Biomedical subjects

T C Shea

Publications and source records attributed to T C Shea.

At least 19 recordsLinked to original sources

PubMed2000

High-dose chemotherapy and autologous stem-cell transplantation for ovarian cancer: an autologous blood and marrow transplant registry report.

BACKGROUND: Autologous transplantation is increasingly used to treat epithelial ovarian cancer. However, it is not clear which patients may benefit. OBJECTIVE: To determine overall and progression-free survival and factors associated with favorable outcome after autotransplantation for ovarian cancer. DESIGN: Observational cohort study. SETTING: 57 centers reporting to the Autologous Blood and Marrow Transplant Registry (ABMTR). PATIENTS: 421 women who received transplants between 1989 and 1996. INTERVENTIONS: High-dose chemotherapy using diverse regimens with hematopoietic stem-cell rescue. MEASUREMENTS: Primary outcomes were progression-free survival and overall survival. Multivariate analyses using Cox proportional hazards regression considered the following factors: age, Karnofsky performance score, initial stage, histologic characteristics, previous therapy, remission status, extent of disease, graft source, transplant regimen, and year of transplantation. RESULTS: Most patients had extensive previous chemotherapy. Forty-one percent had platinum-resistant tumors, and 38% had tumors at least 1 cm in diameter. Only 34 patients (8%) received transplants as part of initial therapy. The probability of death within 100 days was 11% (95% CI, 8% to 14%). Two-year progression-free survival was 12% (CI, 9% to 16%), and 2-year overall survival was 35% (CI, 30% to 41%). Younger age, Karnofsky performance score of at least 90%, non-clear-cell disease, remission at transplantation, and platinum sensitivity were associated with better outcomes. Progression-free and overall survival were 22% (CI, 12% to 33%) and 55% (CI, 42% to 66%), respectively, for women with a high Karnofsky performance score and non-clear-cell, platinum-sensitive tumors. CONCLUSIONS: Some subgroups of patients with ovarian cancer seem to have good outcomes after autotransplantation, although several biases may have affected these observations. Phase III trials are needed to compare such outcomes with outcomes of conventional chemotherapy.

Age Factors↗

PubMed2000

Comparison of granulocyte colony-stimulating factor (G-CSF)--mobilized peripheral blood progenitor cells and G-CSF--stimulated bone marrow as a source of stem cells in HLA-matched sibling transplantation.

HLA-identical bone marrow or stem cell transplantation from a sibling is the preferred treatment for patients with chronic myelogenous leukemia, bone marrow failure syndromes, relapsed acute leukemia, and specific inborn errors of metabolism. Several groups have shown that granulocyte colony-stimulating factor (G-CSF)--mobilized peripheral blood progenitor cells (PBPCs) obtained from HLA-matched siblings are effective in reconstitution of marrow function after marrow ablative conditioning therapy. To evaluate whether G-CSF treatment before bone marrow harvest leads to enhanced recovery of PBPC counts and recovery from limited graft-versus-host disease (GVHD), we assessed the outcome of a sequential cohort of patients treated identically and then given either G-CSF--mobilized PBPCs or G-CSF--stimulated bone marrow from HLA-identical siblings. We show that the time to neutrophil engraftment is identical in the 2 cohorts, whereas platelet engraftment is earlier with the use of PBPCs. The incidence of acute GVHD was decreased, and that of chronic GVHD significantly decreased, in the group receiving bone marrow. Overall survival was not different between the 2 groups. Thus, G-CSF--stimulated bone marrow offers a source of stem cells that allows for early neutrophil engraftment with a decreased risk of GVHD.

Adolescent↗

PubMed2000

CD34+ selection of hematopoietic blood cell collections and autotransplantation in lymphoma: overnight storage of cells at 4 degrees C does not affect outcome.

The purpose of this study was to investigate whether storing mobilized peripheral blood progenitor cell (PBPC) collections overnight before CD34+ selection may delay platelet count recovery after high-dose chemotherapy and CD34+-enriched PBPC re-infusion. Lymphoma patients underwent PBPC mobilization with cyclophosphamide 4 g/m2 i.v. and G-CSF 10 microg/kg/day subcutaneously. Patients were prospectively randomized to have each PBPC collection enriched for CD34+ cells with the CellPro CEPRATE SC System either immediately or after overnight storage at 4 degrees C. Thirty-four patients were randomized to overnight storage and 34 to immediate processing of PBPC; 15 were excluded from analysis due to tumor progression or inadequate CD34+ cell mobilization. PBPC from 23 patients were stored overnight, while 30 subjects underwent immediate CD34+ selection and cryopreservation. Median yield of CD34+ enrichment was 43.6% in the immediate processing group compared to 39.1% in the overnight storage group (P = 0.339). Neutrophil recovery >500 x 10(9)/l occurred a median of 11 days (range 9-16 days) in the overnight storage group compared to 10.5 days (range 9-21 days) in the immediate processing group (P = 0.421). Median day to platelet transfusion independence was 13 (range 7-43) days in the overnight storage group vs 13.5 (range 8-35) days in those assigned to immediate processing (P = 0.933). We conclude that storage of PBPC overnight at 4 degrees C allows pooling of consecutive-day collections resulting in decreased costs and processing time without compromising neutrophil and platelet engraftment after infusion of CD34+-selected progenitor cells. Bone Marrow Transplantation(2000) 25, 559-566.

Adolescent↗

PubMed2000

Utility of obtaining blood cultures in febrile neutropenic patients undergoing bone marrow transplantation.

Infection remains an important cause of morbidity and mortality after bone marrow or stem cell transplantation. To evaluate the role of obtaining blood cultures for intermittent or persistent fever in neutropenic patients on antibiotic therapy, we performed a retrospective chart review of 196 consecutive patients admitted to the Bone Marrow Transplant Unit at the University of North Carolina Hospitals from 1995 to 1998. From the cohort of 196 patients, 154 patients developed neutropenic fever. The initial blood culture was positive in 16 of 145 patients during the first fever episode giving a prevalence of 11%. From the total of 109 patients that had blood cultures drawn after day 1 of fever, five patients had blood cultures positive for a pathogen, a prevalence of 4.6%. In only one patient, did blood cultures drawn after day 1 identify an organism not present on day 1 (prevalence 0.9%). After reviewing the results in the first 105 patients, we changed our timing of collection of blood cultures. Forty-nine patients were treated in this manner and we found that the mean number of blood cultures decreased from 9.2 to 4.7 per patient without a change in the frequency of infectious complications or length of hospitalization.

Adolescent↗

PubMed1999

A randomized phase 3 study of peripheral blood progenitor cell mobilization with stem cell factor and filgrastim in high-risk breast cancer patients.

This randomized study compared the number of leukaphereses required to collect an optimal target yield of 5 x 10(6) CD34(+) peripheral blood progenitor cells/kg, using either stem cell factor (SCF) at 20 micrograms/kg/d in combination with Filgrastim at 10 micrograms/kg/d or Filgrastim alone at 10 micrograms/kg/d, from 203 patients with high-risk stage II, III, or IV breast cancer. Leukapheresis began on day 5 of cytokine administration and continued daily until the target yield of CD34(+) cells had been reached or a maximum of 5 leukaphereses performed. By day 5 of leukapheresis, 63% of the patients treated with SCF plus Filgrastim (n = 100) compared with 47% of those receiving Filgrastim alone (n = 103) reached the CD34(+) cell target yield. There was a clinically and statistically significant reduction (P <.05) in the number of leukaphereses required to reach the target yield for the patients receiving SCF plus Filgrastim (median, 4 leukaphereses) compared with patients receiving Filgrastim alone (median, 6 or more leukapherses; ie, <50% of patients reached the target in 5 leukaphereses). All patients receiving SCF were premedicated with antihistamines, albuterol, and pseudoephedrine. Treatment was safe, generally well tolerated, and not associated with life-threatening or fatal toxicity. In conclusion, SCF plus Filgrastim is a more effective peripheral blood progenitor cell (PBPC)-mobilization regimen than Filgrastim alone. In addition to the potential for reduced leukapheresis-related morbidity and costs, SCF offers additional options for obtaining cells for further graft manipulation.

Adult↗

PubMed1999

Murine T lymphocytes incapable of producing macrophage inhibitory protein-1 are impaired in causing graft-versus-host disease across a class I but not class II major histocompatibility complex barrier.

The routine use of bone marrow transplantation is limited by the occurrence of acute and chronic graft-versus-host disease (GVHD). Current approaches to decreasing the occurrence of GVHD after allogeneic transplantation use T-cell depletion, use immunosuppressive agents, or block costimulatory molecule function. The role of proteins in the recruitment of alloreactive lymphocytes has not been well characterized. Chemokines are a large family of proteins that mediate recruitment of mononuclear cells in vitro and in vivo. To investigate the role of T-cell production of the chemokine macrophage inhibitory protein-1 (MIP-1) in the occurrence of GVHD, splenocytes either from wild-type or from MIP-1-/- mice were administered to class I (B6.C-H2(bm1)) and class II disparate mice (B6-C-H2(bm12)). The incidence and severity of GVHD was markedly reduced in bm1 mice receiving splenocytes from MIP-1-/- mice as compared with mice receiving wild-type splenocytes. Bm1 mice receiving MIP-1-/- splenocytes had significantly less weight loss and markedly reduced inflammatory responses in the lung and liver than mice receiving C57BL/6 splenocytes. Bm1 mice receiving MIP-1-/- splenocytes had a markedly decreased production of antichromatin autoantibodies and impaired generation of bm1-specific T lymphocytes versus wild-type mice. However, MIP-1-/- splenocytes easily induced GVHD when administered to bm12 mice. This data show that blockade of chemokine production or function may provide a new approach to the prevention or treatment of GVHD but that chemokines that recruit both CD4(+) and CD8(+) lymphocytes may need to be targeted.

Animals↗

PubMed1999

Introduction: current issues in high-dose chemotherapy and stem cell support.

In the 1980s it became clear that low numbers of primitive hematopoietic cells were present in the peripheral bloodstream. Early clinical trials by investigators in the USA, Australia, and Germany demonstrated that these cells could be collected and reinfused to support high-dose chemotherapy procedures in patients otherwise unable to undergo bone marrow collection, usually because of prior pelvic irradiation. It was, however, difficult to obtain adequate numbers of stem cells from patients in the steady state. It was not until the demonstration by Socinski in Boston and Gianni in Milan that these circulating cells were markedly increased following the administration of either cytokines, chemotherapy, or a combination of both that the use of peripheral blood stem cells over bone marrow began to be widely undertaken. Since that time, peripheral blood stem cell collection has become the preferred means of stem cell support for high-dose chemotherapy because of the reduction in time to neutrophil and platelet engraftment, reduction in the number of transfusions and hospital stay, and an apparent reduction in tumor cell contamination.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Multiple cycles of high-dose chemotherapy for ovarian cancer.

Recent advances in hematopoietic support have extended the application of high-dose chemotherapy in the treatment of malignancy. The use of colony-stimulating factors and peripheral blood progenitor cells significantly have decreased the morbidity and mortality of such treatment compared with traditional autologous bone marrow transplantation. These innovations facilitate the use of multiple cycles of high-dose chemotherapy as consolidation after achieving best response to conventional chemotherapy or as initial treatment. Developing data suggest that this approach in both of these settings merit further evaluation for the treatment of epithelial ovarian carcinoma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

A method for the production of CD4+ chronic myelogenous leukemia-specific allogeneic T lymphocytes.

The graft-versus-leukemia effect is critical to the maintenance of remission in patients transplanted for the treatment of chronic myelogenous leukemia (CML). A pivotal issue in transplantation for CML is whether donor lymphocytes are specific for host tumor or myeloid cells or a subset of the lymphocytes that cause graft-versus-host disease. We have enrolled seven patients in an experimental trial to evaluate the specificity of HLA-matched donor lymphocytes in vitro. We have produced 11 CD4+ cytotoxic and proliferative T-cell clones from five of the donors that only lyse or proliferate to leukemic myeloid cells. These T lymphocytes do not react with interleukin (IL)-2-stimulated blasts, natural killer-sensitive targets, donor neutrophils, or bcr-abl+ EBV-lymphoblastoid cell lines. We show that the addition of the cytokines IL-7 and IL-12 during the production of T-cell clones enhances the recovery of myeloid-specific clones in vitro. Five of the myeloid-specific clones that we produced maintained specificity over 12 weeks in culture. Adoption of this method should allow for the expansion and in vivo testing of CML-specific CD4+ T-cell clones in adoptive immunotherapy.

Adult↗

PubMed1997

High-dose carboplatin plus paclitaxel with granulocyte colony-stimulating factor and peripheral blood stem-cell support in non-small-cell lung cancer.

The treatment of non-small-cell lung cancer (NSCLC) has recently undergone major changes due to the availability of new drugs that demonstrate substantial activity in NSCLC patients. Although cure for the majority of stage III NSCLC and effectively all stage IV disease patients remains rare, a number of compounds, including carboplatin, paclitaxel, docetaxel, irinotecan, and vinorelbine, have proved useful in the treatment of these patients. Together with a number of phase II trials, phase I trials utilizing escalating doses of carboplatin and paclitaxel with growth factor or growth factor and blood stem-cell support have shown that substantial increases in dose intensity can be achieved. These studies in small numbers of patients have demonstrated that these regimens have encouraging activity and have formed the basis of a Cancer and Leukemia Group B (CALGB) phase II pilot study. This study will utilize two cycles of high-dose carboplatin and Taxol given at an AUC dose of 18 and a 24-h infusion dose of 250 mg/m2, respectively, with growth factor and stem-cell support to treat stage III NSCLC patients. Patients will also receive multimodality therapy, including radiation with or without surgery. It is hoped that this effort to intensify treatment in patients with limited-stage disease will improve survival and benefit the large number of patients with stage III tumors. This paper outlines the phase I results that formed the basis of the CALGB trial and reviews several recent reports of phase II or phase III trials of single-agent and combination regimens for NSCLC.

Antineoplastic Agents, Phytogenic↗

PubMed1997

Prevention of infections in bone marrow transplant recipients.

Bone marrow transplantation (BMT) is increasingly used in the treatment of hematologic malignancies, solid tumors, and congenital diseases. The number of patients receiving a BMT increased from approximately 5000 in 1989 to 12,000 in 1995. Infectious complications are the most common cause of morbidity and mortality in the peritransplant period in patients undergoing autologous BMT. Additionally, infectious complications are a serious cause of complications in recipients of matched sibling allogeneic BMT, unrelated BMT, and related mismatched BMT.

Anti-Bacterial Agents↗

PubMed1997

Long-term engraftment failure after marrow ablation and autologous hematopoietic reconstitution: differences between peripheral blood stem cell and bone marrow recipients.

We infused peripheral blood stem cells (PBSC) into 51 patients with various malignant disorders, after myeloablative conditioning. Twenty-four patients also received autologous bone marrow (PBSC + BM). In a multivariate analysis, the only statistically significant predictors of neutrophil engraftment were log-dose CFU-GM (P < 0.001) and the number of prior chemotherapy regimens (P = 0.004). The factors predicting RBC and platelet engraftment were log-dose CFU-GM (P = 0.002), PBSC + BM infusion (P = 0.007) and the absence of neoplastic bone marrow involvement (P = 0.009). Seven patients remained platelet and/or red cell transfusion-dependent for 100 days or more post-transplant after good neutrophil recovery. Six of these seven long-term engraftment failures, as well as five additional patients, received < 10(5) CFU-GM/kg. Of the 11 patients who received < 10(5) CFU-GM/kg (low-dose patients), seven were PBSC recipients, of whom six were long-term engraftment failures. In contrast, there were no long-term engraftment failures among the four low-dose autologous marrow recipients. This difference in long-term engraftment failure rate was significant (P = 0.015). The low-dose PBSC patients all had a diagnosis of lymphoma with bone marrow involvement. The low-dose PBSC + BM group was more heterogeneous, but no patient had malignant involvement of the marrow. The low-dose PBSC patients had also received significantly more prior chemotherapy regimens than the low-dose PBSC + BM patients and a significantly higher proportion received total body irradiation (TBI) as part of their conditioning regimen. We conclude that marrow damage resulting from a combination of neoplastic infiltration, chemotherapy and TBI may result not only in low PBSC yields but also in an impaired capacity of the marrow microenvironment to support transplanted stem cells.

Adult↗

PubMed1997

Mobilization of peripheral blood progenitor cells with paclitaxel-based chemotherapy.

An essential component of combination high-dose chemotherapy and irradiation for the treatment of a variety of solid and hematologic malignancies is the ability to collect and reinfuse large numbers of peripheral blood progenitor cells (PBPCs). The reinfused PBPCs are used to replace pluripotent hematopoietic stem cells after marrow ablative therapy and to potentiate earlier blood cell count recovery after myelosuppressive (but not truly ablative) treatment. The PBPCs are mobilized from the marrow compartment into the peripheral bloodstream after treatment with chemotherapy, granulocyte colony-stimulating factor, or both. A number of single and combination chemotherapeutic agents have been used to mobilize PBPCs. In administering these agents, a balance must be found in all cases between effective PBPC mobilization and possible damage to the hematopoietic stem cell pool and overall patient tolerance. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) causes no thrombocytopenia or cumulative hematopoietic toxicity and was found to effectively mobilize PBPCs without damaging the stem cell pool. Paclitaxel has the additional advantage of not causing the bladder toxicity seen with cyclophosphamide. Its antitumor effectiveness in breast and ovarian cancer makes it an especially useful component of therapy for both pretreatment cytoreduction as well as PBPC mobilization in these patients.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

High-dose therapy with carboplatin and paclitaxel in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer deaths in the United States. The combination of more active agents like vinorelbine and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) with cisplatin has led to improved survival for patients with advanced metastatic disease. The ability to escalate the dose of cisplatin-based regimens is limited by nonhematologic toxicities and is especially difficult in the population of patients with advanced NSCLC. However, the development of new agents with significant activity against NSCLC as well as new strategies for high-dose therapy have made it possible to examine the potential of dose-intense therapy in this population. A phase I trial performed at the University of North Carolina was designed to evaluate paclitaxel 250 mg/m2 given over 24 hours plus escalating doses of carboplatin starting at an area under the concentration-time curve (AUC) dose of 8 supported by peripheral blood stem cells and filgrastim in the treatment of advanced NSCLC. The AUC dose of carboplatin was escalated in increments of 2. The maximum tolerated dose of carboplatin combined with paclitaxel 250 mg/m2 administered over 24 hours was defined at an AUC of 18. In this study, six of seven patients with advanced NSCLC had major responses. This regimen is currently being tested in patients with locally advanced NSCLC by the Cancer and Leukemia Group B: patients receive two cycles of induction therapy with paclitaxel 250 mg/m2 over 3 hours followed by carboplatin at an AUC of 18 supported by peripheral blood stem cells and filgrastim. Depending on response to induction therapy, patients then receive surgical resection, thoracic radiation therapy, or both. This phase II trial will examine clinical and pathologic responses and the toxicity of this high-dose regimen in patients with locally advanced NSCLC. Ultimately, phase III trials will be needed to establish the role of this approach in NSCLC.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

Dark ring sign: finding in patients with fungal liver lesions and transfusional hemosiderosis undergoing treatment with antifungal antibiotics.

OBJECTIVE: To describe the MR appearance of necrotizing fungal granulomas occurring in the liver of leukemic patients with hepatosplenic fungal disease and transfusional hemosiderosis on antifungal antibiotics. SUBJECTS AND METHODS: Four patients with acute myelogenous leukemia (n = 2) or acute lymphocytic leukemia (n = 2) who developed hepatosplenic fungal disease, and were treated with antifungal medication, underwent MRI examination on a 1.5 T MR imager. MR images were prospectively evaluated and correlated with liver biopsy (three patients), and clinical picture (one patient). RESULTS: Multiple liver lesions measuring approximately 1 cm in diameter were identified in all patients. Lesions possessed a distinctive MR appearance: central mild hyperintensity with a peripheral ring of very low signal intensity on precontrast T1- and T2-weighted images. The central region of the lesions enhanced following gadolinium administration with the peripheral ring remaining low in signal intensity. CONCLUSION: Necrotizing fungal granulomas in the liver of patients with transfusional hemosiderosis on treatment with antifungal antibiotics have a distinctive appearance of moderate high signal intensity center on T1- and T2-weighted and postgadolinium MR images with a peripheral rim of low signal intensity. This appearance reflects the presence of iron-laden macrophages in the periphery of granulomas and may be expected in processes that initiate an immune response involving aggregation of macrophages in the liver of patients with transfusional iron overload.

Acute Disease↗

PubMed1995

Correction of bone marrow nucleated cell counts for the presence of fat particles.

Although the use of bone marrow transplantation has increased greatly in recent years, the quality control procedures used in bone marrow processing laboratories remain less than ideal. Accurate marrow total nucleated cell (TNC) counts are essential for effective monitoring of bone marrow collection and processing. Aspirated marrow is variably contaminated by fat particles, resulting in overestimation of marrow TNC by automated analyzers. A recently-marketed hematological analyzer (Cobas-Helios; Roche Diagnostic Systems, Branchburg, NJ) offers the potential to correct marrow TNC counts for fat particles using available software. The authors investigated the accuracy of corrected TNC counts on 21 marrow samples, using a visual chamber count as the reference method. The correction methods studied were software correction, using the Cobas-Helios differential system, and replacement of the sample plasma with saline. Uncorrected automated marrow TNC counts (mean, 28.4 x 10(9)/L) were significantly higher than the visual reference counts (mean, 23.1 x 10(9)/L). Neither the mean corrected automated count (24.3 x 10(9)/L) nor the mean saline replaced count (24.6 x 10(9)/L) differed significantly from the mean visual reference count. For both the corrected automated and saline replaced counts, 20 of the 21 data points (95%) fell within a 95% confidence interval computed for the reference method. The authors conclude that both the corrected automated method, using the Cobas-Helios, and the saline replacement method are acceptable alternatives to the visual chamber count.

Adult↗

PubMed1994

Reinfusion and serial measurements of carboplatin-mobilized peripheral-blood progenitor cells in patients receiving multiple cycles of high-dose chemotherapy.

PURPOSE: To examine the ability of carboplatin to mobilize peripheral-blood progenitor cells (PBPCs) and to examine the impact of infusing these cells on myelosuppression following multiple cycles of high-dose therapy. Fluctuations in circulating progenitor cell concentration following repeated cycles of this therapy were also measured. PATIENTS AND METHODS: Eight patients received a total of 20 cycles of carboplatin 1,200 mg/m2 per course, granulocyte-macrophage colony-stimulating factor (GM-CSF) 5 micrograms/kg/d, and PBPC reinfusion every 28 days. PBPC were collected following 1 week of GM-CSF and following the first and second cycles of chemotherapy. Hematologic toxicity was correlated with the number of progenitor cells reinfused per cycle. The concentration of PBPC per milliliter of blood was measured at study entry, following GM-CSF priming, and after each cycle of chemotherapy. RESULTS: We observed a strong inverse correlation between the number of PBPCs (CD34 and colony-forming unit granulocyte-macrophage [CFU-GM]), but not mononuclear cells (MNCs) reinfused and the days with neutropenia less than 500/microL and platelets less than 20,000/microL. Compared with baseline levels, the circulating PBPC concentration increased up to 27-fold following the first course of chemotherapy, but decreased toward, and eventually below, baseline following the second and third cycles of carboplatin. CONCLUSION: PBPC reinfusion directly correlated with a reduction in myelosuppression following high-dose carboplatin chemotherapy. While high-dose carboplatin plus GM-CSF leads to a substantially greater mobilization of PBPC than GM-CSF alone, this effect is lost after multiple treatment cycles. These results emphasize the importance of early procurement and value of PBPC reinfusion in conjunction with multiple cycles of dose-intensive chemotherapy.

Adult↗

PubMed1994

Current status of peripheral blood progenitor cell transplantation.

Peripheral blood hematopoietic progenitor cells are primitive cells capable of both self-renewal and terminal differentiation. Cells can be collected in large numbers from the peripheral blood following their stimulation by cytokine administration or during the hematologic recovery phase following chemotherapy administration. Following their collection from the peripheral blood, these cells have been used both as a supplement and an alternative to bone marrow in providing hematologic reconstitution following high-dose chemotherapy and/or radiation. This article describes the biology of these cells, reviews current methods for their acquisition, and discusses the clinical applications in which they have been found useful.

Animals↗