Role of vacuum assisted excision in minimising overtreatment of ductal atypias.

PURPOSE: B3 lesions are indeterminate lesions of uncertain malignant potential. They include lesions with and without epithelial atypia. Those with atypia include atypical intraductal epithelial proliferation (AIDEP)/atypical ductal hyperplasia (ADH) and flat epithelial atypia (FEA). They are traditionally managed with surgery. Vacuum assisted excision (VAE) allows larger samples to be obtained using a vacuum assisted biopsy (VAB) device, which equates to a surgical biopsy. We propose that VAE and mammographic surveillance is a safe alternative to surgery in managing the ductal atypias; (AIDEP/ADH and FEA). METHOD: Retrospective analysis of prospectively collected data on B3 lesions (April 2009 - March 2016) from consecutive breast screening patients diagnosed with AIDEP/ADH or FEA on initial diagnostic core biopsy. Mammographic abnormality, breast density, size, management pathway and upgrade to cancer and types of cancer were also collected during the treatment pathway and 5 year surveillance period (April 2009 - April 2019). RESULTS: 273 cases of ductal atypia were identified. 187/273 (68.5 %) cases were managed with VAE only as no upgrade to malignancy and then 5 year mammographic surveillance. 34/273 (12.5 %) cases had a VAE diagnosing malignancy. 24/273 (8.8 %) cases had a VAE and then a surgical biopsy due to radiological or pathological concern, 8/24 upgraded to malignancy. 22/273 (8%) cases had a surgical diagnostic biopsy, 9/22 (41 %) cases were upgraded to malignancy. In total 51/273 (19 %) cases were diagnosed with cancer on the new pathway (13 invasive (all ER positive and Her2 negative) and 38 non-invasive, (34 ductal carcinoma in situ (DCIS) and 4 cases of lobular carcinoma in situ (LCIS)). While 17/273 (6.2 %) cases developed malignancy (12 invasive (all HER2 negative) and 4 DCIS and 1 LCIS) during the 5 year surveillance period. CONCLUSIONS: VAE is a safe alternative to surgery in managing ductal atypias. 187/273 (68.5 %) women avoided surgery. While 34/51 cancers (66.7 %) were diagnosed preoperatively using VAE, allowing the women to have a single therapeutic procedure.

Outcome of a new patient pathway for managing B3 breast lesions by vacuum-assisted biopsy: time to change current UK practice?

AIMS: B3 lesions of the breast represent a difficult management dilemma. The umbrella term 'B3' incorporates lesions with little associated malignancy risk as well as lesions with significant risk of concurrent neoplasia. Diagnosis of B3 lesions in screening populations is largely made on needle core biopsy, which provides little tissue to adequately diagnose pathologically diverse lesions. The advent of vacuum-assisted biopsy (VAB) provides the multidisciplinary team with a more representative pathology sample to direct management. METHODS: In this unit, in 2009, a pathway to guide management of B3 lesions detected on needle core biopsy in screening patients was implemented to assess whether VAB was a safe and viable alternative to surgery in selected cases.Here we present the 5-year follow-up results of this pathway. RESULTS: 398 patients with B3 lesions were suitable for this pathway, of which 321 went on to have second-line VAB. 24% of these patients subsequently required surgery for malignancy or ongoing concerns, and thus 245 avoided surgery being subsequently referred for 5-year mammographic surveillance or back to screening. Median follow-up was 3 years (IQR 2), and no cancers were detected at the original B3 site during follow-up. CONCLUSIONS: We have demonstrated here that with large volume tissue sampling for indeterminate lesions of the breast surgery can be safely avoided in selected B3 lesions with and without atypia.

Concordance between vacuum assisted biopsy and postoperative histology: implications for the proposed Low Risk DCIS Trial (LORIS).

AIM: The recent Breast Cancer Screening Review has estimated that for one life saved three patients are overtreated. The dramatic increase in the diagnosis of Ductal carcinoma in-situ (DCIS) has not lead to the expected decrease in the incidence of invasive cancer. It is not clear if all DCIS progress to invasive cancer if untreated. The Low Risk DCIS Trial (LORIS) intends to compare the current treatment of low risk DCIS i.e. surgery, with active monitoring. For effective implementation, concordance between diagnostic biopsy using large volume vacuum assisted biopsy (VAB) and excision histology is vital. A two-centre UK audit was done to assess concordance in patients diagnosed with low grade DCIS diagnosed using VAB. METHODS: Data of DCIS diagnosed with VAB from year 2001-2010 in University Hospital Birmingham and Leeds Teaching Hospitals was retrospectively collected and concordance between diagnostic and excision histology was assessed. Low Grade DCIS diagnoses were further evaluated retrospectively with regard to their eligibility for LORIS. RESULTS: Of 225 DCIS diagnoses 128 (57%) were high grade, 66 (29%) intermediate grade and 31 (14%) low grade. Overall 18% were upgraded to invasive cancer. The upgrade rate to invasive cancer for high grade was 23% and for low grade DCIS was 10%. In the low grade group eligible for LORIS, there were no upgrades to invasive cancer. CONCLUSION: The upgrade rates to invasive cancer are comparable to series published in literature. The concordance for the low risk DCIS with zero upgrade to invasive cancer supports the stringent LORIS eligibility criteria for trial selection.

Reduction of digital plantar pressure by debridement and silicone orthosis.

The lesser digits are frequent sites of elevated plantar pressure and ulceration in the diabetic foot. We sought to determine whether debridement of callus and the wearing of a custom molded digital orthosis could significantly reduce digital plantar pressure. Fourteen patients with distal digital callus were studied. For each patient, the toe with the highest plantar pressure was selected. A computerized pressure mat was used to record the plantar pressure before and after debridement with and without a moldable silicone digital orthosis. Mean peak plantar digital pressures before treatment were 2.80+/-0.7 kg/cm2 for the entire group. The digital orthosis alone reduced plantar pressure to a mean of 1.95+/-0.65 kg/cm2 p < 0.05. Treatment by debridement similarly reduced pressure to 1.99+/-0.76 kg/cm2 p < 0.05. The most effective reduction of pressure for all patients, as well as the most statistically significant, occurred when both treatments were given, with mean peak plantar pressure falling to 1.28+/-0.61 kg/cm2 p < 0.01. Debridement and custom molded digital orthoses alleviate distal digital plantar pressure. Since elevated plantar pressure increases the risk of neuropathic ulceration, these treatments should be considered in the prophylactic care of appropriate patients.

Swab cultures accurately identify bacterial pathogens in diabetic foot wounds not involving bone.

AIMS: Current clinical practice assumes swab cultures from wounds are unreliable. However, this assumption is based upon data culled only from wounds in which osteomyelitis and/or gangrene were present. This study aimed to re-evaluate the accuracy of swab cultures vs. deep tissue cultures in diabetic wounds of varying depth and severity. METHODS: A total of 60 infected diabetic foot wounds were cultured. Two specimens were taken from each wound: superficial swab before debridement and deep tissue specimen towards the end of surgical debridement. RESULTS: In 37 wounds (62%), the micro-organisms isolated from the swab specimen and those isolated from the deep tissue specimen were identical. In another 12 wounds (20%), the swab culture contained all micro-organisms isolated from the deep tissue culture, but also contained additional micro-organisms. Analysis according to the depth of the wound, demonstrated that swabs identified all micro-organisms isolated from the deep tissue specimens in 36/40 wounds (90%) that did not extend to bone as opposed to 13/20 wounds (65%) that extended to bone. CONCLUSIONS: Swab cultures are valuable in identifying pathogens in diabetic foot wounds when bone is not involved. When surgical debridement is contraindicated or delayed, swab cultures can be used to select appropriate antibiotic therapy.

Design and synthesis of a series of combined vasodilator/beta-adrenoceptor antagonists based on 6-arylpyridazinones.

A series of new 6-[4-[[(aryloxy)acyl]amino]phenyl]-4,5-dihydropyridazinones have been synthesized and evaluated as combined vasodilator/beta-adrenoceptor antagonists and potential antihypertensive agents. Many of the early compounds displayed an unacceptably high level of intrinsic sympathomimetic activity (ISA) and a relatively short duration of action. Disubstitution in the 2,3-positions or in the 4-position of the aryloxy ring gave compounds with low ISA levels and, in some instances, improved duration of action. All of the compounds were vasodilators, but the 5-methylpyridazinone derivatives showed consistently greater antihypertensive activity than their 5-H lower homologues. Further detailed pharmacological investigations led to the selection of 6-[4-[3-[[2-hydroxy-3-[4-[2- (cyclopropylmethoxy)ethyl]phenoxy]propyl]amino]propionamido] phenyl]- 5-methyl-4,5-dihydro-3(2H)-pyridazinone (4t) (SK&F 95018) as a development candidate.

Synthesis and biological activity of the four stereoisomers of 6-[4-[3-[[2-hydroxy-3-[4-[2- (cyclopropylmethoxy)ethyl]phenoxy]propyl]amino]-propionamido] phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, a combined vasodilator and beta-adrenoceptor antagonist.

6-[4-[3-[[2-Hydroxy-3-[4-[2- (cyclopropylmethoxy)ethyl]phenoxy]propyl]amino]propionamido] phenyl]- 5-methyl-4,5-dihydro-3(2H)-pyridazinone (3) consists of a mixture of four stereoisomers, i.e., two racemates, as a consequence of the two asymmetric centers contained in the structure. An approximately equimolar mixture of these two racemates exhibits a novel combination of vasodilation and beta-adrenergic antagonist activity. This paper describes the synthesis of each of the four possible stereoisomers of 3 and provides clear evidence for the different pharmacological profile of each of the stereoisomers. The RA,SB isomer 3a has an overall profile slightly better than the complete mixture; the other three isomers all show reduced activity as vasodilators and/or beta-adrenergic antagonists.

SK & F 95018, a vasodilator/beta-adrenoceptor antagonist.

The pharmacological properties of a novel vasodilator/beta-adrenoceptor antagonist, SK & F 95018 6-[4-[3-(3-[4-(2-Cyclopropylmethoxyethyl)phenoxy]-2- hydroxypropylamino)propionamido]phenyl]-4,5-dihydro-5-met hylpyridazin- 3(2H)-one methanesulphonate] are described. SK & F 95018 lowered blood pressure and increased hindquarters blood flow in anaesthetised rats over the same dose range 1-5 mumol kg-1. Over a similar dose range SK & F 95018 inhibited isoprenaline-induced tachycardia in ganglion-blocked, anaesthetized cats. SK & F 95018 had minimal effect on bronchial beta 2-adrenoceptors, while simultaneously antagonizing cardiac beta 1-adrenoceptors in anaesthetized guinea-pigs. SK & F 95018 was demonstrated to be a potent antihypertensive agent in conscious spontaneously hypertensive rats over the dose range of 1.6-13 mumol kg-1 i.v. and 13-103 mumol kg-1 p.o. A marked and persistent hypotension was observed in conscious cats at a dose of 7.5 mumol kg-1 i.v. and 19 mumol kg-1 p.o., without reflex tachycardia. In anaesthetized cats, the hypotensive response to the compound was found to be via a reduction in total peripheral resistance with a maintained cardiac output. Vasodilatation and beta-adrenoceptor antagonism have been demonstrated in the same molecule (SK & F 95018) in a combination which would be suitable for effective treatment of hypertension.

Metal binding by pharmaceuticals. Part 4. A comparative investigation of the interaction of metal ions with hydralazine, prizidilol and related compounds.

The metal complexing properties of two antihypertensive drugs, hydralazine (1-hydrazinophthalazine) and prizidilol (a hydrazinopyridazine), and some related ligands, have been studied using potentiometry, elemental analysis, spectrophotometry and computer simulation. The coordination chemistry of 1-hydrazinophthalazine and the hydrazinopyridazines is similar in that Ca(II), Mg(II), and Mn(II) complexes are not formed, whereas Zn(II), Cu(II) and Fe(II)/Fe(III) complexes are produced. Both kinds of ligand react with Fe(II) to form a brightly coloured tetrazene complex which is insoluble for hydralazine but soluble for prizidilol. Computer simulation studies indicate that the most prevalent metal complex of prizidilol in blood plasma is [Fe2+(Priz-)H+]2+ but that this only forms at very high drug concentrations. It is concluded that prizidilol is unlikely to have any direct effects on the metabolism or distribution of the trace elements listed here.

SK&F 92657, a novel antihypertensive acting by precapillary vasodilatation and beta-adrenoreceptor blockade.

1. The properties of a new antihypertensive agent, SK&F 92657, DL-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine, have been studied. 2. The compound caused a sustained fall in blood pressure in several species as a result of precapillary vasodilatation, particularly in the renal and coronary vasculatures. 3. The beta-adrenoreceptor-blocking actions of SK&F 92657 prevent reflex cadiac stimulation.

Potential histamine H2-receptor antagonists. 3. Methylhistamines.

Syntheses are described for all the mono- and some di- and trimethylhistamines. New methods are given for the known Npi, Ntau-, Nalpha-, 2-, and 4-methylhistamines and for the novel compounds, beta-methyl-, 4,Nalpha-dimethyl-, and 4,Nalpha,Nalpha-trimethylhistamines. Agonist activities are reported for stimulation of histamine H1 (guinea-pig ileum) and H2 (rat gastric acid secretion) receptors. H2-Receptor agonist activities indicate that a methyl group is more readily accommodated at the 4 and Nalpha positions than elsewhere in the histamine molecule and that receptor binding is substantially retained with a methyl substituent in these positions. Thus, for the design of potential antagonists, two sites are identified as being worthwhile exploring for the introduction of lipophilic substituents.