were prognostic factors for CR rate. Our results indicate that ProMACE-C-MOPP is an effective regimen for intermediate-grade lymphomas. However, in high-risk patients the regimen seems to be less effective than originally reported.

Dopamine autoreceptor agonists as potential antipsychotics. 2. (Aminoalkoxy)-4H-1-benzopyran-4-ones.

The synthesis and pharmacological properties of a novel type of [(arylpiperazinyl)alkoxy]-4H-1-benzopyran-4-ones with dopaminergic activity are described. The nature of the arylpiperazine (AP) moiety determines the dopamine (DA) agonist/antagonist character of this series of compounds; when the aryl portion of the AP is unsubstituted the compounds appear to be DA autoreceptor agonists while substituted aryl groups seem to impart DA antagonist activity. A heterocyclic piperazine, 7-[3-[4-(2-pyridinyl)-1-piperazinyl]propoxy]-4H-1-benzopyran-4-one (31, PD 119819) has been identified as an extremely selective DA autoreceptor agonist in tests that include [3H]haloperidol binding, inhibition of spontaneous locomotor activity, inhibition of brain DA synthesis, inhibition of brain DA neuronal firing, stereotypy assessment, and reversal of 6-hydroxydopamine (6-OHDA) induced akinesia in rats. In addition, 31 possesses good oral activity in the Sidman avoidance test in squirrel monkeys, a predictor of clinical antipsychotic efficacy. In another primate model, 31 has been found to lack the liability for extrapyramidal side effects observed with currently available antipsychotic drugs.

Synthesis and dopamine agonist properties of (+-)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano [4,3-b]-1,4-oxazin-9-ol and its enantiomers.

The dopamine agonist profile of (+-)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano [4,3-b]-1,4-oxazin-9-ol (16a) and its enantiomers (16b-c) was examined. Racemic 16a exhibited moderate affinity for the dopamine (DA) D2 receptor labeled with the DA antagonist ligand [3H]haloperidol and moderate in vivo activity; it attenuated gamma-butyrolactone-stimulated DA synthesis, decreased DA neuronal firing of substantia nigra DA neurons, and inhibited exploratory locomotor activity in rats, a profile consistent with a DA autoreceptor agonist mechanism of action. The (+)-enantiomer 16b possessed greater DA receptor affinity with the agonist ligand [3H]-N-propylnorapomorphine than with the antagonist ligand. In rats it potently inhibited DA synthesis and neuronal firing and also inhibited exploratory locomotion. The (-)-enantiomer, on the other hand, did not have significant activity in any of these tests. This profile indicates that like many other rigid DA agonists, the dopaminergic activity resides in one enantiomer, in this case the (+)-enantiomer 16b. On the basis of single-crystal X-ray analysis of a key intermediate, the absolute configuration of 16b was found to be 4aR, 10bR.