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W F Knox

Publications and source records attributed to W F Knox.

At least 19 recordsLinked to original sources
PubMed2006

Survivin expression in in situ and invasive breast cancer relates to COX-2 expression and DCIS recurrence.

In lung cancer cyclooxygenase-2 (COX-2) expression has been reported to stabilise survivin, an inhibitor of apoptosis (IAP) which prevents cell death by blocking activated caspases. COX-2 expression limits the ubiquitination of survivin, protecting it from degradation. To determine if COX-2 expression in breast cancer showed an association with survivin expression, we assessed the levels of each protein in ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC); relating expression patterns to recurrence of DCIS after surgery. Patterns of COX-2 and survivin expression were determined by intensity-graded immunohistochemistry of the primary tumours. Patients with DCIS (n=161) which had either recurred (n=47) or shown no evidence of recurrence (n=114) 5 years following primary surgery were studied. These were compared to 58 cases of IBC. Survivin was expressed in the cytoplasm of 59% of DCIS and 17% of IBC. High levels of both cytoplasmic survivin and COX-2 expression significantly correlated to DCIS recurrence. COX-2 expression was present in 72% of DCIS, and levels of expression positively correlated with cytoplasmic survivin expression in DCIS and invasive disease. The majority of DCIS that recurred expressed both proteins (69%) vs 39% nonrecurrent. Recurrence was not seen in DCIS lacking both proteins at 5 years (P=0.001). Expression of the IAP survivin is increased in DCIS and correlates closely with COX-2 expression. Increased expression of IAP, (leading to reduced apoptosis) may explain the effect of COX-2 in increasing recurrence of DCIS after surgical treatment.

Biomarkers, Tumor↗
PubMed2005

Relationship between hormone receptor status and tumour size, grade and comedo necrosis in ductal carcinoma in situ.

BACKGROUND: Results of the National Surgical Adjuvant Breast Project B-24 trial indicate that adjuvant tamoxifen therapy is of benefit only in oestrogen receptor (ER)- positive ductal carcinoma in situ (DCIS). In the UK, ER status is not routinely determined in DCIS. The aim of this study was to assess the ER status in women with DCIS to determine whether any clinicopathological factors could predict positivity instead of immunohistochemical assessment. METHODS: The ER and progesterone receptor (PR) status of consecutive women diagnosed with DCIS during 2001 and 2002 was determined by immunohistochemistry. RESULTS: One hundred and nineteen tumours diagnosed between 2001 and 2002 were analysed; 73.0 per cent were ER positive and 61.1 per cent were PR positive. PR positivity was associated with ER positivity (P < 0.001). Increasing tumour grade correlated with a decrease in ER and PR positivity (both P = 0.002). Comedo necrosis was associated with ER negativity (P = 0.026), PR negativity (P = 0.033) and a lower percentage of ER expression in ER-positive tumours (mean(s.d.) 82(27) versus 93(10) per cent; P = 0.021). CONCLUSION: Tumour grade and comedo necrosis were not strong enough predictors to be used as surrogates for immunohistochemical assessment. ER status should be determined before commencing endocrine therapy.

Adult↗
PubMed2004

COX-2 expression is associated with an aggressive phenotype in ductal carcinoma in situ.

Cyclooxygenase type-2 (COX-2) is overexpressed in malignant tumours including breast cancers, though the mechanism of upregulation is unclear. This study aimed to determine COX-2 expression in ductal carcinoma in situ (DCIS) in comparison to invasive breast cancer (IBC) and normal breast, and also to investigate the relationship of COX-2 expression with HER-2 expression, oestrogen receptor (ER), tumour grade and cellular proliferation (Ki67) in DCIS. Cyclooxygenase type-2, HER-2, ER and Ki67 expression were determined by immunohistochemistry on paraffin tissue sections of DCIS (n=187), IBC (n=65) and normal breast reduction tissue (n=60). Cyclooxygenase type-2 expression in DCIS (67%, P<0.001) and IBC (63%, P<0.001) was significantly greater than in normal breast (23%). There was no difference in COX-2 expression level between DCIS and IBC (P=0.87) or between normal breast from reduction mammoplasty tissue and normal breast ducts around DCIS (22%, P=0.29). In DCIS, COX-2 expression was associated with higher cellular proliferation rates (P<0.0001), nuclear grade (P=0.003), with ER negativity (P=0.003) and with HER-2 positivity (P<0.0001). Cyclooxygenase type-2 expression is upregulated in in situ breast cancer and is associated with surrogate markers of an aggressive DCIS phenotype including nonoestrogen-regulated signalling pathways. Cyclooxygenase type-2 inhibition may potentially prevent the development of ER-positive and ER-negative breast cancers.

Adult↗
PubMed2003

Biological response to hormonal manipulation in oestrogen receptor positive ductal carcinoma in situ of the breast.

Adjuvant antioestrogen therapy with tamoxifen is recommended for all women following breast-conserving surgery for ductal carcinoma in situ (DCIS) to reduce local recurrence, despite 50% of lesions being oestrogen receptor (OR) negative. We have investigated the response to hormone manipulation in DCIS by studying changes in epithelial proliferation and progesterone receptor (PR) expression as surrogate molecular markers of treatment effects in DCIS of known OR status. Women were identified who had undergone diagnostic core biopsy followed by surgery for DCIS 14-41 days later. Ki67 (a measure of epithelial cell proliferation) and PR expression were determined by immunohistochemistry on paired paraffin sections of the core biopsy and operative specimens for each patient, with OR and HER-2 measured on the operative specimen. Women were divided into three groups according to whether they had changed hormone therapy (stopped hormone replacement therapy (HRT), group 1), continued taking HRT (group 2) or were not taking HRT (group 3) between core biopsy and surgery. In OR-positive (but not in OR-negative) DCIS after oestrogen withdrawal (group 1), a fall in the mean cell proliferation (P&<0.01) was observed. A fall in PR expression between core biopsy and surgery was also seen in this group (P=0.02). No change in either mean cell proliferation or PR expression was seen in the other two groups in OR-positive or -negative DCIS. The fall in proliferation and PR expression occurred regardless of HER-2 status. In conclusion, a biological response to hormone manipulation is only seen in OR-positive DCIS tumours. Any clinical value of antioestrogen therapy is likely to be restricted to this group.

Adult↗
PubMed2003

Value of the Van Nuys Prognostic Index in prediction of recurrence of ductal carcinoma in situ after breast-conserving surgery.

BACKGROUND: The Van Nuys Prognostic Index (VNPI), an algorithm based on tumour size, tumour grade, presence of necrosis and excision margin width, is claimed to predict local recurrence after breast-conserving surgery for ductal carcinoma in situ (DCIS). The aim of this study was to examine the validity of the VNPI in a UK population. METHODS: Clinicopathological data, including VNPI subgroups, for 237 patients who had breast-conserving operations for DCIS were examined. Multivariate data analysis was performed using a Cox regression model to examine the independence and relative importance of different variables in predicting recurrence, and to compare the data with those used in derivation of the VNPI. RESULTS: The median follow-up was 47 months. There were 37 ipsilateral local recurrences. Excision margin width (P < 0.001) and tumour grade (by Van Nuys grading (P = 0.014) or simple nuclear grading (P = 0.004)) were the only independent risk factors for local recurrence. Excision margin width had three times more power than grade in predicting local recurrence. Subgrouping data by VNPI score predicted recurrence-free survival (P < 0.001), but stratified 78 per cent of patients into a group with a moderate risk of local recurrence. CONCLUSION: Excision margin width is the most important predictor of local recurrence after breast-conserving surgery for DCIS. The VNPI lacked discriminatory power for guiding further patient management.

Adult↗
PubMed2001

Extent of excision margin width required in breast conserving surgery for ductal carcinoma in situ.

BACKGROUND: Breast conserving surgery (BCS) is common practice for unifocal ductal carcinoma in situ (DCIS) less than 4 cm in size, but the extent of tumor free margin width around DCIS necessary to minimize recurrence is unclear. METHODS: Clinical and pathologic details were recorded from all patients with pure DCIS < 4 cm in size, treated with BCS between 1978 and 1997. Histologic margins were measured by using an ocular micrometer. Patients with clear margins (> 1 mm) were divided up into 3 groups for analysis based on margin of normal tissue excised: 1.1-5 mm, 5.1-10 mm, and 10.1-40 mm. RESULTS: There were 66 patients with close margins (< or = 1 mm), of which 25 cases (37.9%) recurred. The recurrence rates for the 3 clear margin groups ranged from 4.5-7.1%. Median followup was 47 months (range 12-197 mos). Risk of recurrence in the group with close margins was greater than the subgroups with clear margins (P < 0.001); no differences in recurrence was seen between the individual subgroups with clear margins. Nuclear Grade 3 was predictive of recurrence (P = 0.03). Following excision alone, the recurrence rate was 18.6%, compared with 11.1% when radiotherapy was given as adjuvant therapy. Women with clear margins following excision had a recurrence rate of only 8.1%. CONCLUSION: After BCS for DCIS, close margins were associated with a high risk of local recurrence. Radiotherapy did not compensate for inadequate surgical clearance.

Adult↗
PubMed2001

Blockade of growth factor receptors in ductal carcinoma in situ inhibits epithelial proliferation.

BACKGROUND: Ductal carcinoma in situ (DCIS) expresses c-erbB-2 receptor and epidermal growth factor receptor (EGFR). The aim of this study was to determine whether blocking of c-erbB-2 receptor with a humanized monoclonal antibody, 4D5 (HerceptinTM), or of EGFR with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (IressaTM), would decrease epithelial proliferation in DCIS. METHODS: DCIS tissue from 18 women undergoing surgery was implanted into 16 to 20 athymic nude mice per experiment (eight xenografts per mouse). Treatment commenced 2 weeks after implantation and consisted either of twice-weekly intraperitoneal injections of 4D5 10 mg/kg or of daily gavage with ZD1839 at 100-200 mg/kg for 14 days; appropriate controls were included. Xenografts were removed on days 14, 21 and 28. Proliferation was assessed by counting 1000 epithelial cells after Ki67 immuno- staining. RESULTS: ZD1839 inhibited proliferation compared with that in controls after 14 days (P < 0.01), whereas 4D5 did not. CONCLUSION: Proliferation in DCIS was decreased by EGFR tyrosine kinase inhibition but not by c-erbB-2 receptor blockade. ZD1839, an orally active and selective EGFR-TKI, has potential as adjuvant therapy in DCIS.

Adult↗
PubMed2000

Effects of a pure antiestrogen on apoptosis and proliferation within human breast ductal carcinoma in situ.

Adjuvant antiestrogen (AE) therapy has been proposed for all women with ductal carcinoma in situ (DCIS). However, many cases of DCIS are of the high-grade, estrogen receptor (ER)-negative subtype that are unlikely to respond to AE treatment. Hormonal agents work by increasing apoptosis and/or decreasing cell proliferation; therefore, we studied the effect of a pure AE on levels of apoptosis and proliferation in human DCIS xenografts using an in vivo model. Women (n = 23) with mammographic microcalcification suggestive of DCIS were identified at the time of surgery (day 0), a sample of representative tissue was obtained, divided into multiple 2x2x1-mm xenografts, and implanted s.c. into female BALB/c nu/nu mice (eight xenografts/mouse). Day 0 grafts underwent immunohistochemical assessment of ER status. Fourteen days after implantation, four xenografts were retrieved and mice were randomly divided into one of three treatment groups: (a) insertion of a slow release 2-mg 17beta-estradiol pellet; (b) weekly 5-mg injections of the pure AE Faslodex (Zeneca Pharmaceuticals); and (c) injections of a control vehicle oil alone. After 2 weeks of treatment, the remaining four xenografts were retrieved from each mouse. Retrieved xenografts containing DCIS were assessed for morphological evidence of apoptotic cell death [apoptotic index (AI)] and cell proliferation (by immunohistochemical detection of the Ki67 proliferation antigen LI). Both AI and LI were higher in the day 0 specimens of 16 ER- DCIS lesions compared with 7 ER+ DCIS lesions (mean values, 1.47% versus 0.32% and 20.6% versus 3.1%; both P<0.0001). AI and LI values within ER- DCIS did not differ between xenografts exposed to 17beta-estradiol or AE treatment compared with the controls or pretreatment values (mean AI and LI in estradiol-treated, antiestrogen-treated, and control groups 1.04% versus 0.98% versus 1.29% and 17.2% versus 20.5% versus 17.7% respectively). In contrast, treatment of mice bearing ER+ DCIS xenografts with 17beta-estradiol raised both the AI (1.03% versus 0.40%, P = 0.03) and LI (11.0% versus 5.1%, P = 0.007) compared with controls. AE therapy of ER+ DCIS xenografts did not affect proliferation but resulted in higher apoptosis than in controls (0.9% versus 0.4% respectively, P = 0.04). AE therapy should be reserved for patients with estrogen receptor positive DCIS.

Adolescent↗
PubMed1999

Endotoxin in blood and tissue in the sudden infant death syndrome.

Although the explanation for sudden infant death syndrome (SIDS) remains unknown, an increasing body of evidence now exists to suggest a possible role for bacterial toxins in the aetiology, and a number of investigators have considered that endotoxaemia could explain some of the associated features. Following the development of an animal model which confirmed that endotoxaemia could be detected after death, we studied endotoxin levels in blood and tissue samples taken at autopsy from SIDS infants, child controls and adult controls. There were significant correlations between endotoxin levels in blood and the various organs sampled particularly in SIDS cases and child controls, and blood endotoxin levels in SIDS cases were higher in those infants where there was histological evidence of mild to moderate inflammation. However, overall no significant differences were found between endotoxin levels in blood or tissue in the three study groups. Further studies into possible actions or interactions of endotoxin in SIDS are required.

Adult↗
PubMed1998

The importance of complete excision in the prevention of local recurrence of ductal carcinoma in situ.

Mastectomy probably represents over-treatment for the majority of women with screen detected ductal carcinoma in situ (DCIS) and breast-conserving surgery is now widely advocated. In this study, biopsy cavity shavings were used to ensure complete excision in 129 women undergoing breast-conserving surgery for screen detected DCIS. A margin was considered clear if DCIS was > 1 mm from any margin of excision and shavings were clear. Patients with involved margins (DCIS at resection margin) underwent re-excision, irrespective of shaving status. After re-excision, 101 women (78%) had clear margins and 28 (22%) close margins (DCIS < or = 1 mm from resection margin). Cavity shavings were histologically clear of DCIS in all cases. Ipsilateral DCIS recurrence occurred in 12 (9.3%) patients. Two recurrences also contained invasive carcinoma. The median time to diagnosis was 14 months and all recurrences occurred at the site of the previous biopsy. Seven recurrences were detected at the first annual mammogram, four at the second and one at the third. Ipsilateral recurrence was related to margin status; only 2 out of 101 (2%) patients with clear margins recurred, compared with 10 out of 28 (36%) patients with close margins. Local recurrence and close margin status both correlated with a high modified Van Nuys prognostic index score. Our results indicate that local relapse represents residual DCIS rather than true recurrence in the majority of cases. Cavity shavings have proved ineffective in ensuring complete excision. We now ensure a minimum 10 mm margin of excision around all screen-detected DCIS lesions.

Adult↗
PubMed1998

Evidence of significant apoptosis in poorly differentiated ductal carcinoma in situ of the breast.

Following breast-conserving surgery for ductal carcinoma in situ (DCIS), the presence of comedo necrosis reportedly predicts for higher rates of post-operative recurrence. To examine the role of programmed cell death (apoptosis) in the aetiology of the cell death described as comedo necrosis, we studied 58 DCIS samples, using light microscopy, for morphological evidence of apoptotic cell death. The percentage of apoptotic cells (apoptotic index, AI) was compared between DCIS with and without evidence of 'comedo necrosis' and related to the immunohistochemical expression of the anti-apoptosis gene bcl-2, mitotic index (MI), the cellular proliferation antigen Ki67, nuclear grade and oestrogen receptor (ER) status. AI was significantly higher in DCIS samples displaying high-grade comedo necrosis than in low-grade non-comedo samples: median AI = 1.60% (range 0.84-2.89%) and 0.45% (0.1-1.31%) respectively (P < 0.001). Increasing nuclear grade correlated positively with AI (P < 0.001) and negatively with bcl-2 expression (P = 0.003). Bcl-2 correlated negatively with AI (P = 0.019) and strongly with ER immunoreactivity (P < 0.001). Cellular proliferation markers (MI and Ki67 immunostaining) correlated strongly with AI and were higher in comedo lesions and tumours of high nuclear grade (P < 0.001 in all cases). Thus, apoptosis contributes significantly to the cell death described in ER-negative, high-grade DCIS in which a high proliferative rate is associated with a high apoptotic rate. It is likely that dysregulation of proliferation/apoptosis control mechanisms accounts for the more malignant features typical of ER negative comedo DCIS.

Adult↗
PubMed1997

Assessment of hormone dependence of comedo ductal carcinoma in situ of the breast.

BACKGROUND: Ductal carcinoma in situ (DCIS) represents 20%-30% of breast cancers detected by clinical screening (i.e., mammography). More than 50% of DCIS lesions may be estrogen receptor negative and, therefore, hormone independent. However, the role of estrogen in the natural history of DCIS is unknown. PURPOSE: A novel in vivo (i.e., xenograft) model was developed to determine to what degree DCIS lesions depend on estrogen for growth. METHODS: Specimens of breast tissue were collected from 52 women during diagnostic or therapeutic surgical procedures. Portions of each specimen were randomly selected and analyzed by histology and thymidine labeling (to measure cell proliferation). The remainder of each specimen was implanted into five to 18 athymic BALB/c nu/nu mice (depending on the amount of tissue available), with eight pieces of approximately 2 mm x 2 mm x 1 mm implanted at different locations on the back of each mouse. Half of the mice received implants containing estrogen (2 mg 17 beta-estradiol), and the other half received placebo implants. Levels of cell proliferation in xenografts, recovered after 14, 28, 42, or 56 days in the mice, were measured by thymidine labeling or by immunohistochemistry through use of an antibody specific for the Ki-67 nuclear antigen. Immunohistochemistry was also used to measure the levels of estrogen receptor in the tissue specimens. Serum 17 beta-estradiol levels in the mice were measured by radioimmunoassay. RESULTS: Initial levels of cell proliferation were approximately 10-fold higher in 10 specimens with estrogen receptor-negative, comedo (i.e., more malignant in appearance) DCIS than in four specimens with estrogen receptor-positive DCIS (mean proliferation indices: 22% versus 1.9%, respectively; two-sided P < .001). Xenografts from the majority of specimens survived up to 56 days in the mice and maintained good architectural and cellular preservation. Estrogen treatment of the xenograft-bearing mice had no effect on the high level of cell proliferation observed in estrogen receptor-negative, comedo DCIS specimens (two-sided P = .89). In contrast, increased levels of cell proliferation in response to estrogen supplementation were measured in three estrogen receptor-positive, noncomedo DCIS specimens (two-sided P < .001). However, even with estrogen treatment, cell proliferation levels in estrogen receptor-positive DCIS specimens did not reach those seen in estrogen receptor-negative DCIS specimens. CONCLUSION AND IMPLICATION: Estrogen receptor-negative, comedo DCIS lesions appear to be estrogen independent; therefore, antiestrogen (e.g., tamoxifen) therapy may not benefit patients with comedo DCIS.

Adult↗
PubMed1995

Can histopathologists diagnose bronchopneumonia?

OBJECTIVES: To assess histopathologists' ability to accurately diagnose bronchopneumonia, both on naked eye and microscopic examination; to extrapolate from the error rate to determine whether the role of the necropsy in monitoring the epidemiology of clinical error might be compromised. METHODS: Review of archival histological sections and necropsy reports from two teaching hospitals in Manchester. The main outcome measures identified were the proportions of macroscopic diagnoses of bronchopneumonia which were confirmed by the original pathologist on histological examination, and which could be confirmed on histological review by independent pathologists, together with the proportion of discrepant diagnoses remedied in the final report by the original pathologist. RESULTS: Of 279 cases where a macroscopic diagnosis of bronchopneumonia had been noted in the original provisional necropsy report, the original histopathologist described bronchopneumonia in only 206 (73.8%) in the subsequent final report, which took histology into account. Bronchopneumonia could be confirmed on independent histological review in only 193 (69.2%) of these cases. The original histopathologist diagnosed 74 cases of bronchopneumonia on histological grounds only, of which only 57 (77.0%) could be confirmed on review. Of a total of 160 discrepancies between the original naked eye diagnoses and the final reviewed diagnoses, only 130 (81.3%) had been remedied by the original pathologist. CONCLUSIONS: There is a considerable discrepancy rate between naked eye diagnoses of bronchopneumonia at necropsy and diagnoses confirmed on microscopy. If this discrepancy rate is extrapolated to other common lesions, then the role of the necropsy in clinical audit may be compromised. Pathologists need to take steps to monitor and improve their own diagnostic standards.

Autopsy↗
PubMed1994

Periductal inflammation and cigarette smoke.

BACKGROUND: Cigarette smoking has been implicated in the etiology of periductal mastitis. The mechanism by which it causes inflammation around the mammary ducts is unknown. STUDY DESIGN: Inflammation and dilatation of the mammary ducts were compared in two groups of women with proven histologic diagnoses of periductal mastitis (PDM, n = 133) and intraductal papilloma (IDP, n = 98) over an eight year period. This study was done to determine if the number of cigarettes smoked correlated with the amount of periductal inflammation seen in PDM. Duct dilatation, periductal inflammation, and squamous metaplasia were assessed objectively by two pathologists without knowledge of the clinical parameters. RESULTS: Women with PDM were significantly more likely to be smokers than women with IDP (p < 0.001). Women with severe periductal inflammation were more likely to be younger (p < 0.05) whereas those with duct dilatation were more likely to be older (p < 0.02). Women with PDM who were heavy smokers (more than ten cigarettes per day) had more periductal inflammation (p = 0.0006) and squamous metaplasia of the lactiferous ducts (p < 0.02) compared with light or nonsmokers. Duct dilatation did not correlate with smoking habits. CONCLUSIONS: Cigarette smoking appears to be an important etiologic factor in periductal mastitis and appears to have direct toxic effects on the mammary ducts.

Adult↗
PubMed1993

Assessment of tumour vascularity as a prognostic factor in lymph node negative invasive breast cancer.

The association between tumour vascularity and relapse was examined in 93 patients with lymph node negative (LNN) invasive breast cancer. Factor VIII-related antibody was used to stain the microvessels. Vascularity was defined by the number of vessels per field counted in the area of highest vascular density at 100 x magnification. These vascular counts were divided into three groups of vascular density (group I: < 67, group 2: 68-100, group 3: > 101 vessels/field). Cross-tabulation analysis revealed a significant relationship between vascular density and tumour grade (P = 0.027). No association was found between vascularity and tumour size, tumour type, age or menopausal status. Survival analysis showed no association between vascularity and relapse-free (P = 0.92) or overall survival (P = 0.99). Significant associations between tumour grade and relapse-free (P = 0.0048) and overall survival (P = 0.0064) and between tumour size at the cut off of 15 mm diameter and relapse-free (P = 0.0097) and overall survival (P = 0.0271) were found. When grade was taken into account the effect of tumour size became non-significant (P = 0.059). Our results suggest that assessment of vascularity is not an independent prognostic factor in LNN invasive breast cancer.

Adult↗
PubMed1993

Foreign body giant cell reactions and ossification associated with benign melanocytic naevi.

AIMS: To assess the incidence of foreign body giant cell reactions and ossification in benign/melanocytic naevi; and to examine their pathological features to gain an insight into their pathogenesis. METHODS: Intradermal (n = 185) and compound naevi (n = 110) from a routine histology service, together with 60 naevi submitted to an ophthalmic pathologist, were examined for foreign body reactions and ossification. Additional cases were identified prospectively in the course of routine reporting. The clinical and pathological features of positive cases were assessed. RESULTS: Foreign body reactions were identified in nine (4.9%) intradermal and four (3.6%) compound naevi, but in none of the naevi from around the eye. One intradermal naevus showed ossification. A further 11 naevi showing foreign body reaction and five showing ossification alone were identified prospectively. The 24 naevi showing a foreign body reaction had a similar age and sex distribution to controls but were more likely to occur on the head and neck. The reaction usually occurred deep to the naevus, sometimes in relation to a hair follicle, and fragments of hair or keratin were identified in most. Osteoid or bone was present within the reaction in five. In six other naevi, all from the head and neck of women, osteoid or mature bone was present deep to the naevus in the absence of a giant cell reaction. CONCLUSIONS: Foreign body giant cell reactions occur not uncommonly in relation to benign naevi, as a result of follicular damage, possibly due to trauma. The similar siting of foci of bone suggests that ossification occurs as a secondary phenomenon in these cases.

Adult↗