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PubMed1989

The percentage of aneuploid cells is significantly correlated with survival in accurately staged patients with stage 1 resected squamous cell lung cancer and long-term follow up.

Previous studies have shown that ploidy is an important prognostic determinant in lung cancer, but in those studies followup was restricted to three years, while patients with Stage 1, 2 and 3 disease and with different histological subtypes were included. Theoretically, these factors could have influenced the findings, especially since aneuploidy strongly correlated with the stage of disease. Because of this, tumor ploidy was studied in surgically resected stage 1 (T1/2, N0M0) squamous cell lung cancer patients with a minimal followup of 6 years. All patients were accurately staged by mediastinal lymph node mapping. Fifty-two from a group of 1539 patients with lung cancer diagnosed between 1980 and 1986 inclusive, fulfilled these criteria. Of these tumors, 23 (44%) were diploid with a 6-year survival of 53% and 29 (56%) were aneuploid with a 6-year survival of 48%. Although diploidy tended to be associated with local relapse of the tumor and aneuploidy with distant metastases, the difference was not significant and neither showed a survival advantage. However, within the aneuploid tumors, there was a significant correlation between the percentage of aneuploid cells and survival, defined as event-free or time to death. Seventeen patients with a percentage of more than 10 had a worse outcome (12 died, 6 years survival 35%), than to the other 12 patients with less than 10% aneuploid cells (2 died, 6-year survival 78%) (Mantel-Cox = 6.04, P = 0.01). This implies that in patients with accurately staged and histologically proven Stage 1 squamous cell lung cancer and long-term follow up, DNA content classified as diploid and aneuploid is not a prognostic factor for survival, but the percentage of aneuploid tumor cells is correlated with the prognosis.

Aged↗

PubMed1994

Prognostic significance of cell DNA content in early-stage ovarian cancer (FIGO stages I and II/A) by means of automatic image cytometry.

Paraffin-embedded material from 69 patients with epithelial ovarian cancer FIGO stages I and II/A (including 21 patients with borderline carcinoma) was studied with automatic DNA image cytometry. Univariate analysis indicated a significant difference in survival based on the presence of nuclei with high DNA content (higher than 5 C). A group of patients with less than 0.2% cells with high DNA content had a 6-year survival of 87%, whereas in a group of patients with more than 0.2% of such cells, 6-year survival was 49%. This parameter remained significant when used in a group of stage I/a and I/b patients. Statistical analysis of diploid vs. non-diploid tumors also showed significant difference in survival. Separate analysis of 48 invasive ovarian cancers indicated that ploidy, the percentage of cells with high DNA content and tumor stage (stage I/a + b vs. stages I/c + II/a) reached significance for survival, whereas grading did not. In addition, comparison of clinical stage, grading, ploidy and the percentage of cells exceeding 5 C with a threshold at 0.2% by means of a multivariate analysis (Cox regression model) showed that only the percentage of cells exceeding 5 C remained statistically significant.

Adult↗

PubMed1999

Trisomy 8 in stage I and stage III ovarian cancer detected by fluorescence in situ hybridization.

Ovarian cancer is the leading cause of death from gynecologic maligancy among women in the United States. In 1997, there were nearly 27,000 ovarian cancer cases with over 14,000 deaths. Recent attempts at early detection of ovarian cancer have been aimed at the identification of biomarkers that would indicate an underlining malignant process or reflect the biological behavior of the tumor. Our previous studies revealed that chromosome 8 copy number abnormality, especially trisomy, is common in several cancers. Archival tissues from 24 cases of papillary serous ovarian carcinoma (10 stage I and 14 stage III) were analyzed by fluorescence in situ hybridization (FISH) with a chromosome 8-specific alpha-satellite probe (Oncor, Gaithersburg, MD). The analysis was done according to standard protocols of the Lifespan Academic Medical Center Cytogenetics Laboratory at Rhode Island Hospital. Twenty-one of 24 cases (87.5%) were found to be trisomic for chromosome 8, if a cutoff point of >/=15% cells with three signals is adopted. Overall, 80% of stage I and 93% of stage III tumors had trisomy 8. This study confirms the presence of a high frequency of trisomy 8 in both early and late stages of the disease and suggests that trisomy 8 may be an early event in the multistep process leading to ovarian cancer. It is of interest to note that a higher frequency of trisomy 8 was found in a higher stage of disease, consistent with our previous results on breast cancer. Thus, additional FISH studies of ovarian tumors for chromosome 8 copy number assessment may be warranted.

Adult↗

PubMed1997

Stage T1c prostate cancer: defining the appropriate staging evaluation and the role for pelvic lymphadenectomy.

A good staging system should be able to accurately reflect the natural history of a malignant disease, to express the extent of the disease at the time of diagnosis, and stratify patients in prognostically distinctive groups. The staging system for prostate cancer, as it is today, fails to fulfill these requirements. Approximately one third of the patients who undergo surgery for complete excision of prostate cancer in fact do not have a localize disease. The incidence of tumor at the inked margin may reach 30% for T1 stage and up to 60% for clinical T2b prostate cancer according to comparison with pathologic examination of resected specimen. Several concepts have been recently proposed as a means of improving the accuracy of the available staging system. In this paper, we review current aspects of clinical and pathological staging of prostate cancer, and the importance of these new concepts on the early stages of prostate cancer.

Humans↗

PubMed2001

Adjuvant chemotherapy in stage I and stage II testicular cancer.

Adjuvant chemotherapy in low-stage testis cancer is an accepted treatment option for two clinical situations: (1) chemotherapy after complete removal of the primary tumor by orchidectomy without clinical evidence of metastasis (clinical stage I), and (2) chemotherapy after complete surgical removal of non-seminomatous retroperitoneal metastases up to 5 cm in greatest transverse diameter by retroperitoneal lymph node dissection in clinical stage II. Aim of treatment is the prevention of tumor recurrences. The risk of recurrence depends on the type and stage of disease and ranges from 16% (clinical stage I seminoma) to 50% (pathological stage II B non-seminoma). Thus, 50-84% of patients receive adjuvant treatment unnecessarily. Prognostic factors have been developed in each tumor entity to tailor treatment to patients with high risk of recurrence.

Antineoplastic Agents↗

PubMed1998

Endothoracic sonography with color Doppler availability during video assisted thoracic surgery (videothoracoscopic operative staging with ultrasound color Doppler) for lung cancer staging.

BACKGROUND: The preoperative staging of lung cancer can be problematical when we attempt to evaluate T factor (T2-T3 versus T4) and N factor (N0 versus N1-N2). In some cases, radiology tests (CT scan, magnetic resonance imaging) cannot entirely dispel the possibility that the mediastinal structures have been infiltrated. N factor is evaluated mainly by dimensional criteria. However, mediastinoscopy and mediastinotomy do not allow the full exploration of all mediastinal mode stations. METHOD: Starting in 1995, we submitted 10 consecutive patients to videothoracoscopic operative staging with ultrasound color Doppler (VOS-USCD). In five cases, preoperative staging showed possible infiltration of the pulmonary artery (T4). In nine cases, we found involvement of the mediastinal nodes, seven patients were N2, and two were N3. Videothoracoscopy was performed under general anesthesia using a double-lumen endotracheal tube. The videothoracoscope and sonographic probe were inserted via three thoracoports placed in the axillary triangle. RESULTS: Following the results of VOS-USCD, the staging and subsequently the therapeutic program were modified in seven of 10 cases (70%). CONCLUSIONS: Our preliminary experience indicates that VOS-USCD should be applied to the diagnosis of patients in stage IIIA (N2) and that it is particularly valuable for patients in stage IIIB.

Aged↗

PubMed2006

Retroperitoneal lymph node dissection for high-risk stage I and stage IIA seminoma.

INTRODUCTION: The clinical results of radiotherapy in low-stage seminoma are excellent with negligible early morbidity. However, in a long-term follow-up various complications may occur. On the other hand, experience in nonseminomas shows that surgical morbidity has decreased markedly after invention of a nerve-sparing technique. These issues served as a rationale for us to perform the primary retroperitoneal lymph node dissection (RPLND) in seminoma patients. MATERIALS AND METHODS: Fourteen pure seminoma patients (10 high-risk stage I and four with clinical stage IIA) underwent nerve-sparing RPLND from September, 1997 to December, 2002. RESULTS: Pathological evaluation revealed lymph node involvement in three out of 10 clinical stage I and in all four stage IIA cases. The patients' acceptance of the surgery was good. Minor intra- and early postoperative complications were observed in two cases. Antegrade ejaculation was preserved in all patients. No retroperitoneal or distant recurrences have been observed. All patients were free of disease with the mean follow-up period of 56 months. CONCLUSION: The excellent results and minimum morbidity of nerve-sparing RPLND together with the increased concerns on late complications of radiotherapy may turn the preference of surgery in low-stage seminoma into the subject of future discussion.

Adult↗

PubMed1991

Evaluation of surgical staging in stage I low malignant potential ovarian tumors.

The charts and pathology specimens of 27 patients with ovarian tumors of low malignant potential were reviewed in an attempt to document the rationale for a second laparotomy in those patients with clinical stage 1 disease and who did not have a complete staging laparotomy at their initial surgery. Four of 13 patients with serous tumors, none of 12 patients with mucinous tumors, and one patient with a mixed tumor of LMP were upstaged at the staging laparotomy. The major morbidity rate associated with the procedure was 7.4%. The low yield of a staging laparotomy in patients with mucinous tumors (0%) does not warrant a second operation. The higher yield of a staging laparotomy in patients with serious tumors (30.8%) suggests that the likelihood of upstaging the disease exceeds the potential morbidity, and for this reason, the procedure may be warranted. However, the specific role of a staging laparotomy even in those with serous tumors awaits further study of the prognostic significance of invasive versus noninvasive implants.

Adult↗

PubMed1999

Extrathoracic staging is not necessary for non-small-cell lung cancer with clinical stage T1-2 N0.

BACKGROUND: In the official guidelines published recently, radiographic staging procedures were not recommended for patients who have non-small-cell lung cancer with negative clinical evaluation. METHODS: We did a retrospective analysis of 755 patients with non-small-cell lung cancer in clinical stage T1-2 N0 between 1982 and 1996. The patients all had a full series of imaging procedures, based on the staging protocol. Their medical records were reviewed with respect to how often distant metastasis was detected by these procedures and whether the patients showed any symptoms and laboratory abnormalities indicating extrathoracic metastasis. RESULTS: The incidence of distant metastasis detected by the imaging procedures was 2.1% (nine of 419) in T1 N0 cases and 5.4% (18 of 335) in T2 N0 cases. Silent metastasis was found only in 0.5% (2 of 419) of the T1 N0 cases and 0.9% (3 of 335) of the T2 N0 cases. The cost of these staging procedures was approximately one million dollars. CONCLUSIONS: Considering the cost and time savings, staging procedures are not warranted for patients with non-small-cell lung cancer stage T1-2 N0 with negative clinical evaluations.

Adult↗

PubMed1989

Pathological stage is higher in older men with clinical stage B1 adenocarcinoma of the prostate.

We examined the relationship between age and pathological stage in 444 consecutive patients who underwent pelvic lymphadenectomy and radical retropubic prostatectomy for clinically localized adenocarcinoma of the prostate. Pathological stage of cancer was determined postoperatively as organ-confined, capsular penetration (cancer through prostatic capsule), seminal vesicle involvement or lymph node metastases. Patient age ranged from 34 to 75 years. The majority of the patients had clinical stage B1 disease with induration confined to less than 1 lobe of the gland. In this group a statistically significant (p equals 0.001, chi-square test for trend) correlation between increased age and higher pathological stage was found. We also found that older men with clinical stage B1 disease had a statistically significant trend toward higher Gleason grade. An explanation for our findings might be the masking of prostatic induration by benign prostatic hypertrophy, clearly a disease of aging men. We suggest that increased age is a relative risk factor for advanced pathological findings in men with clinical stage B1 prostatic cancer.

Adenocarcinoma↗

PubMed2003

Stage IC adenocarcinoma of the endometrium: survival comparisons of surgically staged patients with and without adjuvant radiation therapy.

OBJECTIVE: The goal of this study was to determine the outcomes of stage IC endometrial carcinoma patients who are managed with and without adjuvant radiation therapy after comprehensive surgical staging. METHODS: Patients with FIGO stage IC adenocarcinoma of the endometrium diagnosed from 1988 to 1999 were identified from tumor registry databases at four institutions. A retrospective chart review identified 220 women who underwent comprehensive surgical staging including a total hysterectomy, bilateral salpingo-oophorectomy, pelvic/paraaortic lymphadenectomy, and peritoneal cytology. RESULTS: Of the 220 stage IC patients, 56 (25%) patients received adjuvant brachytherapy (BT), 19 (9%) received whole-pelvis radiation (WPRT), and 24 (11%) received both WPRT and BT. One hundred twenty-one patients (55%) did not receive adjuvant radiation. There were 6 recurrences (6%) in the radiated group and 14 (12%) in the observation group (P = 0.20). Seven of fourteen recurrences in the observation group were local, and all local recurrences were salvaged with radiation therapy. Two of seven distant recurrences in this group were also salvaged with surgery and chemotherapy. The overall salvage rate for the observation group was 64%. There was a statistical difference in 5-year disease-free survival between the radiated and observation groups (93% vs 75%, P = 0.013). However, the 5-year overall survival was similar in the two groups (92% vs 90%, P = 0.717). CONCLUSION: Adjuvant radiation therapy improves disease-free survival in surgical stage IC patients; however, overall survival is not improved with adjuvant radiation therapy since the majority of local recurrences in conservatively managed patients can be salvaged with radiation therapy.

Adenocarcinoma↗

PubMed1999

Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial.

BACKGROUND: Colon cancer is curable by surgery, but cure rate depends on the extent of disease. We investigated whether adjuvant active specific immunotherapy (ASI) with an autologous tumour cell-BCG vaccine with surgical resection was more beneficial than resection alone in stage II and III colon cancer. METHODS: In a prospective randomised trial, 254 patients with colon cancer were randomly assigned postoperative ASI or no adjuvant treatment. ASI was three weekly vaccinations starting 4 weeks after surgery, with a booster vaccination at 6 months with 10(7) irradiated autologous tumour cells. The first vaccinations contained 10(7) BCG organisms. We followed up patients for time to recurrence, and recurrence-free and overall survival. Analysis was by intention to treat. FINDINGS: The 5.3 year median follow-up (range 8 months to 8 years 11 months) showed 44% (95% CI 7-66) risk reduction for recurrence in the recurrence-free period in all patients receiving ASI (p=0.023). Overall, there were 40 recurrences in the control group and 25 in the ASI group. Analysis by stage showed no significant benefit of ASI in stage III disease. The major impact of ASI was seen in patients with stage II disease, with a significantly longer recurrence-free period (p=0.011) and 61% (18-81) risk reduction for recurrences. Recurrence-free survival was significantly longer with ASI (42% risk reduction for recurrence or death [0-68], p=0.032) and there was a trend towards improved overall survival. INTERPRETATION: ASI gave significant clinical benefit in surgically resected patients with stage II colon cancer. ASI has minimal adverse reactions and should be considered in the management of stage II colon cancer.

Adjuvants, Immunologic↗

PubMed2001

MR staging of clinical stage I and IIa cervical carcinoma: a reappraisal of efficacy and pitfalls.

The purpose of this study was to evaluate the diagnostic efficacy and pitfalls of magnetic resonance (MR) imaging in preoperative staging of cervical cancer. MR imaging was performed to determine the tumor staging for 31 patients with cervical carcinoma emphasizing tumor size, parametrial invasion, vaginal invasion and lymph node metastases. Tumor size was 3.23+/-1.75 cm (mean+/-standard deviation) at MR imaging compared with 2.79+/-1.76 cm at surgical-pathologic evaluation. The discrepancy between the tumor size determined by MR imaging and the measured surgical specimens was consistent in tumors larger than 1 cm. In assessing parametrial invasion, vaginal invasion and lymph node metastases, MR imaging had an accuracy of 96.7 and 87%. In determining stage of disease and differentiating operable (< or =stage IIA) from advanced disease (> or =stage IIB), MR imaging had an accuracy of 83.8 and 96.7%. Pitfalls leading to staging errors included difficulties in differentiating cancer foci from surrounding tissue edema and excluding vaginal invasion in the presence of large cervical cancer. In conclusion, MR imaging is accurate in the evaluation of parametrial invasion and useful in the differentiation of operable from advanced disease. The ability of MR imaging to exclude vaginal invasion in the presence of large cervical cancer and differentiate cancer foci from surrounding tissue edema is not as reliable.

Adenocarcinoma↗

PubMed2002

Tumour stage, node stage, p53 gene status, and bcl-2 protein expression as predictors of tumour response to platin-fluorouracil chemotherapy in patients with squamous-cell carcinoma of the head and neck.

The purpose of this study was to establish the relative contribution of tumour stage, node stage, p53 gene status, p53 expression, and bcl-2 protein expression to tumour response to platin-fluorouracil chemotherapy in 141 patients with squamous-cell carcinomas of the head and neck. Tumour response was measured at the primary site after three cycles of chemotherapy. Exons 2-10 and the coding part of exon 11 were sequenced on both strands. Bcl-2 or p53 expression was detected by immunohistochemistry. Predictor variables of objective response (reduction of at least 50% of tumour size) were tested in univariate and multivariate analyses. P53 mutations were found in 52 patients (37%). Tumour cells expressed p53 in 84 cases (59%) and bcl-2 in 25 cases (18%). T1 or T2 stage (adjusted odds ratio, 3.3; 95% confidence interval 1.3-8.7; P=0.01), N0 node stage (adjusted odds ratio, 2.7; 95% confidence interval 1.1-6.4; P=0.03), p53 wild-type gene (adjusted odds ratio, 4.0; 95% confidence interval 1.7-9.5; P=0.002), and bcl-2 protein expression (adjusted odds ratio, 20; 95% confidence interval 2.3-170; P=0.006), were positively associated with tumour response. P53 protein expression was not predictive of response. In conclusion, tumour stage, node stage, p53 gene status, and bcl-2 expression are independent predictors of tumour response to platin-fluorouracil in patients with squamous-cell carcinomas of the head and neck.

Adult↗

PubMedDate not supplied

Laparoscopic lower para-aortic staging lymphadenectomy in stage IB2, II, and III cervical cancer.

The presence of metastases in the para-aortic lymph nodes has important implications in the management of cervical carcinoma in many centers. In this study we investigated the role of laparoscopic lower para-aortic lymphadenectomy in patients with cervical carcinoma. In 42 consecutive patients with stage IB2-IIIB cervical carcinoma without suspicious para-aortic lymph nodes on CT scanning, a laparoscopic lower para-aortic lymphadenectomy was performed between January 1998 and April 2001. The transperitoneal route was used in the first 21 patients, and in the remaining 21 patients the procedure was started with the left retroperitoneal approach. The number of patients with stage IB2, II, and III was 7, 30, and 5, respectively. The median age was 51 years (range 30-81). The median weight and length were 62 kg (range 45-83) and 162 cm (range 150-175), respectively. In four patients-two operated via the transperitoneal route and the other two operated via the retroperitoneal route-the procedure was abandoned, in three patients because of adhesions following prior surgery and in one because of a camera failure. Conversion from the retropertitoneal to the transperitoneal approach was necessary because of a peritoneal tear in five of the 21 cases (all of them in the first 10 cases). Median estimated blood loss during the operation was 78 ml (range 10-300). The median hemoglobin (Hb) decrease was 1.3 g/dL (range 0-3.7). The median duration of the procedure was 64 min (range 20-115). Lymphadenectomy was stopped when one of the nodes was positive on frozen section. The number of para-aortic lymph nodes removed ranged from one to 15 (median 6). In seven (18%) of the 38 patients with successful lymphadenectomy, para-aortic metastases were observed (stage IB2, 1/6; stage II, 5/28 and stage III, 1/4). The only major complication was the development of a retroperitoneal hematoma on the first postoperative day in one patient (Hb fall of 3.7 g/dL). Patients with para-aortic lymph node metastases were treated with extended field para-aortic radiotherapy. None of these developed bowel obstruction. The median follow-up was 15 months (range 1-40 months). Actuarial 1-year crude survival was 88% and 33%, respectively, for patients with negative and positive para-aortic nodes. Laparoscopic para-aortic staging in cervical carcinoma is feasible with low morbidity. Eighteen percent of the patients, without suspicion of para-aortic metastases on CT, proved to have metastases in the lower para-aortic region.

Adenocarcinoma↗

PubMed1990

Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials.

About a third of patients with ovarian cancer present with localized disease; despite surgical resection, up to half the tumors recur. Since it has not been established whether adjuvant treatment can benefit such patients, we conducted two prospective, randomized national cooperative trials of adjuvant therapy in patients with localized ovarian carcinoma (International Federation of Gynecology and Obstetrics Stages Ia to IIc). All patients underwent surgical resection plus comprehensive staging and, 18 months later, surgical re-exploration. In the first trial, 81 patients with well-differentiated or moderately well differentiated cancers confined to the ovaries (Stages Iai and Ibi) were assigned to receive either no chemotherapy or melphalan (0.2 mg per kilogram of body weight per day for five days, repeated every four to six weeks for up to 12 cycles). After a median follow-up of more than six years, there were no significant differences between the patients given no chemotherapy and those treated with melphalan with respect to either five-year disease-free survival (91 vs. 98 percent; P = 0.41) or overall survival (94 vs. 98 percent; P = 0.43). In the second trial, 141 patients with poorly differentiated Stage I tumors or with cancer outside the ovaries but limited to the pelvis (Stage II) were randomly assigned to treatment with either melphalan (in the same regimen as above) or a single intraperitoneal dose of 32P (15 mCi) at the time of surgery. In this trial (median follow-up, greater than 6 years) the outcomes for the two treatment groups were similar with respect to five-year disease-free survival (80 percent in both groups) and overall survival (81 percent with melphalan vs. 78 percent with 32P; P = 0.48). We conclude that in patients with localized ovarian cancer, comprehensive staging at the time of surgical resection can serve to identify those patients (as defined by the first trial) who can be followed without adjuvant chemotherapy. The remaining patients with localized ovarian cancer should receive adjuvant therapy, and with adjuvant melphalan or intraperitoneal 32P should have a five-year disease-free survival of about 80 percent.

Adult↗

PubMedDate not supplied

Staging of squamous cell carcinoma of the oral cavity and oropharynx: a comparison of MRI and CT in T- and N-staging.

PURPOSE: Our purpose was to assess the accuracy of CT and MRI in staging of squamous cell carcinoma (SCC) of the oral cavity and oropharynx. METHOD: Fifty-one episodes of primary and recurrent SCC were assessed with CT and MRI. The results were compared with pathological staging. RESULTS: For staging primary tumours, the accuracy of MR was 77% and that of CT was 67%. For detecting recurrent tumour, the accuracy of MR was 89% and that of CT was 100%. For N-staging, nodal sites were divided, according to the site of the primary tumour, into high and low risk. Sensitivity for high risk sites was 60% for clinical assessment, 35% for CT, and 75% for MR. Negative predictive value (NPV) was < or = 50% for all methods. For low risk sites, the NPV was > or = 95% for all methods. CONCLUSION: For T-staging, MR scanning is overall more accurate than CT. If degraded images and T1 tumours are excluded, the techniques are comparable. MR scanning is oversensitive for recurrent disease. For N-staging, all methods failed to detect small metastatic deposits.

Adult↗

PubMed2003

Was breast conserving surgery underutilized for early stage breast cancer? Instrumental variables evidence for stage II patients from Iowa.

OBJECTIVE: To estimate the average survival effects of breast conserving surgery plus irradiation relative to mastectomy for marginal stage II breast cancer patients in Iowa from 1989-1994. DATA SOURCES/DATA SETTING: Secondary linked Iowa SEER Cancer Registry--Iowa Hospital Association discharge abstract data for women in Iowa with stage II breast cancer from 1989-1994. STUDY DESIGN: Observational instrumental variables (IV) analysis. DATA COLLECTION/EXTRACTION METHODS: Women with stage II breast cancer from the Iowa SEER Cancer Registry 1989-1994 who received all of their inpatient care in Iowa were linked with their respective hospital discharge abstracts. PRINCIPAL FINDINGS: Breast conserving surgery plus irradiation decreased survival relative to mastectomy for marginal stage II breast cancer patients in Iowa during the early 1990s. In this study marginal patients were those whose surgery choices were affected by differences in area treatment rates and access to radiation facilities. CONCLUSIONS: If marginal patients are representative of patients whose treatment choices would be affected by changes in treatment rates, an increase in the breast conserving surgery plus irradiation rate for stage II early stage breast cancer patients would have decreased survival in Iowa during the early 1990s. Further research with newer data and broader samples is needed to make more current and specific assessments.

Aged↗