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J M Connors

Publications and source records attributed to J M Connors.

At least 55 records · Page 3Linked to original sources

Long-term follow-up of patients who achieved complete remission after donor leukocyte infusions.

Donor leukocyte infusions (DLI) can induce a direct graft-vs-leukemia (GVL) reaction and restore complete remission for patients who relapse after allogeneic bone marrow transplantation (BMT). A critical and unanswered concern is the long-term safety and durability of DLI. To determine remission duration, long-term toxicity, and survival after DLI-induced remissions, we identified 73 patients who achieved complete remission after DLI. Follow-up information was obtained for 66 of the 73 patients, including 39 patients with chronic myelogenous leukemia (CML) and 27 patients with other diseases. Median follow-up for all patients was 32 months; the probability of survival at 1, 2, and 3 years was 83% (95% confidence interval [CI] 74-92), 71% (60-83), and 61% (49-74), respectively. For CML, survival probability at 1, 2, and 3 years was 87% (76-98), 76% (62-90), and 73% (58-88). For other diseases, survival probability at 1 and 2 years is 77% (61-93) and 65% (46-84). Five of 39 patients with CML relapsed, and 11 of 27 patients with other diseases relapsed. Treatment-related toxicity accounted for 10 deaths. Extended follow-up shows that DLI-induced remissions are durable, especially for patients with CML. Late relapses still occur, however, and toxicity remains significant. Continued follow-up will best define the long-term GVL effects of DLI, especially for diseases other than CML.

Adolescent↗

Graft-versus-tumor induction with donor leukocyte infusions as primary therapy for patients with malignancies.

PURPOSE: Histocompatible allogeneic donor leukocyte infusions (DLIs) were administered as primary cancer therapy in a phase I trial to determine (1) whether mixed chimerism could be detected without a prior allogeneic transplantation, (2) the toxicity of primary DLI, and (3) whether a graft-versus-tumor (GVT) reaction could be observed. PATIENTS AND METHODS: Eighteen patients were studied. Patients received interferon alfa-2b for a minimum of 4 weeks, followed by DLI (level 1). Patients with no toxicity or engraftment were eligible to receive cytarabine or cyclophosphamide followed by another course of DLI (level 2). Engraftment was determined using polymerase chain reaction amplification of donor and host-specific DNA polymorphisms. RESULTS: Donor cells were detected in the blood in 14 of 16 assessable patients within 1 hour of DLI. Chimerism detectable 4 weeks after DLI was observed in four patients, and five patients were not assessable. Prior autologous transplantation was associated with late chimerism (P =.0014). Acute graft-versus-host disease (GVHD) occurred in four of 16 assessable patients (grade 1, two patients; grade 2, one patient; grade 4, one patient). One patient with grade 4 acute GVHD developed pancytopenia. Only the four patients treated after prior autologous transplantation developed acute GVHD (P =.0005). Three of four patients with acute GVHD and late chimerism responded to primary DLI, and one patient was not assessable for response. CONCLUSION: Allogeneic adoptive immunotherapy resulted in sustained chimerism, acute GVHD, and a GVT response in heavily pretreated patients. This indicates that it may be possible to generate a direct GVT response for patients with malignancies without the need for intensive conditioning therapy immediately before DLI. Immunosuppression may be required for sustained donor cell engraftment.

Adolescent↗

Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group.

Standardized guidelines for response assessment are needed to ensure comparability among clinical trials in non-Hodgkin's lymphomas (NHL). To achieve this, two meetings were convened among United States and international lymphoma experts representing medical hematology/oncology, radiology, radiation oncology, and pathology to review currently used response definitions and to develop a uniform set of criteria for assessing response in clinical trials. The criteria that were developed include anatomic definitions of response, with normal lymph node size after treatment of 1.5 cm in the longest transverse diameter by computer-assisted tomography scan. A designation of complete response/unconfirmed was adopted to include patients with a greater than 75% reduction in tumor size after therapy but with a residual mass, to include patients-especially those with large-cell NHL-who may not have residual disease. Single-photon emission computed tomography gallium scans are encouraged as a valuable adjunct to assessment of patients with large-cell NHL, but such scans require appropriate expertise. Flow cytometric, cytogenetic, and molecular studies are not currently included in response definitions. Response rates may be the most important objective in phase II trials where the activity of a new agent is important and may provide support for approval by regulatory agencies. However, the goals of most phase III trials are to identify therapies that will prolong the progression-free survival, if not the overall survival, of the treated patients. We hope that these guidelines will serve to improve communication among investigators and comparability among clinical trials until clinically relevant laboratory and imaging studies are identified and become more widely available.

Clinical Trials as Topic↗

Small noncleaved, non-Burkitt's (Burkit-Like) lymphoma: cytogenetics predict outcome and reflect clinical presentation.

PURPOSE: To correlate cytogenetic abnormalities with clinical presentation and outcome in Burkitt-like, small noncleaved non-Burkitt's lymphoma (SNC-NB). PATIENTS AND METHODS: Thirty-nine patients with SNC-NB lymphoma and a clonal karyotype were evaluated between January 1989 and January 1996. All were from British Columbia, Canada, underwent uniform clinical staging, and were treated on investigational protocols by a small group of clinicians. RESULTS: Three groups of patients were identified by clonal karyotype on cytogenetic analysis: (1) those with a c-myc translocation (n = 11); (2) those with dual translocation of c-myc and bcl-2 (n = 13); and (3) those with other cytogenetic abnormalities (n = 15). The c-myc group was younger, presented with earlier stage de nova disease, and had a better clinical prognostic factor profile. The dual-translocation and other groups were older and presented in advanced stage with poorer prognostic features, and a larger proportion of the dual-translocation group patients had transformed from previously diagnosed follicular lymphoma. The median overall survival (OS) time for all patients was 5 months. The median OS time for the dual-translocation group was only 2.5 months, as compared with 7 months and 8 months for the c-myc and other group, respectively (P < .001). There were no survivors beyond 7 months among the dual-translocation group, as opposed to 32% and 25% 2-year OS rates in the c-myc and other group. CONCLUSION: SNC-NB lymphoma is a clinically and cytogenetically heterogenous disease. Dual translocation of c-myc and bcl-2 is characterized by a rapid clinical course and extremely poor outcome. This latter entity may represent the most clinically aggressive lymphoma thus far characterized and warrants intensive investigational treatment where feasible.

Adolescent↗

Concurrent chromosomal alterations at 3q27, 8q24 and 18q21 in B-cell lymphomas.

Recurrent chromosomal translocations in malignant lymphomas most commonly involve 18q21(bcl-2), 8q24 (c-myc) and 3q27 (bcl-6), with an incidence of 27%, 11% and 6%, respectively. Individual cases concurrently harbouring two of these three rearrangements have been previously reported. This report describes four patients with cytogenetic alterations affecting all three loci, which was confirmed by molecular analysis in one case. Clinically, each patient had aggressive B-cell lymphoma with disseminated disease often involving the central nervous system, poor response to chemotherapy and short survival. Activation of c-myc in association with deregulation of bcl-2, bcl-6 or both confers high-grade disease with a poor prognosis.

Adult↗

Second malignancies in patients with hairy cell leukemia in british columbia: a 20-year experience.

The purpose of this study was to compare the relative risk of second malignancies in a cohort of patients with hairy cell leukemia (HCL) against the normal population. Potential effects of type of treatment and duration of follow-up and the site distribution of cancer were also examined. Between 1976 and 1996, 117 patients were diagnosed with HCL in British Columbia who were referred to the British Columbia Cancer Agency (BCCA) for treatment. All additional malignancies were traced using a provincial population-based cancer registry and follow-up records from the BCCA. There were 90 men and 27 women. Median age at diagnosis was 53 years. The median follow-up time was 68 months. Twenty-three patients underwent primary splenectomy, 65 received interferon alpha, 24 deoxycoformycin, and 67 cladribine (2-chlorodeoxyadenosine). Thirty-six patients had an additional malignancy (30.7%) with a total of 44 tumors. Six patients (5.1%) had two or more malignancies. Twenty-five patients had malignancies diagnosed after HCL (21.3%), three concurrent with HCL (2.6%), and 12 preceding HCL (10.2%). Second tumors (n = 28 tumors) occurred at a median of 40 months after HCL (range, 3 to 167). The relative rate (RR) of second malignancy among men and women was 2.91 (P < .001) and 1.65 (P = .23), respectively, compared with age and secular trend-matched controls. There were eight prostate cancers, nine nonmelanoma skin cancers, two lung cancers, and four gastrointestinal adenocarcinomas. The RR (90% confidence interval [CI]) in the various treatment groups were: splenectomy (RR = 0.21 to 3.81), purine analogues (RR = 0.60 to 5.69), interferon then purine analogues (RR = 1.60 to 4.31), interferon alone (RR = 1. 57 to 8.40). Cancer risk peaked at 2 years after HCL (RR = 4.13) and fell steadily afterwards, reaching a RR of 1.82 at 6 years. Twenty patients died, six due to HCL, 10 due to second malignancies, and four of unrelated causes. HCL patients appear to be inherently prone to malignancies. This appears to be more related to HCL tumor burden than to genetic predisposition or treatment effect. RR tends to fall with time after effective treatment. However, close monitoring for and vigorous prevention of cancer in HCL patients is advisable.

Adult↗

Prolonged erythroid aplasia after major ABO-mismatched transplantation for chronic myelogenous leukemia.

Erythroid engraftment after non-T cell-depleted allogeneic bone marrow transplant (BMT) is reviewed in 112 patients treated for chronic myelogenous leukemia (CML). Twenty-two of 76 evaluable patients were transplanted over a major ABO-mismatch compatibility barrier. These patients showed an increased delay in erythroid engraftment and in time to red blood cell transfusion independence when compared with ABO-identical or minor mismatched recipients. No difference in granulocyte or platelet engraftment was evident. Erythroid engraftment usually occurred spontaneously without specific intervention. One patient was found to have erythroid hypoplasia at day 201 after BMT, despite therapy with intravenous immunoglobulin and high-dose erythropoietin. An anti-A titer of 16,000 was documented. This patient was successfully treated with an aggressive course of 18 plasmapheresis procedures and with donor-type plasma replacement. Delayed erythroid engraftment is common after non-T cell-depleted major ABO-mismatched BMT in CML, but rarely requires intervention other than transfusion support. Rare cases of refractory erythroid aplasia may be treated without additional immunosuppression by aggressive plasma exchange with donor-type plasma.

ABO Blood-Group System↗

Treatment of follicular lymphoma.

Follicular lymphoma is one of the most common neoplastic lymphoproliferative diseases encountered in the western world. Intensive scientific scrutiny has led to detailed understanding of the nature of the malignant cell and the specific genetic abnormalities which are frequently encountered and likely to be etiologic. Clinical research focusing on the treatment of follicular lymphoma continues to reveal new insights into the natural history of the disease. Investigations reported during the past year have focused on a number of important issues with regard to the management of patients with the diseases.

Antineoplastic Combined Chemotherapy Protocols↗

Clinicopathological analysis of follicular lymphoma with a polyploid karyotype.

The prognostic significance of specific cytogenetic abnormalities in follicular lymphoma (FL) is an area of ongoing research. A small percentage of FL are characterized by a polyploid karyotype. Several studies have analyzed ploidy level to determine its role as an independent prognostic factor in non-Hodgkins lymphoma, with equivocal results, mostly using DNA flow cytometry to ascertain ploidy status. We have performed cytogenetic analyses on 180 cases of FL with a t(14;18) diagnosed between 1980 and 1995. Cases were divided into a polyploid group (20 cases) and a non-polyploid group (160 cases), polyploidy defined as a modal chromosome number of 58 or greater. Each group included examples of the 3 subtypes of FL, [Working Formulation]: 1) follicular small cleaved cell (FSC), 2) follicular mixed, small and large cell (FM), and 3) follicular large cell (FLC). The median follow-up time was 38.5 months. The histological subclassification of the polyploid group revealed much less FSC (30% vs 66%, p < 0.004) and much more FLC (25% vs 4%, p < 0.003) than the non-polyploid group, implying histological progression may occur in parallel with the development of polyploidy. Recognized clinical prognostic factors were evenly distributed between the two groups and no survival difference was detected. We show that polyploidy as determined by classical cytogenetics is present in different frequencies across the subtypes of FL with a t(14;18), but is not an independent prognostic factor for survival in FL.

Cohort Studies↗

Problems in lymphoma management: special sites of presentation.

The staging and treatment of the common presentations of malignant lymphoma are readily familiar to experienced medical oncologists and hematologists. However, because of their rarity and variable and unusual behavior, certain special sites of lymphoma present a major challenge even to experienced clinicians. This article focuses on five such special sites of presentation: the eye, paranasal sinuses, central nervous system (CNS), testicle, and stomach. In each case, an appreciation of the usual histologic types, unique mode of metastatic spread, special patterns of resistance to systemic treatment, and, in the stomach, the remarkable association with a causative organism, Helicobacter pylori, is needed to optimize management. Only if these special characteristics are understood can the clinician plan a multiphase treatment course that offers each patient the best chance of disease control or cure.

Central Nervous System Neoplasms↗

Prognostic significance of Bax protein expression in diffuse aggressive non-Hodgkin's lymphoma.

Bax is a proapoptotic member of the Bcl-2 protein family. The incidence and prognostic significance of Bax protein expression in diffuse non-Hodgkin's lymphomas with a large cell component (DLCL) was determined by an immunohistochemical method by using paraffin-embedded tumors from a cohort of patients treated uniformly with combination chemotherapy (n = 139). All patients were between 16 and 70 years of age and had advanced stage disease of diffuse large cell type (diffuse mixed, diffuse large cell, immunoblastic, or anaplastic large cell). Paraffin sections from diagnostic biopsies were successfully immunostained for Bax in 113 cases. Of these, 7 (6%) tumors were scored as Bax immunonegative (< 1% Bax-stained tumor cells), 42 (37%) as low (1% to 10%), 9 (8%) as low-intermediate (11% to 30%), 25 (22%) as high-intermediate (31% to 70%), and 30 specimens (27%) as high for Bax expression (> 70%). Of the 7 Bax-immunonegative lymphomas, all also scored low (< or = 10% immunostained tumor cells) for Bcl-2 expression, whereas 78 of the 106 (74%) Bax-immunopositive tumors had low Bcl-2 expression. By itself, Bax expression was not of prognostic significance in univariate analysis, although there was a clear trend for patients with Bax-immunonegative lymphomas (n = 7) to relapse sooner and to die faster than patients whose tumors contained Bax-immunopositive malignant cells (n = 106; 8-year overall survival 29% versus 55%; P = .06). When combined with Bcl-2 immunostaining data, Bax provided additional prognostic information. Among patients with Bcl-2 low-expressing DLCLs, for example, Bax immunonegativity was associated with lower 8-year relapse-free survival (RFS; 29% v 61%; P < .01) and lower 8-year overall survival (OS; 29% v 63%; P < .05), suggesting that absence of Bax protein connotes a more aggressive phenotype when Bcl-2 protein is also not expressed at high levels. In contrast, low Bax expression was associated with improved 8-year disease-free survival (52% v 16%; P < .02), RFS (47% v 11%; P < .02), and OS (64% v 11%; P < .01) in patients whose tumors expressed Bcl-2 at high levels, suggesting that the combination of high levels of Bax and Bcl-2 expression is more deleterious than high levels of Bcl-2 expression alone. Bax expression failed to provide additional prognostic information beyond Bcl-2 expression in multivariate analysis that included the clinical International Prognostic Index factors (age, stage, lactate dehydrogenase, performance status, and number of extranodal sites) and immunophenotype. Taken together, the results suggest that Bax expression is not a major prognostic marker in DLCL. However, the interactions of the Bcl-2 and Bax expression data with respect to clinical outcome may shed new insights into the biological significance of Bcl-2/Bax protein heterodimerization.

Adolescent↗

Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma.

The prognostic significance of Bcl-2 protein expression and bcl-2 gene rearrangement in diffuse large cell lymphomas (DLCL) is controversial. Bcl-2 protein expression prevents apoptosis and may have an important role in clinical drug resistance. The presence of a bcl-2 gene rearrangement in de novo DLCL suggests a possible follicle center cell origin and perhaps a distinct clinical behavior more akin to low-grade non-Hodgkin's lymphoma (NHL). The purpose of this study was to determine the impact of Bcl-2 protein expression and bcl-2 gene rearrangement (mbr and mcr) on survival of a cohort of patients with DLCL who were uniformly evaluated and treated with effective chemotherapy. Patients included the original MACOP-B cohort (n = 121) and the initial 18 patients treated with the VACOP-B regimen (total = 139). All patients had advanced-stage disease, were 16 to 70 years old, and corresponded to Working Formulation categories F, G, or H. No patients had prior treatment, discordant lymphoma, or human immunodeficiency virus seropositivity. Paraffin sections from diagnostic biopsies were analyzed for bcl-2 gene rearrangement including mbr and mcr breakpoints by polymerase chain reaction and Bcl-2 protein expression by immunohistochemistry. With a median follow-up of 81 months, overall (OS), disease-free (DFS), and relapse-free survival (RFS) were measured to determine the prognostic significance of these parameters. Analyzable DNA was present in 118 of 139 (85%) cases, with 14 demonstrating a bcl-2 rearrangement (11 mbr, 3 mcr). All 14 of these bcl-2 gene rearrangement-positive cases were found in the 102 patients with a B-cell immunophenotype, but the presence of this rearrangement had no significant influence on survival. Bcl-2 protein expression was interpretable in 116 of 139 (83%) cases, with immunopositivity detected in 54 of 116 (47%). Using a cut-off of greater than 10% Bcl-2 immunopositive tumor cells for analysis, positive Bcl-2 protein expression was seen in 28 of 116 (24%) patients and the presence of this expression correlated with decreased 8-year OS (34% v 60%, P < .01), DFS (32% v 66%, P < .001), and RFS (25% v 59%, P < .001). Bcl-2 protein expression remained significant in multivariate analysis that included the clinical international prognostic index factors and immunophenotype (P < .02). In conclusion, although bcl-2 gene rearrangement status could not be shown to have an impact on outcome, Bcl-2 protein expression is a strong significant predictor of OS, DFS, and RFS in DLCLs.

Adolescent↗

Mantle cell lymphoma: a clinicopathologic study of 80 cases.

Mantle cell lymphoma (MCL) is a relatively uncommon yet distinct type of malignant lymphoma whose clinical and pathological characterization has been limited by the small numbers of cases published to date. We studied 80 cases of MCL seen at a single institution over 7 years to determine both clinical and pathological prognostic factors. The patients in this study were predominantly male (70%) and older (mean age, 63 years) and presented with advanced-stage disease (88%). Extranodal involvement was common. Median overall survival (OS) was 43 months. Except for performance status, prognosis was not significantly influenced by clinical prognostic factors. Histologically, MCL architecture was classified as diffuse (78%), nodular (16%), or mantle zone (6%); the OS among these groups was identical. Increased mitotic activity (>20 mitotic figures per 10 high power fields), blastic transformation, and peripheral blood involvement at diagnosis also predicted for a worse outcome, but bone marrow involvement did not. The presence or absence of a translocation t(11; 14) by cytogenetic analysis or a bcl-1 rearrangement by Southern analysis did not significantly predict outcome. In summary, this study of 80 cases of MCL highlights its distinctive clinicopathologic features and shows that increased mitotic activity, blastic morphology, and peripheral blood involvement at diagnosis are prognostically important factors.

Adult↗

Treatment considerations in the elderly patient with lymphoma.

One half of all non-Hodgkin's lymphomas occur in the elderly, a growing segment of the population in North America. Significantly, the incidence of lymphoma in general, and especially in the elderly, is rising rapidly. These trends will combine to double the number of cases of lymphoma in the elderly in the next 2 to 3 decades. Certain lymphomas can be treated as effectively in the elderly as in the young, and others are treatable but with only half the expectation of cure. Further improvements will be made as future clinical investigation focuses on the elderly with lymphoma as a special group.

Age Factors↗

t(11;18)(q21;q21) is the most common translocation in MALT lymphomas.

BACKGROUND: Low grade malignant lymphomas arising from mucosa associated lymphoid tissue (MALT) represent a distinct clinicopathological entity. The cytogenetic findings and molecular genetics of MALT lymphomas remain minimally defined. Cytogenetic studies infrequently constitute part of the diagnostic work-up of MALT lymphomas, most commonly due to small biopsy size and their extranodal localization. Only 28 MALT cases with a clonal karyotype have been published to date. A number of chromosomal abnormalities have been observed with the majority of the cases featuring trisomy of chromosome 3 which is present in up to 78% of the cases. MATERIALS AND METHODS: A total of 116 cases of MALT lymphoma were diagnosed at BCCA between 1988 and 1997. Eleven cases of pathologically confirmed MALT lymphomas were subjected to cytogenetic analysis at the time of the initial evaluation. Eight of 11 cases yielded successful cultures and the presence of a clonal karyotype using standard cytogenetic methodology. In addition, a single case of orbital MALT lymphoma with a clonal karyotype has been obtained through our consultative practice from University of Nebraska Medical Center. These nine cases of MALT lymphoma with a clonal karyotype are the subject of this report. RESULTS AND CONCLUSION: In this study we report nine cytogenetically studied MALT lymphomas, three of which feature a novel t(11;18)(q21;q21) translocation which has also been observed in five other MALT cases described in the literature. This recurrent translocation is the most common translocation associated with MALT lymphomas being present in 33% (three of nine) of our cases and 18% (five of 28) of the previously published cases. The results suggest that a potentially important gene located at one of these breakpoints may be involved in the pathogenesis of MALT lymphomas.

Adult↗

Advanced diffuse large-cell lymphoma treated with 12-week combination chemotherapy: natural history of relapse after initial complete response and prognostic variables defining outcome after relapse.

PURPOSE: To define both the natural history of and prognostic factors affecting outcome post relapse from a complete response in advanced stage diffuse large-cell lymphoma. PATIENTS AND METHODS: A total of 468 patients aged 17-74 years received the 12-week duration chemotherapy regimens MACOP-B, VACOP-B and ACOP-12 between 1 April 1981 and 31 December 1995 for advanced stage diffuse large, mixed or immunoblastic lymphoma. Of these 402 entered a complete remission, 97 (24%) of whom subsequently relapsed. Initial staging data, follow-up, and relapse information were analyzed to define the natural history of relapse and also subjected to univariate and multivariate correlation with overall (OS) and failure free survival (FFS). RESULTS: Eleven percent of the relapses were low grade. All other relapses were of intermediate grade with 75% occurring within the first two years, the remainder up until the eleventh year. Median and five-year OS from the time of relapse for intermediate grade relapse were 12 months and 20%; for FFS they were eight months and 18% respectively. Adverse independent factors, for both OS and FFS were: less than one year to relapse, decreasing performance status at relapse, and more than three nodal sites at relapse. CONCLUSIONS: Low-grade relapse is not uncommon in patients who initially presented with diffuse large cell lymphoma. As the management of low- and intermediate grade disease is so different biopsy proof of the nature of the relapse is of value. The prognostic factors identified need to be taken into consideration when analyzing results from trials of secondary treatment so as to avoid erroneous conclusions about comparative treatment efficacy.

Adolescent↗

Bone marrow involvement in T-cell-rich B-cell lymphoma.

We describe the histologic and immunohistochemical findings in specimens from bone marrow (BM) biopsies performed for staging purposes in 13 patients with a previous tissue-based diagnosis of T-cell-rich B-cell lymphoma (TCRBCL). Bone marrow involvement was found in 8 (62%) of 13 cases and was often paratrabecular. The histologic appearance was not pathognomonic of TCRBCL, with the differential diagnosis including Hodgkin's disease and peripheral T-cell lymphoma. The infiltrates typically had a pale low-power appearance (due to histiocytic infiltration, relative hypocellularity, or both) that, in conjunction with the presence of a polymorphous infiltrate of scattered large atypical cells amid a mixed infiltrate of small lymphocytes and histiocytes, was suggestive of Hodgkin's disease. Immunohistochemistry revealed CD20 reactivity of the large atypical cells with the absence of CD15 and CD30 reactivity, supporting the diagnosis of TCRBCL. A prominent small T-cell infiltrate accompanying the large atypical cells was observed in all positive BM biopsy specimens. The increased incidence of BM involvement in TCRBCL is significantly higher than that found in de novo B-cell diffuse large cell lymphoma, suggesting a possible biologic difference between the two entities. Our cases share some similar clinicopathologic features with histiocyte-rich B-cell lymphoma and with diffuse lymphocyte-predominant Hodgkin's disease, paragranuloma type. We discuss the possible relationship to these two entities.

Adult↗