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Dried blood spots (DBSs) biomarkers are convenient for monitoring for specific lysosomal storage diseases (LSDs), but they could have relevance for other LSDs. To determine the specificity and utility of glycosphingolipidoses biomarkers against other LSDs, we applied a multiplexed lipid liquid chromatography tandem mass spectrometry assay to a DBS cohort of healthy controls (n = 10) and Gaucher (n = 4), Fabry (n = 10), Pompe (n = 2), mucopolysaccharidosis types I–VI (n = 52), and Niemann–Pick disease type C (NPC) (n = 5) patients. We observed no complete disease specificity for any of the markers tested. However, comparison among the different LSDs highlighted new applications and perspectives of the existing biomarkers. We observed elevations in glucosylceramide isoforms in the NPC and Gaucher patients relative to the controls. In NPC, there was a greater proportion of C24 isoforms, giving a specificity of 96–97% for NPC, higher than 92% for the NPC biomarker N-palmitoyl-O-phosphocholineserine ratio to lyso-sphingomyelin. We also observed significantly elevated levels of lyso-dihexosylceramide in Gaucher and Fabry disease as well as elevated lyso-globotriaosylceramide (Lyso-Gb3) in Gaucher disease and the neuronopathic forms of Mucopolysaccharidoses. In conclusion, DBS glucosylceramide isoform profiling has increased the specificity for the detection of NPC, thereby improving diagnostic accuracy. Low levels of lyso-lipids can be observed in other LSDs, which may have implications in their disease pathogenesis.

IntroductionArgininosuccinate lyase is integral to the urea cycle, which enables nitrogen waste and biosynthesis of arginine, a precursor of nitric oxide. Inherited argininosuccinate lyase deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy and movement disorder. Here we aim to characterise epilepsy, a common and neurodebilitating complication in argininosuccinic aciduria.Patients and MethodsWe conducted a retrospective study in seven tertiary metabolic centres in the UK, Italy and Canada from 2020 to 2022 to assess the phenotype of epilepsy in ASA and correlate it with clinical, biochemical, radiological and electroencephalographic data.ResultsThirty-seven patients aged 1 to 31 years old were included. Twenty-two (60%) patients presented epilepsy. Median age at epilepsy-onset was 24 months. Generalized tonic clonic and focal seizures were most common in early-onset patients whilst atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and 6 (27%) had partially controlled or refractory epilepsy. Epileptic patients presented with a severe neurodebilitating disease with higher rates of speech delay (p=0.04) and autism spectrum disorders (p=0.01) and more frequent arginine supplementation (p=0.01) compared to non-epileptic patients. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy-onset in early infancy (p=0.05) and electroencephalographic background asymmetry (p=0.0007) were significant predictors of partially controlled or refractory epilepsy.ConclusionsEpilepsy in argininosuccinic aciduria is frequent, polymorphic, associated with more frequent neurodevelopmental complications. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests roles of arginine toxicity and central dopamine deficiency.Key PointsEpilepsy in ASA is frequent, polymorphic, occurring in early childhood and associated with a more severe neurodevelopmental phenotype.Early-onset epilepsy and electroencephalographic background asymmetry are prognostic for pharmaco-resistance of epilepsy in ASA.Hyperammonaemia is suggested not to be the primary pathophysiological mechanism for epileptogenesis in ASA.Central dopamine deficiency is suggested to have a role in pathophysiology of epilepsy in ASA.Arginine-related neurotoxicity is suggested to be associated with increased in frequency and severity of epilepsy in ASA.

Because of the widespread use of breast screening mammography, the number of women diagnosed with ductal carcinoma in situ (DCIS) has increased dramatically in recent years. DCIS is a noninvasive form of breast cancer, accounting for up to 30% of breast cancers in screening populations and approximately 5% of breast carcinomas in symptomatic patients (1–3). DCIS has a variety of mammographic presentations, but the most common mammographic feature is microcalcification (4). Indeed 80%–90% of DCIS lesions present with microcalcifications only, without any accompanying mass lesions (4). Other findings such as masses, nodular abnormalities, dilated retroareolar ducts, architectural distortions, and developing densities have also been reported (5). Ultrasound-guided biopsy is often the method of choice for sonographically visible breast lesions as it provides easy access for biopsy. However, in cases when the abnormality seen on mammography is not visible on ultrasonography, stereotactic biopsy is the recommended sampling method. For microcalcification-only lesions with no accompanying mass, ultrasonography often fails to identify the site of the lesion; hence, stereotactic biopsy is used more frequently. In most breast units, stereotactic 14-gauge automated core biopsy has been replaced by stereotactic vacuum-assisted biopsy (SVAB) using 8- to 11-gauge needles (6). Large core SVAB allows larger samples to be obtained in a shorter period of time compared with samples obtained using automated core biopsy devices (7). Moreover, this technique has the advantage of a single insertion in the area of interest compared with automated core biopsy devices, which require repeated insertions. Several published articles have shown that SVAB decreased the rate of cancer underestimation and the rate of failure to retrieve breast microcalcifications (8). The management of noninvasive and invasive breast cancers is different and therefore, an accurate preoperative diagnosis is crucial for adequate surgical planning. Underestimation of DCIS lesions occurs when an invasive component is found after surgery, which had been missed at the initial preoperative sampling. The underestimation rate of stereotactic 14-gauge automated core biopsy in DCIS was reported as 16%–35% (9–11), while that of SVAB was 5%–29% (6, 9, 11–13). The purpose of this study was to determine the rate, causes, and predictive factors of underestimation of invasive carcinoma in patients diagnosed with DCIS following SVAB of microcalcification-only lesions.

OBJECTIVE: To compare the experience of four UK Centres in the use of intradermal microbubbles and contrast enhanced ultrasound (CEUS) to pre-operatively identify and biopsy sentinel lymph nodes (SLN) in patients with breast cancer. METHODS: In all centres, breast cancer patients had a microbubble/CEUS SLN core biopsy prior to axillary surgery and patients in Centres 1 and 2 had a normal greyscale axillary ultrasound. Data were collected between 2010 and 2016; 1361 from Centre 1 (prospective, sequential), 376 from Centre 2 (retrospective, sequential), 121 from Centre 3 (retrospective, selected) and 48 from Centre 4 (prospective, selected). RESULTS: SLN were successfully core biopsied in 80% (Centre 1), 79.6% (Centre 2), 77.5% (Centre 3) and 88% (Centre 4). The sensitivities to identify all SLN metastases were 46.9% [95% confidence intervals (CI) (39.4-55.1)], 52.5% [95% CI (39.1-65.7)], 46.4% [95% CI (27.5-66.1)] and 45.5% [95% CI (16.7-76.6)], respectively. The specificities were 99.7% [95% CI (I98.9-100)], 98.1% [95% CI (94.5-99.6)], 100% [95% CI (93.2-100%)] and 96.3% [95% CI (81-99.9)], respectively.The negative predictive values were 87.0% [95% CI (84.3-89.3)], 84.5% [95% CI (78.4-89.5)], 86.9% [95% CI (82.4-90.3)] and 86.2% [95% CI (78.4-91.5)], respectively. At Centres 1 and 2, 12/730 (1.6%) and 7/181 (4%), respectively, of patients with a benign microbubble/CEUS SLN core biopsy had two or more lymph node (LN) macrometastases found at the end of primary surgical treatment. CONCLUSION: The identification and biopsy of SLN using CEUS is a reproducible technique. Advances in knowledge: In the era of axillary conservation, microbubble/CEUS SLN core biopsy has the potential to succeed surgical staging of the axilla.

The N-linked glycans on transferrin and α1-antitrypsin from patients with congenital disorders of glycosylation type I have increased fucosylation and branching relative to normal controls. The elevated levels of monofucosylated biantennary glycans are probably due to increased α-(1 → 6) fucosylation. The presence of bi- and trifucosylated triantennary and tetra-antennary glycans indicated that peripheral α-(1 → 3), as well as core α-(1 → 6), fucosylation is increased. Altered processing was observed on both the fully and underglycosylated glycoforms.

PURPOSE: The purpose of this study was to identify the factors that may have an impact on upgrading atypical ductal hyperplasia (ADH) lesions to malignancy. MATERIALS AND METHODS: Between February 1999 and December 2010, the records of 150 ADH lesions that had been biopsied were retrospectively reviewed. The biopsy types included 11-gauge stereotactic vacuum-assisted biopsy (SVAB) (n=102) and ultrasonography (US)-guided 14-gauge automated biopsy (n=48). The patients were divided into two groups: those who had cancer in the final pathology and those who did not. Variables associated with underestimation of ADH lesions were compared between the groups. RESULTS: The underestimation rates according to the biopsy types were 41.7% (20/48) for the US-guided 14-gauge automated biopsy and 20.6% (21/102) for the 11-gauge SVAB (P = 0.007). The rate of underestimation was significantly higher in lesions greater than 7 mm than it was in smaller lesions, with both US-guided 14-gauge automated biopsy and 11-gauge SVAB (P = 0.024 and P = 0.042, respectively). The rate of underestimation was significantly higher with the 11-gauge SVAB (P = 0.025) in lesions that were suspicious (R4) and highly suggestive of malignancy (R5) than in those that were probably benign (R3). CONCLUSION: The underestimation rate in ADH lesions was significantly higher with US-guided 14-gauge automated biopsy compared to the 11-gauge SVAB. The underestimation rate was also significantly higher in lesions greater than 7 mm regardless of the biopsy type, and in lesions biopsied using SVAB that were regarded as suspicious (R4) or highly suggestive of malignancy (R5) on imaging.

The aim of this study was to determine the causes and rate of failure in removing calcification in microcalcification-only lesions using 11-gauge stereotactic vacuum-assisted breast biopsy.In total, 1365 microcalcification-only lesions were included in this study. The breast biopsy database was reviewed retrospectively. The biopsies were divided into two groups based on whether the specimen X-ray showed calcium within the cores. Breast composition, lesion size, calcification distribution, density on mammography, and the number of specimens were compared between the two groups.In 11 (0.8%) biopsies, no calcium in the specimen radiography could be identified. Re-biopsy was performed in five cases. The initial biopsy result was unchanged at the second biopsy in three cases containing calcium, while in the other two cases, a benign biopsy result was upgraded to atypical ductal hyperplasia and ductal carcinoma in situ, respectively. In six cases, the biopsy was not repeated despite the absence of calcium in the specimen X-ray. In three of these cases, calcifications were reported histopathologically and deemed to be too small to be identified on specimen X-ray. In two of six patients, sufficient information was found in the cores without microcalcification to indicate the need for surgery. One patient refused re-biopsy. A statistically significant higher failure rate was observed in low-density calcification compared with intermediate or high-density calcification on mammography.The failure to retrieve microcalcification is uncommon when an 11-gauge vacuum-assisted breast biopsy is used. Low-density calcifications have a higher rate of failure. In cases in which no calcium is observed in specimen radiography, repeated biopsy is recommended.

To investigate the feasibility of percutaneous removal of the entire sentinel lymph node (SLN) in an animal model using a breast lesion excision system after identifying these nodes using contrast-enhanced ultrasound (CEUS) and intradermal microbubbles. Animal studies approval was obtained. SLNs were identified using CEUS and intradermal injection of microbubbles in two young pigs. Microbubbles were mixed with blue dye and injected around the mammary papillae to access lymphatic drainage to the superficial inguinal lymph nodes. When enhancing nodes were identified, the breast lesion excision system (BLES) was used to remove these nodes percutaneously. Both animals then underwent surgical lymph node dissection. Histopathological examination of all the samples was performed. Removal of the entire SLN was successful in three groins in the pigs. All three nodes were stained with blue dye. No other stained nodes were observed in the node dissection specimens. The nodal architecture of removed lymph nodes was well preserved on microscopy. There were no signs of excess trauma within the biopsy bed. The results obtained from the swine model demonstrated that it is feasible to remove the entire SLN percutaneously under the guidance of CEUS and microbubbles. • Intradermal injection of microbubbles and CEUS can identify sentinel lymph nodes • Ultrasound could then guide percutaneous removal of intact and complete SLNs • We have shown this was feasible in pigs but not yet in humans • This technique may eventually have the potential to reduce futile SLN biopsies.

Sentinel lymph node (SLN) biopsy is the standard procedure for axillary staging in early breast cancer. Lymphatic imaging after peritumoral microbubble injection has been described in animal models. The aim of this study was to identify and localize SLNs preoperatively by contrast-enhanced sonography after intradermal injection of microbubbles in patients with breast cancer.Eighty consecutive consenting patients with primary breast cancer were recruited. Patients received a periareolar intradermal injection of microbubble contrast agent. Breast lymphatics were visualized by sonography and followed to the axilla to identify SLNs. A guidewire was deployed to localize the SLN. The next day, patients underwent standard tumor excision and SLN biopsy.In 71 (89%) of the 80 patients, SLNs were identified and guidewires were inserted. In these patients, operative findings using conventional radioisotope and blue dye techniques confirmed that the wired nodes were SLNs. Fourteen patients were found to have metastases in SLNs. In these patients, the SLNs were identified correctly and were localized with guidewires before surgery.SLNs may be identified and localized before surgery using contrast-enhanced sonography after injection of microbubbles.

PURPOSE The aim of this study was to determine the causes and rate of failure in removing calcification in microcalcification-only lesions using 11-gauge stereotactic vacuum-assisted breast biopsy. MATERIALS AND METHODS In total, 1365 microcalcification-only lesions were included in this study. The breast biopsy database was reviewed retrospectively. The biopsies were divided into two groups based on whether the specimen X-ray showed calcium within the cores. Breast composition, lesion size, calcification distribution, density on mammography, and the number of specimens were compared between the two groups. RESULTS In 11 (0.8%) biopsies, no calcium in the specimen radiography could be identified. Re-biopsy was performed in five cases. The initial biopsy result was unchanged at the second biopsy in three cases containing calcium, while in the other two cases, a benign biopsy result was upgraded to atypical ductal hyperplasia and ductal carcinoma in situ, respectively. In six cases, the biopsy was not repeated despite the absence of calcium in the specimen X-ray. In three of these cases, calcifications were reported histopathologically and deemed to be too small to be identified on specimen X-ray. In two of six patients, sufficient information was found in the cores without microcalcification to indicate the need for surgery. One patient refused re-biopsy. A statistically significant higher failure rate was observed in low-density calcification compared with intermediate or high-density calcification on mammography. CONCLUSION The failure to retrieve microcalcification is uncommon when an 11-gauge vacuum-assisted breast biopsy is used. Low-density calcifications have a higher rate of failure. In cases in which no calcium is observed in specimen radiography, repeated biopsy is recommended.

A breast mass caused by foreign body type granulomatous reaction to surgical material is a very rare lesion and may mimic carcinoma. Reported foreign materials have included suture materials, silicone, paraffin, gunpowder and carbon particles used for localization of a nonpalpable breast lesions. To our knowledge, a foreign body reaction to gauze sponge has not been reported previously. A 58-year-old woman who had an enlarging mass that mimicked breast carcinoma, due to foreign body reaction to gauze sponge is presented here, and relevant literature is reviewed.

In vivo and in vitro 31P-NMR spectroscopy was used to study the high energy phosphate metabolism of VX-2 tumors implanted into rabbit liver, kidney, and hind-limb muscle. Tumors, at various stages of growth, were first examined by in vivo 31P-NMR spectroscopy, then they were excised and underwent histologic examination and biochemical analysis; both in vitro 31P-NMR and standard enzymatic techniques were used. There was good correlation among the in vivo NMR spectra, the in vitro NMR data, and the biochemical analyses. Although the tumor spectra showed characteristics similar to those reported in the other tumor models, there was a striking variability in the spectra obtained from tumors implanted in the same site and from different sites. There was poor correlation between the degree of necrosis in the tumor and the tumor pH and between the Pi:ATP ratio and necrosis. This variability has important implications for the potential value of using 31P-NMR spectroscopy to monitor tumor growth and therapy in vivo.