Spindle cell neoplasms with novel LTK fusion - Expanding the spectrum of kinase fusion-positive soft tissue tumors.

AIMS: Kinase fusion-positive soft tissue tumors represent an emerging, molecularly defined group of mesenchymal tumors with a wide morphologic spectrum and diverse activating kinases. Here, we present two cases of soft tissue tumors with novel LTK fusions. METHODS AND RESULTS: Both cases presented as acral skin nodules (big toe and middle finger) in pediatric patients (17-year-old girl and 2-year-old boy). The tumors measured 2 and 3 cm in greatest dimension. Histologically, both cases exhibited bland-looking spindle cells infiltrating adipose tissue and accompanied by collagenous stroma. One case additionally displayed perivascular hyalinization and band-like stromal collagen. Both cases exhibited focal S100 staining, and one case had patchy coexpression of CD34. Targeted RNA-seq revealed the presence of novel in-frame MYH9::LTK and MYH10::LTK fusions, resulting in upregulation of LTK expression. Of interest, DNA methylation-based unsupervised clustering analysis in one case showed that the tumor clustered with dermatofibrosarcoma protuberans (DFSP). One tumor was excised with amputation with no local recurrence or distant metastasis at 18-month follow-up. The other case was initially marginally excised with local recurrence after one year, followed by wide local excision, with no evidence of disease at 10 years of follow-up. CONCLUSIONS: This is the first reported case series of soft tissue tumors harboring LTK fusion, expanding the molecular landscape of soft tissue tumors driven by activating kinase fusions. Furthermore, studies involving a larger number of cases and integrated genomic analyses will be warranted to fully elucidate the pathogenesis and classification of these tumors.

Novel MAP4::RAF1 Fusion in a Primary Bone Sarcoma: Expanding the spectrum of RAF1 Fusion Sarcoma.

Soft tissue tumors with RAF1 fusion had been emerging as a group of tumors with peculiar histology and immunoprofile. While a case series and rare case reports of RAF1 translocated sarcoma had been reported, to our knowledge a primary bone tumor with RAF1 translocation and fusion partner with MAP4 had not been described in the literature. The patient was a 60-year-old lady, with strong family history of breast cancer, who presented with pathological fracture of right humerus. X-ray revealed a 9.7 cm juxta-articular lesion of the proximal humerus, which was expansile and lytic with a non-sclerotic well defined border distally, radiologically suggestive of a giant cell tumor of bone. Excision was performed after initial biopsy. Histology showed a monomorphic low grade spindle cell lesion with prominent hyalinized stroma. Immunohistochemistry demonstrated diffuse CD34 staining, with focal staining for S100. Gene sequencing for histone 3 H3 genes was negative for hotspot mutation. Targeted RNA-seq sequencing revealed the presence of MAP4::RAF1 fusion, which was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescence in-situ hybridization (FISH) break-apart probes involving both genes. The overall features were consistent with a primary bone sarcoma with RAF1 fusion. This report expanded the spectrum of RAF1 fusion sarcoma and was the first report documenting its primary occurrence in bone.

KRAS Mutation Testing on Endoscopic Ultrasound-Guided Fine-Needle Aspiration Samples Improves the Diagnostic Accuracy of Pancreatic Cancer.

OBJECTIVES: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) cytology was one of the investigations for pancreatic masses. While the specificity approached 100%, its sensitivity remained low because of high rate of indeterminate and false-negative results. Meanwhile, KRAS gene was frequently mutated in up to 90% of pancreatic ductal adenocarcinoma and its precursor lesions. This study aimed to determine whether KRAS mutation analysis could improve the diagnostic sensitivity in EUS-FNA samples for pancreatic adenocarcinoma. METHODS: The EUS-FNA samples from patients with a pancreatic mass obtained between January 2016 and December 2017 were reviewed retrospectively. The cytology results were classified as malignant, suspicious for malignancy, atypical, negative for malignancy, and nondiagnostic. KRAS mutation testing was performed using polymerase chain reaction followed by Sanger sequencing. RESULTS: A total of 126 EUS-FNA specimens were reviewed. The overall sensitivity and specificity by cytology alone were 29% and 100%, respectively. When KRAS mutation testing was performed in cases with indeterminate and negative cytology, the sensitivity increased to 74.2%, and the specificity remained at 100%. CONCLUSIONS: KRAS mutation analysis, especially when performed in cytologically indeterminate cases, improves the diagnostic accuracy for pancreatic ductal adenocarcinoma. This may reduce the need to repeat invasive EUS-FNA for diagnosis.

Case report on metastatic pelvic bone tumor treated with frozen autograft by liquid nitrogen.

INTRODUCTION AND IMPORTANCE: Frozen autograft recycling has been used for biological reconstruction of bone defects following tumor excision, more commonly in extremities. We report on the histological outcome of a pelvic recycled frozen autograft. CASE PRESENTATION: We investigated the pelvic frozen autograft removed in 2 years and 8 months after surgery because of soft tissue recurrence in pelvic floor. The autograft bone showed no evidence of revitalization and was non-viable with patchy inflammation, and no residual tumor. There was only fibrous union but the autograft bone remained mechanically stable. CLINICAL DISCUSSION: We confirmed the clearance of tumor cells with the treatment with liquid nitrogen. The union at the host-graft junction might be affected by the previous radiotherapy, the presence of infection, the small contact area limited by the anatomy, and the inadequate compression across the osteotomy interface with the fixation. CONCLUSION: Frozen autograft treated by liquid nitrogen can be used safely for biological reconstructions after pelvic tumor excision.

Effect of Thyroid Remnant Volume on the Risk of Hypothyroidism After Hemithyroidectomy: A Prospective Study.

BACKGROUND: Hypothyroidism is a common sequel after a hemithyroidectomy. Although various risk factors leading to hypothyroidism have been reported, the effect of the contralateral lobe's volume has been understudied. This study aimed to examine the association between the preoperative contralateral lobe's volume and the risk of postoperative hypothyroidism. METHODS: During a 2-year period, 150 eligible patients undergoing a hemithyroidectomy were evaluated. The volume of the contralateral nonexcised lobe was estimated preoperatively by independent assessors on ultrasonography using the following formula: width (in cm) × depth (in cm) × length (in cm) × (π/6), adjusted for the body surface area (BSA). Postoperative hypothyroidism was defined as serum thyroid-stimulating hormone (TSH) exceeding 4.78 mIU/L. Any significant characteristics in the univariate analysis were entered into the multivariate analysis to determine independent factors. RESULTS: After a mean follow-up period of 53.5 ± 9.4 months, 44 patients (29.3 %) experienced postoperative hypothyroidism, and 10 of these patients required thyroxine replacement. Hypothyroidism was associated with a higher preoperative TSH level (p < 0.001), a smaller BSA-adjusted volume (p < 0.001), fewer ipsilateral nodules (p = 0.037), and the presence of thyroiditis (p = 0.050). After adjustment for thyroiditis, preoperative TSH (p < 0.001), number of ipsilateral nodules (p = 0.048), and BSA-adjusted volume (p < 0.001) were independent factors for hypothyroidism. Patients with a BSA-adjusted volume smaller than 3.2 ml had a threefold greater hypothyroidism risk than those with a BSA-adjusted volume of 3.2 ml or more (p < 0.001). CONCLUSIONS: A significant inverse association between the preoperative contralateral lobe's volume and hypothyroidism risk was observed after hemithyroidectomy. Together with a higher preoperative TSH level and fewer ipsilateral nodules, a smaller BSA-adjusted volume measured by preoperative ultrasonography independently predicted hypothyroidism.

Significance of Size of Persistent/Recurrent Central Nodal Disease on Surgical Morbidity and Response to Therapy in Reoperative Neck Dissection for Papillary Thyroid Carcinoma.

BACKGROUND: To balance the risk of disease progression, morbidity, and efficacy of reoperative central neck dissection (RCND) in papillary thyroid carcinoma, the latest clinical guidelines recommend early surgery over surveillance when the largest diseased node is >8 mm in its smallest dimension. However, the evidence remains scarce. To determine an appropriate size for first-time RCND, the relationship between size of largest diseased central node, morbidity, and response-to-therapy following RCND was examined. METHODS: A total of 130 patients who underwent RCND following initial surgery for persistent/recurrent nodal disease were reviewed. Patients with largest diseased central node measured preoperatively by ultrasonography were included. Eligible patients were categorized into three groups: largest central node <10 mm (group I), 10-15 mm (group II), and >15 mm (group III). Surgical morbidity and response to therapy at one year after RCND were compared between groups. To evaluate biochemical response, patients with structural incompleteness were excluded. RESULTS: Group III not only had significantly more high-risk tumors (by American Thyroid Association risk stratification) at initial therapy (64.5% vs. 44.4%, respectively; p = 0.038), but this group also a higher risk of extranodal extension (35.5% vs. 16.0%; p = 0.055), recurrent laryngeal nerve involvement (19.4% vs. 0.0%; p < 0.001), incomplete surgical resection (48.4% vs. 7.4%; p < 0.001), new-onset vocal cord paresis (16.7% vs. 2.5%; p = 0.017), overall surgical morbidity (22.6% vs. 7.4%; p = 0.021), and biochemical incompleteness (80.6% vs. 67.9%; p = 0.004) than groups I and II combined did. However, overall morbidity did not differ between groups I and II (5.7% vs. 8.7%; p = 0.694). After adjusting for American Thyroid Association risk stratification, only the size of the largest diseased central node ≥15 mm (odds ratio = 7.256 [confidence interval 1.302-40.434], p = 0.001) was an independent risk factor for biochemical incompleteness following RCND. CONCLUSIONS: Patients with larger diseased central node(s) had a significantly higher risk of local invasion, surgical morbidity, and biochemical incompleteness. Relative to nodal size <10 mm, size >15 mm in the largest disease central node was an independent risk factor for incomplete biochemical response, while nodal size 10-15 mm was not. These findings imply that the recommended threshold of 8 mm might be too stringent and could be raised to 15 mm without increasing the surgical morbidity from RCND.

The significance of unrecognized histological high-risk features on response to therapy in papillary thyroid carcinoma measuring 1-4 cm: implications for completion thyroidectomy following lobectomy.

BACKGROUND: Although lobectomy is an alternative to total thyroidectomy (TT) for 1-4 cm papillary thyroid carcinoma (PTC) without high-risk features (HRFs) such as aggressive histology, vascular invasion, lymphovascular invasion (LVI), microscopic extrathyroidal extension, positive margin, nodal metastasis >5 mm and multifocality, these HRFs are not recognized until after surgery. Therefore, the chance of completion TT being required following lobectomy might be high. We evaluated the frequency of unrecognized HRFs and how they affected the response to therapy following TT and radioiodine (RAI). METHODS: Altogether, 1513 patients were analysed. Only 1-4 cm PTCs without recognizable HRFs were included. For response-to-therapy evaluation, only patients who had TT and post-RAI-stimulated thyroglobulin were analysed. Patients without an excellent response were defined as having 'incomplete response'. A multivariate analysis for incomplete response was performed. RESULTS: Of the 600 patients eligible for lobectomy, 257 (42·8%) had ≥1 unrecognized histological HRF before surgery. The prevalence of unrecognized HRFs was similar between 1-2 cm and >2-4 cm PTCs (P = 0·393). Of the 330 patients eligible for response-to-therapy evaluation, 260 (78·8%) had an excellent response while 70 (21·2%) had an incomplete response. LVI was the only independent unrecognized HRF for incomplete response (P = 0·021). CONCLUSIONS: The prevalence of unrecognized histological HRFs under the current recommendations is relatively high among 1-4 cm PTCs. Among the unrecognized histological HRFs, LVI was the only one which independently associated with an incomplete response (i.e. posing an increased risk of persistent/recurrent disease after curative surgery). These findings may have implications for patients who undergo lobectomy for 1-4 cm PTCs with no clinically recognizable HRFs under the current recommendations.

The total number of tissue blocks per centimetre of tumor significantly correlated with the risk of distant metastasis in patients with minimally invasive follicular thyroid carcinoma.

BACKGROUND: Given that careful histological examination plays a pivotal role in follicular thyroid carcinoma categorization, we hypothesize that the number of blocks taken at initial specimen review may be associated with survival outcomes of patients initially diagnosed with minimally invasive follicular thyroid carcinoma. METHODS: A total of 162 patients with confirmed minimally invasive follicular thyroid carcinoma were analyzed. The number of tissue blocks taken from each patient was recorded and the number of blocks per each centimeter of tumor was calculated. A multivariate analysis was conducted to identify independent factors for distant metastasis-free survival. RESULTS: After a mean follow-up of 197.88 ± 155.39 months, 7 (4.3%) patients developed distant metastasis during follow-up (group II). Relative to those who remained disease-free (group I), group II were significantly older at initial operation (p = 0.022), had larger tumors (p = 0.002) and fewer number of blocks taken/cm of tumor (p = 0.001). However, after adjusting for age at initial operation and tumor size, total number of tissue blocks taken/cm of tumor was the only independent determinant for distant metastasis-free survival (p = 0.049). The 10-year distant metastasis-free survival was significantly better in those who had ≥ 4 blocks/cm of tumor (n = 82) than those with ≤ 3 block/cm of tumor (n = 80) (100 vs. 84.7%, p = 0.005, by log rank). CONCLUSIONS: Although our study was not able to identify the precise cause for the association between the total number of tissue blocks taken/cm of tumor and distant metastasis-free survival, our data support a more liberal approach in taking tissue blocks on thyroid nodules especially those showing well-differentiated follicular cell differentiation.

Does microscopically involved margin increase disease recurrence after curative surgery in papillary thyroid carcinoma?

BACKGROUND: The prognostic significance of microscopically involved margin in papillary thyroid carcinoma (PTC) following curative surgery remains unclear. We aimed to evaluate the impact of an involved margin and its location (anterior vs. posterior) on disease recurrence. METHODS: Of the 638 eligible patients, 538 (85.9%) did not have an involved margin (group I) while 100 (14.1%) did (group II). The latter group was further classified according to its location relative to the surface of the thyroid gland (anterior or posterior). A multivariate analysis was conducted to identify independent factors for recurrence risk. RESULTS: After a mean of 130.1 ± 93.5 months, 22 patients had disease recurrence. The 10-year disease-free survival (DFS) was significantly worse in group II (95.0% vs. 97.0%, P = 0.011). After adjusting other significant factors, involved margin was not an independent risk factor for disease recurrence (P = 0.358). Compared to a negative margin, an anterior involved margin did not pose increased recurrence risk (HR = 1.21, 95%CI = 0.93-500.00, P = 0.368), whereas a posterior involved margin had almost 23 times higher recurrence risk (HR = 22.95; 95%CI = 4.33-121.70, P < 0.001). CONCLUSIONS: Overall, a microscopically involved margin was not an independent factor for DFS. However, although an anterior involved margin itself did not increase disease recurrence, a posterior involved margin did. J. Surg. Oncol. 2016;113:635-639. © 2016 Wiley Periodicals, Inc.

Impact of microscopic extra-nodal extension (ENE) on locoregional recurrence following curative surgery for papillary thyroid carcinoma.

BACKGROUND: The presence of microscopic extra-nodal extension (ENE) may increase locoregional recurrence (LRR) in papillary thyroid carcinoma (PTC). We aimed to evaluate the association between microscopic ENE, response to initial therapy and LRR risk following total thyroidectomy, therapeutic neck dissection, and radioactive iodine (RAI) ablation in PTC. METHODS: Of the 369 eligible PTC patients, 264 (71.5%) did not have microscopic ENE (group I) while 105 (28.5%) did (group II). All presented with clinical nodal metastasis (cN1) and underwent therapeutic neck dissection and RAI ablation. Biochemical incompleteness meant post-ablation stimulated thyroglobulin (sTg) >10 ng/ml. Multivariate analyses were conducted to identify independent factors for LRR. RESULTS: Biochemical incompleteness was significantly more common group II (43.8% vs. 17.4%, P < 0.05). The 10-year locoregional free-survival was significantly worse in group II than I (52.0% vs. 86.2%, P = 0.005). After adjusting for other significant factors, age <45 (P < 0.05), multifocality (P < 0.05), presence of ENE (P = 0.027) were independent risk factors of LRR. The number and size of positive lymph nodes were not independent factors. CONCLUSIONS: Patients with microscopic ENE were significantly more likely to have biochemical incompleteness after initial therapy. After adjusting for other significant primary and nodal characteristics, microscopic ENE was an independent factor for LRR in patients with cN1. J. Surg. Oncol. 2016;113:526-531. © 2016 Wiley Periodicals, Inc.

Association of exon 19 and 21 EGFR mutation patterns with treatment outcome after first-line tyrosine kinase inhibitor in metastatic non-small-cell lung cancer.

BACKGROUND: This study investigated whether there were differential survival outcomes to first-line tyrosine kinase inhibitors (TKI) in patients with metastatic non-small-cell lung cancer harboring different subtypes of exon 19 and exon 21 mutations on epidermal growth factor receptor (EGFR). METHODS: Of 452 patients with stage IIIB and IV non-small-cell lung cancer, 192 patients (42.5%) harbored EGFR mutation and 170 (37.5%) received TKI as first-line treatment. EGFR mutation analysis was performed by direct sequencing. Survival and response outcome were compared among different subtypes of exon 19 and exon 21 EGFR mutations in these 170 patients. RESULTS: Patients harboring exon 19 18-nucleotide deletion (delL747_P753insS) had the shortest median progression-free survival (PFS) (6.5 months), followed by those with 15-nucleotide deletion (delE746_A750) (12.4 months) and mixed insertion/substitution mutations (22.3 months; p = 0.012). However, patients who had exon 19 deletions starting on codon E746 had better median PFS (14.2 months) than those starting on L747 (6.5 months; hazard ratio, 0.445; 95% confidence interval [0.219-0.903]; p = 0.021). Besides, exon 21 L858R derived a longer median PFS than L861R/L861Q (11.4 months versus 2.1 months, respectively; hazard ratio, 0.298; 95% confidence interval [0.090-0.980]; p = 0.034). CONCLUSIONS: Different subtypes of EGFR exon 19 and 21 mutations exhibited differential survival to first-line TKI therapy. Detailed sequence evaluation of exon 19 deletions may provide important prognostic information on survival outcome after TKI.

Diabetic mastopathy.

Diabetic mastopathy is an uncommon condition found in patients with long-standing diabetic mellitus (DM). Although benign in nature, it can sometimes not be distinguishable from breast carcinoma, and may lead to unnecessary anxiety or intervention. Clinicopathologic features of 10 patients were reviewed in detail. Only three of the 10 patients had type I DM. All patients had over a 10-year history of DM, and presented with unilateral, solitary, palpable breast mass, ranging in size from 1.5 to 5 cm. Radiologic and pathologic features of each patient were described. None of the patients in our series developed malignancy during the follow-up period. Diabetic mastopathy is a benign condition and not unique to type I DM. Surgeons should be aware of this distinct fibroinflammatory breast condition and its association with long-standing DM.

Asymptomatic grade-2 central chondrosarcoma of the distal femur with non-aggressive radiological features.

This paper discusses the case of a 57-year-old man with an incidental finding of a radiologically non-aggressive chondroid lesion and concomitant osteonecrosis in the left distal femur. The final resected specimen showed a grade-2 chondrosarcoma. This case illustrates that long-term follow-up is necessary for non-aggressive chondroid lesions. If surgical management is considered, resection with an adequate margin is superior to intralesional curettage.

Combined use of 18F-FDG PET/CT, DW-MRI, and DCE-MRI in treatment response for preoperative chemoradiation therapy in locally invasive rectal cancers.

We investigated if 18F-FDG PET/CT, DW-MRI, and DCE-MRI are able to predict preoperative chemoradiation therapy (CRT) response in patients with T3-4 rectal adenocarcinomas. MRI and PET/CT scans were performed within 1 week, at baseline, early midtreatment (2 weeks of CRT), and posttreatment (6 weeks after completing CRT). Responders (n = 4) and nonresponders (n = 4) were defined according to tumor regression grade by histology. Only SUVmax (P = 0.030) at early midtreatment could significantly differentiate between responders and nonresponders, suggesting that 18F-FDG PET/CT may be effective to predict early treatment response compared with DW-MRI and DCE-MRI in T3-4 rectal cancer.

A sarcoma of 23 years' duration: symptom duration is not a reliable parameter to exclude malignancy.

This report describes a 31-year-old woman with a 23-year history of a right buttock mass that was otherwise asymptomatic, but was proven to be a low-grade fibromyxoid sarcoma (a fully malignant soft tissue tumour with a potential for distant metastasis). This case illustrates that a long-standing tumour does not necessarily imply a benign pathology. A vigilant approach should be taken for any tumours that are of significant size (larger than 5 cm).

Factors affecting the adequacy of lymph node yield in prophylactic unilateral central neck dissection for papillary thyroid carcinoma.

BACKGROUND: Determinants for adequate lymph node yield (LNY) in prophylactic central neck dissection (pCND) for papillary thyroid carcinoma (PTC) remain unclear. We aimed to determine factors affecting LNY in pCND. METHODS: Of 230 patients, 109 (47.4%) had total thyroidectomy and unilateral pCND. A specimen of ≥ 6 central lymph nodes (CLNs) was considered adequate. Factors such as patient clinicopathologic features, specimen dimensions, and pathologists' experience were compared between those with LNY < 6 (n = 52) and LNY ≥ 6 (n = 57). A multivariate analysis was conducted to identify independent factors for LNY ≥ 6. RESULTS: Age, sex, presentation, body mass index, tumor characteristics, TNM stages, MACIS score, and pathologist's experience were not significant determinants for LNY ≥ 6. In the univariate analysis, the length (P = 0.021), width (P = 0.047), thickness (P = 0.024), and pN1a (P = 0.042) were significant determinants but in the multivariate analysis, the length (OR = 1.486 (95% CI: 1.053-2.097), P = 0.024) was the only independent factor for LNY ≥ 6. Postoperative vocal cord palsy, hypoparathyroidism, stimulated thyroglobulin and recurrences were similar between LNY <6 and ≥ 6. CONCLUSIONS: Length (or the longest measured dimension) of the fresh CLN specimen was the only factor assuring LNY ≥ 6. Surgical complications and short-term outcomes appeared similar between LNY <6 or ≥ 6.

Significance of size of lymph node metastasis on postsurgical stimulated thyroglobulin levels after prophylactic unilateral central neck dissection in papillary thyroid carcinoma.

BACKGROUND: The prognostic significance of size of central lymph node metastasis (CLNM) in papillary thyroid carcinoma (PTC) remains unknown. Because postsurgical detectable stimulated thyroglobulin (DsTg) after radioiodine ablation may imply persistent or recurrent disease, we evaluated the association between size of CLNM and rate of DsTg in patients with PTC who underwent unilateral prophylactic central neck dissection. METHODS: To be eligible for analysis, the prophylactic central neck dissection specimen with <3 central lymph nodes (CLNs) or size of CLNM ≥1 cm as measured under the microscope was excluded. Of 132 specimens, 89 (67.4%) were eligible. Forty patients (44.9%) had no metastasis or pN0, 20 (22.5%) had micrometastasis (<2 mm) or pN1mic and 29 (32.6%) had macrometastasis (≥2 mm) or pN1mac. Postablation sTg level was measured 9 months after surgery. A multivariable analysis was conducted to identify independent factors for postablation DsTg. RESULTS: Larger-sized CLNM correlated significantly with younger age (p = 0.028), greater number of CLN retrieved (p = 0.016), greater number of metastatic CLN excised (p < 0.001), higher metastatic CLN ratio (p = 0.006) and postablation sTg level (p = 0.012). In the multivariable analysis, after adjusting for tumor size and metastatic CLN ratio, size of CLNM was an independent predictor of postablation DsTg (odds ratio 1.56, 95% confidence interval 1.09-2.24, p = 0.015). Relative to pN0, the odds ratios for postablation DsTg in pN1mic and pN1mac were 2.53 (95% confidence interval 0.35-19.00, p = 0.351) and 5.81 (95% confidence interval 1.22-27.70, p = 0.027), respectively. CONCLUSIONS: Size of CLNM was an independent factor for DsTg 9 months after surgery. Patients with pN1mac were almost 6 times more likely to have postablation DsTg than those with pN0 or pN1mic.

Pictorial essay: imaging of peripheral nerve sheath tumours.

Peripheral nerve sheath tumours (PNST) may be benign or malignant. Benign PNSTs include neurofibroma and schwannoma. Neurogenic tumours share certain characteristic imaging features, suggested by a fusiform-shaped mass with tapered ends, the "split-fat" sign, atrophy of the muscles supplied by the involved nerve, the "fascicular sign," and the "target sign"; these imaging features are best demonstrated on magnetic resonance imaging. This pictorial essay emphasizes the characteristic signs and distinguishing features of PNSTs on imaging.