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PubMed2003

Brief assessment of priority symptoms in hormone refractory prostate cancer: the FACT Advanced Prostate Symptom Index (FAPSI).

BACKGROUND: The objective of this study was to construct and validate a brief, clinically-relevant symptom index for advanced prostate cancer. METHODS: Questions were extracted from a commonly-used multi-dimensional cancer quality of life instrument with prostate-specific items, the Functional Assessment of Cancer Therapy-Prostate (FACT-P). Surveys of disease-related symptoms were presented to an international sample of 44 expert physicians. Each expert narrowed the list to no more than five of the most important symptoms or concerns to monitor when assessing the value of treatment for advanced prostate cancer. Symptoms/concerns endorsed at a frequency greater than chance probability (17%) were retained for the symptom index and called the FACT Advanced Prostate Symptom Index-8 (FAPSI-8): pain (three items), fatigue, weight loss, urinary difficulties (two items), and concern about the condition becoming worse. The FAPSI-8 was validated using data from a clinical trial of 288 men being treated for hormone refractory prostate cancer. RESULTS: The FAPSI-8 showed good internal consistency (r = 0.67-0.80); association with existing FACT scales (e.g., FACT-P, Physical Well-being, Functional Well-being; r = 0.44-0.85, p <.0001), responsiveness to clinical change (Guyatt's Responsiveness statistic = 1.29), and ability to differentiate patients by performance status (p <.0001). A six-item alternate version of the FAPSI was also evaluated with comparable results. CONCLUSIONS: This project produced a reliable and valid list of the eight most important clinician-rated targets of drug therapy for advanced prostate cancer. These questions perform comparably to the longer derivative questionnaire. Examination of patient agreement with this priority list and the extent to which changes in these 8 targets are related to meaningful clinical benefit to the patient are important next steps for future research.

Aged↗

PubMed1988

The value of the measurement of serum prostate specific antigen in patients with benign prostatic hyperplasia and untreated prostate cancer.

Serum prostate specific antigen (PSA) levels were measured in 139 patients with benign prostatic hyperplasia (BPH) and in 88 patients with prostate cancer who were managed by deferred treatment. Acute urinary retention and large prostate glands tended to be associated with high PSA levels, but at levels greater than 10 ng/ml there was a significant risk of carcinoma being found on subsequent histological examination. The risk of progression of untreated prostate cancer was associated with levels of PSA greater than 20 ng/ml and with a high rate of change of PSA level. The value of measuring PSA in these patients is discussed.

Aged↗

PubMed1999

[Interstitial radiotherapy and prostate cancer. Analysis of the literature. Subcommittee of Prostate Cancer of C.C.A.F.U].

The C.C.A.F.U. reviewed the role of interstitial radiotherapy by analysing 66 references published over the last 10 years, obtained from the Medline database. RESULTS IN TERMS OF PSA MONITORING: Various modalities of analysis of the laboratory follow-up after radiotherapy have been reported in the literature. The American Society of Therapeutic Radiation Oncology (ASTRO) defines biochemical progression after irradiation by the existence of three consecutive elevations of PSA above the nadir without taking into account the value of this nadir, but the risk of progression appears to continually increase as a function of the PSA nadir; this definition also makes it difficult to compare radiotherapy and surgery. Consequently, we only analysed series reporting results according to strict laboratory criteria (PSAn < or = 1 ng/ml, PSAn < or = 0.5 ng/ml) more than 4 years after treatment. For stage T1-T2 and well differentiated tumours, the 5-year results of interstitial radiotherapy were comparable to those of surgery, and superior to those of external radiotherapy for poorly differentiated tumours. For stage T3 tumours, only 192Ir and, to a lesser extent, 103Pd associated with external irradiation gave slightly better results than those of external irradiation. RESULTS IN TERMS OF FOLLOW-UP BIOPSIES: Post-treatment biopsies may become negative after a considerable period of time, which justifies follow-up biopsies beyond the 24th month. The significance of persistence of tumour cells on the follow-up biopsy is unclear. A correlation between the follow-up biopsy and PSA monitoring has been demonstrated. RESULTS IN TERMS OF MORBIDITY: Frequency of early irritating symptoms (45% of cases). Dysuria and retention are frequent late complications, and there is a high risk of incontinence after associated endoscopic resection. The impotence rate is low (25%), but sexual potency decreases with time. CONCLUSION: Interstitial radiotherapy can be rightfully considered to be a curative treatment for localized prostate cancer. However, this treatment modality requires further evaluation due to the insufficient follow-up of recent series and the absence of comparative studies.

Brachytherapy↗

PubMed1997

[Serum prostate-specific antigen in a urological outpatient clinic. Efficacy of age-specific and prostate volume-specific reference range in detection of prostate cancer].

BACKGROUND: Prostate specific antigen (PSA) is the most available marker for early detection of prostate cancer. Nevertheless, the standard upper range of PSA (4.0 ng/ml) does not demonstrate sufficient specificity. Thus, we evaluated the distribution of PSA by age and prostate volume in urological patients, and determined PSA reference ranges by the each parameter. Diagnostic efficacy was also evaluated. METHODS: Three-hundred-seventy-five patients who visited the urological outpatient clinic between January, 1994 and February, 1996, and were considered not to have prostate cancer, were analyzed PSA levels by age. Among them, two-hundred-seventy-six patients in whom prostate volumes were presumed by means of transabdominal ultrasonography, were evaluated a correlation of PSA values with prostate volumes. Using the age-specific and volume-specific reference ranges determined by this analysis, sensitivity, specificity, and positive predictive value were compared with those in case using the 0.0 to 4.0 ng/ml reference range and the 0.0 to 11.7 ng/ml reference range, in 72 patients (cancer 24, noncancer 48) in whom histological examinations were performed in the same period. RESULTS: We found statistically significant slight correlations among age, prostate volume, and PSA. By using the age-specific reference range, volume-specific reference range, and 0.0 to 11.7 ng/ml reference range, we could elevate the specificity and positive predictive value approximately by 65% and 35%, respectively, compared with those of the 0.0 to 4.0 ng/ml reference range. CONCLUSION: In order to decrease the number of rather invasive than necessary prostate biopsies, age-specific and volume-specific reference ranges are useful in urological outpatient clinic.

Age Factors↗

PubMed1997

Orthotopic implantation of human prostate cancer cell lines: a clinically relevant animal model for metastatic prostate cancer.

BACKGROUND: To study the metastatic behavior of human prostate cancer cell lines, orthotopic injection in nude mice was performed. METHODS: Local tumor growth, metastasis formation, prostate-specific antigen, and androgen receptor expression were examined. RESULTS: Hormone-independent cell lines (PC-3, PC-3-125-IL, and TSU-Pr1) were highly tumorigenic and had a higher rate of lymph node metastasis after orthotopic than after subcutaneous implantation. PC-3 cell lines also consistently metastasized to the lungs. The androgen-sensitive LNCaP cell line showed local growth in 7 of 10, and lymph node metastasis in 4 animals. Significant serum PSA levels and strong receptor expression in primary and metastatic tumor tissues were observed. CONCLUSIONS: These results demonstrates that orthotopic implantation of human prostate cancer cell lines, including LNCaP, reproducibly leads to metastasis formation in nude mice.

Animals↗

PubMed2000

Medical therapy of prostate cancer: 1999.

Prostate cancer is the most commonly diagnosed male malignancy and the second most common cause of male cancer death in the U.S. The principles of management of newly diagnosed metastatic prostate cancer have changed little in the last 50 years. Medical therapy continues to have no standard role in the management of localized disease. The various hormonal monotherapy approaches targeting androgen deprivation yield comparable results in the treatment of advanced disease. Supplementing an LHRH agonist (but not orchiectomy) with an antiandrogen may improve survival in men with minimal disease, but the economic cost and the risk for significant impairment of quality of life are quite high. The benefit of combined androgen blockade for patients with more extensive disease remains unclear, with support for this approach waning in recent years. New chemotherapeutic agents and combinations of such, as well as agents with entirely new mechanisms of action, recently have shown encouraging results in the treatment of HRPC. Much additional research is needed to improve our armamentarium against this epidemic disease.

Androgen Antagonists↗

PubMed1999

Prostate-Specific Membrane Antigen: Much More Than a Prostate Cancer Marker.

Prostate cancer continues to be the most common cancer and second leading cause of cancer-related death among men. The use of markers, particularly serum-based prostate specific antigen (PSA), has contributed to the rapid rise in diagnosed cases in the late 1980s and early 1990s, but new diagnostic and possible therapeutic markers are needed and are currently being evaluated. One of these, prostate-specific membrane antigen (PSMA), is an approximately 100-kDa type II transmembrane protein originally thought to be highly selectively expressed in all types of prostatic tissue, with expression being upregulated in androgen-depleted or androgen-independent states. The radioimmunoconjugate form of the anti-PSMA monoclonal antibody (mAb) 7E11 is currently being used to diagnose prostate cancer metastasis and recurrence. In addition, Phase I and II trials have started utilizing PSMA in different therapeutic ways, with promising results. Recent exciting work has demonstrated PSMA expression in endothelial cells of vessels restricted to the tumor-associated neovasculature. This finding expands the possible beneficial uses of PSMA, as new anti-PSMA mAbs continue to be developed.

Journal Article↗

PubMed1999

Estrogen receptors in the human male prostatic urethra and prostate in prostatic cancer and benign prostatic hyperplasia.

Estrogen receptors (ERs) in the prostate and prostatic urethra were examined in 33 men with benign prostatic hyperplasia (BPH) and in 11 with prostate cancer (PC). The Abbot monoclonal ER-ICA assay was used for immunohistochemical investigation. In the BPH group, ERs were revealed in the prostatic stroma in eight cases and in the glandular epithelium in one. In four cases ERs were seen in the prostatic stroma and in the glandular epithelium. In the prostatic urethra, ERs were found in 19 cases located in the urothelium, lamina propria and/or periurethral glands. In the PC group, ERs were demonstrated in the prostatic stroma and/or prostatic urethra in 6 out of 11 cases. In both BPH and PC patients, immunoreactivity was weak and confined to few cells, indicating low ER content in the prostate as well as in the prostatic urethra. Dextran-coated charcoal (DCC) analysis was used for detection and quanticization of cytosolic and nuclear ERs. In the BPH group, ERs were detected once in the prostate and prostatic urethra in the nuclear and cytosol, and additionally in the prostatic urethra in the cytosol fraction in three cases. In all cases, ER content was low, ranging from 10-15 fmol/mg protein. In the PC group, ERs were detected in the prostatic urethra and/or prostate in the cytosol fraction from two patients. The contents were low, ranging from 10-13 fmol/mg protein. We conclude that in human BPH and PC, ERs can be present in the prostate and prostatic urethra. In the prostate, ERs are mainly located in the stroma, but in BPH specimens they can also be found in the glandular epithelium. Biochemically, the use of the DCC analysis is of limited value, since ER content in the human prostate and prostatic urethra is at the limit of detection with this method.

Adenocarcinoma↗

PubMedDate not supplied

From "death sentence" to "good cancer": couples' transformation of a prostate cancer diagnosis.

BACKGROUND: While little is known about the couple's process of moving from diagnosis of prostate cancer to treatment, it is acknowledged that cancer-and prostate cancer in particular-affects the couple, not just the patient. This highlighted the need to illuminate this process as a foundation for development of nursing interventions. OBJECTIVES: To describe the experience of men who are diagnosed with prostate cancer and their wives, from the time of diagnosis through staging to the completion of radical prostatectomy. METHODS: A qualitative cross-sectional approach was used to elicit couples' experiences from diagnosis to the time of the interview including their response to diagnosis, their treatment decision-making process, and how the couple moved from the decision to have surgery through the staging process to the time that the surgery was completed. A total of 20 couples participated. RESULTS: Analysis of the data revealed that a number of themes related to the couples' process of moving from diagnosis to treatment. Initially, the diagnosis of prostate cancer represented a loss of control that led these couples to put themselves through a "crash course" on prostate cancer. The information gathered led these couples to conclude that prostate cancer was "good cancer." This enabled them to refocus their energies and start their "quest for the best" treatment and surgeon. Once this was accomplished, the couples began to prepare for surgery that culminated in the turning over of complete control to the surgeon and hospital staff at the time of surgery. CONCLUSIONS: The participants discovered they were able to manage the demands presented by the intrusion of a cancer diagnosis and mount a response to what at first threatened to be a "death sentence." By engaging in the challenge of gathering a volume of facts and a variety of details, they could make informed decisions. Couples were able to regain a sense of control through the engagement in decision-making related to treatment, surgeon, and hospital, and through the transformation of the meaning of the malignant diagnosis to that of a "good cancer."

Adaptation, Psychological↗

PubMed2001

Differential diagnosis of prostate cancer and benign prostate hyperplasia using two-dimensional electrophoresis.

Prostate specific antigen (PSA) is a protease which is characteristic of the prostate. It is widely used as a serum marker for the early diagnosis of prostate cancer (PCa). Nevertheless, for concentrations between 4 and 10 ng/mL, PSA does not enable PCa to be distinguished from benign diseases, such as benign prostate hyperplasia (BPH). In sera, the use of a ratio between free PSA (PSA uncomplexed with protease inhibitor) and total PSA (free PSA and PSA bound to alpha-1 anti-chymotrypsin) enables the "gray zone" to be reduced, but an important proportion of patients are still wrongly classed. Using two-dimensional electrophoresis, we demonstrated using 52 PCa and 40 BPH well-documented clinical cases that BPH sera show a significantly greater percentage of low-molecular-weight free PSA elements (IwPSA) than PCa sera. In our study, the use of a ratio between IwPSA and standard free PSA enables the correct diagnosis of 100% of PCa and 82.5% of BPH cases as against when 73.1% and 42.5% respectively were correctly diagnozed using the total PSA and the free/total PSA ratio. This important finding may be related to differences in the mechanism secreting PSA from the prostate into the bloodstream. We have shown how a tissue marker may be turned into a powerful tumor marker by events probably unrelated to its expression.

Adult↗

PubMed2006

Computer-aided detection of prostate cancer.

BACKGROUND: Prostate cancer is one of the most frequent cancers in men and is a major cause of mortality in developed countries. Detection of prostate carcinoma at an early stage is crucial for successful treatment. MATERIAL AND METHODS: A method for the analysis of transrectal ultrasound images aimed at computer-aided diagnosis of prostate cancer is tested in this paper. First, two classifiers based on k-nearest neighbors and Hidden Markov models are compared. Second, the diagnostic capacity of our system is tested by means of a set of experiments where humans with varying degrees of experience classified a set of ultrasound images with and without the aid of the computer-aided system. The corpus used in this study was specifically acquired for this purpose. It consists of 4944 ultrasound images corresponding to 303 patients, and is publicly available for non-commercial use upon request. RESULTS: The best classification results achieve an area under the receiver operating characteristic curve of 61.6%. However, the diagnostic capacity of an expert urologist using the computer-aided system improves only slightly compared with his/her capacity without the aid of the system. CONCLUSIONS: Despite the difficulty of this task, the obtained results indicate that discrimination between cancerous and non-cancerous tissue is possible to a certain degree. The computer-aided system helps an inexperienced user to make a better diagnosis, however it must be able to perform better in order to be useful in a real-world clinical context.

Diagnosis, Computer-Assisted↗

PubMed2001

[Management of a hormone dependent cancer with endocrine therapy--prostate cancer].

We offer a historical overview of endocrine therapy for prostate cancer. Hormone therapy remains the cornerstone of treatment for patients with locally advanced or metastatic prostate cancer. Although this therapy has been traditionally performed by oral estrogen or bilateral orchiectomy, there are now two most important pharmacological hormonal therapies: LH-RH agonist and antiandrogen therapy. We do not have yet sufficient data to conclude whether maximal androgen blockade from the combined use of an LH-RH agonist and an antiandrogen will prolong the survival in patients with metastatic prostate cancer, nor to conclude whether neoadjuvant androgen ablation therapy improves the disease-free survival of patients after radical prostatectomy. New treatment strategies and modalities such as LH-RH antagonists, intermittent hormonal therapy, and antiandrogen monotherapy are appearing and being tested in clinical trials. However, to date there is still no effective therapy for patients who have hormone refractory disease.

Androgen Antagonists↗

PubMed1998

Calcium channel blocker use and the risk of prostate cancer.

A recent study suggested that the risk of all cancers, including prostate cancer, is increased by the use of calcium channel blockers. The objective of this study was to determine whether prostate cancer is associated with calcium channel blocker use. A case-control study was conducted in Massachusetts using cases diagnosed from December 1992 through February 1995. Cases were men identified by tumor registrars who were less than 70 years old with newly diagnosed prostate cancer. Controls were men with no history of prostate cancer or symptoms of undiagnosed prostate cancer, and were matched to the cases on precinct of residence and half-decade of age. A total of 1217 cases of prostate cancer and 1400 community controls are included in this analysis. Data were collected by telephone interview. Multiple logistic regression was used to estimate relative risks for calcium channel blockers use while controlling for confounding. The relative risk for prostate cancer for any use of calcium channel blockers relative to nonuse was 1.2 (95% confidence interval [CI], 0.9-1.5). There was no evidence of a trend according to duration of use. When the analysis was confined to symptomatic men, the relative risk estimate was 1.1 (0.8-1.4) overall and 1.2 (0.8-1.7) among those aged 65 to 69 years. Relative risk estimates for the use of other classes of antihypertensive drugs among symptomatic men were close to 1.0; the corresponding estimates among asymptomatic men were generally further from 1.0. These findings suggest that calcium channel blockers do not increase the risk of prostate cancer. The differences in the relative risk estimates between symptomatic and asymptomatic men are compatible with detection bias. Because of the widespread use of Prostate-Specific Antigen testing for early detection of prostate cancer, potential detection bias needs to be considered in future studies of prostate cancer.

Adult↗

PubMed2002

Diagnostic approach to prostate cancer using total prostate specific antigen-based parameters together.

This prospective study investigated the value of serum total prostate specific antigen (tPSA)-based parameters in the diagnosis of prostate cancer (PCa). Serum tPSA, free to tPSA ratio (f/tPSA), PSA density (PSAD), and PSA transition zone (PSAT) were evaluated in 110 patients with histologically confirmed benign prostate hyperplasia (BPH) and 98 patients with PCa. Once the serum tPSA was elevated (greater than 4 ng/ml) or digital rectal examination (DRE) was suspicious, transrectal ultrasound-guided biopsies were recommended. The tPSA, f/tPSA, PSAD, and PSAT levels were significantly different between the BPH and PCa groups. In patients with a tPSA level of 4.1-9.9 ng/ml or an abnormal DRE finding, only PSAT was found to have discriminating power. The cut-off values were 0.15 for f/tPSA, 0.30 for PSAT, and 0.15 for PSAD. The diagnostic sensitivity of a positive result for one of these parameters in the whole group was 84%, but 75% in patients with a tPSA of 4.1-9.9 ng/ml or an abnormal DRE finding. The diagnostic specificity of positive results for 3 parameters was 92% in the whole group and 93% in patients with a tPSA of 4.1-9.9 ng/ml or an abnormal DRE finding. All parameters were influenced by the histological grades. Histological grades showed a negative correlation (r = -0.56) with f/t PSA and a positive correlation (r = 0.44) with PSAT. No diagnostic marker investigated heretofore was able to rule out or detect early PCa in patients with a PSA level of 4.1-9.9 ng/ml. Using the PSA-based parameters together can be helpful in management of these patients. If all of the PSA-based parameters are negative, biopsy might be postponed; patients who have three positive PSA-based parameters should be biopsied. In case of one or two of the parameters, the patient's age and race should be considered in clinical decision-making.

Aged↗

PubMed2004

Dietary influences on endocrine-inflammatory interactions in prostate cancer development.

Prostate cancer is the most frequently diagnosed non-cutaneous cancer and is the second leading cause of cancer death in American men. The focus of this review is to define the relationship between hormonal (testosterone/estrogens) stimulation of chronic inflammation, generation of reactive oxygen species (ROS), and uncontrolled prostate cell proliferation, and review putative dietary chemoprevention strategies that focus on these processes. It has been proposed that elevated estrogen in men who already have high blood testosterone are at high risk for prostate cancer. We hypothesized that elevated estrogen, in the presence of testosterone, causes prolonged activation of a redox-sensitive transcription factor, nuclear factor kappa B (NF kappa B), that initiates and amplifies an inflammatory cascade within the prostate and results in sustained oxidative and nitrative damage. The inflammatory cascade is proposed to link with uncontrolled proliferation through up-regulated Wnt signal and abnormal catenin accumulation in the prostate. Finally, a strategy that emphasizes a "whole food" based approach to cancer prevention by selecting food products that bear anti-inflammatory and anti-proliferative properties may be most promising as an effective dietary chemopreventive strategy.

Diet Therapy↗

PubMed2005

Bayesian neural networks for bivariate binary data: an application to prostate cancer study.

Prostate cancer is one of the most common cancers in American men. The cancer could either be locally confined, or it could spread outside the organ. When locally confined, there are several options for treating and curing this disease. Otherwise, surgery is the only option, and in extreme cases of outside spread, it could very easily recur within a short time even after surgery and subsequent radiation therapy. Hence, it is important to know, based on pre-surgery biopsy results how likely the cancer is organ-confined or not. The paper considers a hierarchical Bayesian neural network approach for posterior prediction probabilities of certain features indicative of non-organ confined prostate cancer. In particular, we find such probabilities for margin positivity (MP) and seminal vesicle (SV) positivity jointly. The available training set consists of bivariate binary outcomes indicating the presence or absence of the two. In addition, we have certain covariates such as prostate specific antigen (PSA), gleason score and the indicator for the cancer to be unilateral or bilateral (i.e. spread on one or both sides) in one data set and gene expression microarrays in another data set. We take a hierarchical Bayesian neural network approach to find the posterior prediction probabilities for a test and validation set, and compare these with the actual outcomes for the first data set. In case of the microarray data we use leave one out cross-validation to access the accuracy of our method. We also demonstrate the superiority of our method to the other competing methods through a simulation study. The Bayesian procedure is implemented by an application of the Markov chain Monte Carlo numerical integration technique. For the problem at hand, our Bayesian bivariate neural network procedure is shown to be superior to the classical neural network, Radford Neal's Bayesian neural network as well as bivariate logistic models to predict jointly the MP and SV in a patient in both the data sets as well as in the simulation study.

Bayes Theorem↗

PubMed2006

[Screening for prostate cancer: arguments "against"].

Prostate cancer screening is controversial since PSA assay has been made available. Screening supporters consider that early diagnosis allows better and less aggressive treatment. These arguments lie on longitudinal cohort studies without controls. Randomized studies are required to assess the correlation between screening and mortality lowering. Two studies are being performed and their results will be available within three or four years. Consequently, the validity of screening is unknown. Nevertheless, the analysis of various parameters demonstrates that the reduction of cancer mortality related to screening is low. According to these data and as recommended by health institutions prostate cancer screening is not required. At the present time, detection asked by the patient himself remains the good attitude between negligence and excessive attitude.

Humans↗

PubMed2001

Testosterone and prostate specific antigen stimulate generation of reactive oxygen species in prostate cancer cells.

Prostate specific antigen, the clinical marker for prostate cancer, is a neutral serine protease whose function is to lyse seminal proteins. Recent work by our laboratory has suggested that prostate specific antigen stimulates the generation of reactive oxygen species in prostate cancer cells. Using 2',7'-dichlorofluorescin diacetate, a dye that fluoresces in the presence of hydrogen peroxide or hydroxyl radicals, we found that prostate specific antigen markedly stimulated reactive oxygen species generation in LNCaP cells. The effect was concentration dependent and its specificity was supported by the fact that anti-prostate specific antigen antibodies abolished the response. Since testosterone stimulates the production of prostate specific antigen, we considered that the reactive oxygen species response to testosterone may be linked to prostate specific antigen. We found that the testosterone effect on reactive oxygen species was blocked by flutamide and by anti-prostate specific antigen antibody. Additionally, though PC3 and DU145 could not respond to testosterone, they readily increased reactive oxygen species in response to prostate specific antigen. Focusing on the mechanism of the prostate specific antigen effect, we tested two other serine proteases, trypsin and chymotrypsin, but found no effect on reactive oxygen species in LNCaP cells. Nevertheless, serine protease inhibitors, alpha(1)-antichymotrypsin, alpha(2)-macroglobulin and Bowman-Birk inhibitor, blocked reactive oxygen species generation stimulated by prostate specific antigen. This apparent paradox was investigated with the use of a specific anti-'prostate specific antigen' antibody which recognizes an epitope away from the catalytic site and which does not inhibit protease activity. Despite the lack of inhibition of proteolytic activity, this antibody blocked the effect of prostate specific antigen on reactive oxygen species generation. These findings suggest that although the integrity of the prostate specific antigen molecule is necessary for stimulating reactive oxygen species generation, its proteolytic activity is not. The underlying mechanism is currently under investigation.

Blotting, Western↗