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Biomedical subjects

J Wilimas

Publications and source records attributed to J Wilimas.

At least 19 recordsLinked to original sources

Second malignancy risk associated with treatment of Hodgkin's lymphoma: meta-analysis of the randomised trials.

BACKGROUND: Despite several investigations, second malignancy risks (SMR) following radiotherapy alone (RT), chemotherapy alone (CT) and combined chemoradiotherapy (CRT) for Hodgkin's lymphoma (HL) remain controversial. PATIENTS AND METHODS: We sought individual patient data from randomised trials comparing RT versus CRT, CT versus CRT, RT versus CT or involved-field (IF) versus extended-field (EF) RT for untreated HL. Overall SMR (including effects of salvage treatment) were compared using Peto's method. RESULTS: Data for between 53% and 69% of patients were obtained for the four comparisons. (i) RT versus CRT (15 trials, 3343 patients): SMR were lower with CRT than with RT as initial treatment (odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.62-0.98 and P = 0.03). (ii) CT versus CRT (16 trials, 2861 patients): SMR were marginally higher with CRT than with CT as initial treatment (OR = 1.38, CI 1.00-1.89 and P = 0.05). (iii) IF-RT versus EF-RT (19 trials, 3221 patients): no significant difference in SMR (P = 0.28) although more breast cancers occurred with EF-RT (P = 0.04 and OR = 3.25). CONCLUSIONS: Administration of CT in addition to RT as initial therapy for HL decreases overall SMR by reducing relapse and need for salvage therapy. Administration of RT additional to CT marginally increases overall SMR in advanced stages. Breast cancer risk (but not SMR in general) was substantially higher after EF-RT. Caution is needed in applying these findings to current therapies.

Combined Modality Therapy↗

Transient erythroblastopenia of childhood associated with transient neurologic deficit: report of a case and review of the literature.

OBJECTIVE: Patients with transient erythroblastopenia of childhood (TEC) may also have a transient neurologic disorder. We present a case history and propose a mechanism for this syndrome. PATIENT AND METHODOLOGY: We describe a 20-month-old girl with TEC and transient hemiparesis. Records from the period January 1993 through December 1994 were reviewed to identify other patients with TEC and to determine whether neurologic deficits were noted in these cases. RESULTS: Of seven patients diagnosed with TEC over a 2-year period, only one had a neurologic deficit. This child's hemiparesis resolved within 24 h after the appearance of her symptoms. Her TEC resolved within 4 weeks, without long-term sequelae. Our experience and review of the literature suggest that focal neurologic deficits in TEC patients are uncommon, transient, lack long-term sequelae, and usually resolve prior to hematologic recovery. CONCLUSIONS: Previous reports suggested that the anaemia resulting from TEC might induce neurologic deficits. We suggest an alternative mechanism in which viral infection triggers a host immune response that independently leads to both TEC and neurologic abnormalities. Future studies should address the role of viral infection in TEC patients with focal neuropathies.

Diagnosis, Differential↗

The factor V Leiden mutation in children with cancer and thrombosis.

Thromboembolic phenomena, frequently observed in children with cancer who are undergoing chemotherapy, can cause significant morbidity and, less frequently, mortality. Many contributory factors have been identified. Whether the recently identified and most common coagulation defect predisposing to thrombosis, factor V Leiden, is associated with thrombosis in this setting, has not been explored. The current study was undertaken to determine the prevalence of the factor V Leiden mutation in children with cancer who developed thromboembolic phenomena as compared to those with cancer who did not. Genomic DNA was amplified using the polymerase chain reaction (PCR), followed by digestion of the amplification product with the restriction enzyme MnlI. The digested PCR products were then size-fractionated to classify samples as heterozygous, homozygous or normal for the factor V Leiden mutation. 67 children with cancer were evaluated for the factor V Leiden mutation. One of 32 children with cancer and thrombosis, and none of 35 who had not experienced thrombotic problems, was found heterozygous for this mutation. We conclude that the factor V Leiden mutation does not play a significant role in the overall incidence of thromboses that occur in children with cancer.

Adolescent↗

Local control in synchronous bilateral Wilms tumor.

PURPOSE: To evaluate the role of radiation therapy (RT), chemotherapy (CT), and surgery in the local control of synchronous bilateral Wilms Tumor (WT). METHODS AND MATERIALS: Between 1962 to 1993, 45 children were treated for bilateral WT; 38 patients with synchronous tumors were reviewed. Initial surgery depended on the era of treatment and included unilateral nephrectomy (N)/partial nephrectomy (PN) and contralateral PN in 6, unilateral N/PN alone in 7, and biopsy only in 25. Chemotherapy (CT) consisted of vincristine, actinomycin-D, and adriamycin in 32 and vincristine/ actinomycin-D in 6. Radiation therapy (RT) was given to 32 patients. Treatment included both kidneys in 20, unilateral kidney plus contralateral renal bed in 9, unilateral kidney in 2, and unilateral renal bed in 1. Follow-up was 16 months to 25 years (median: 6.3 years). RESULTS: Local control (LC) has been maintained in 66 out of 76 sites (87%). For Stage I-II disease with initial N/PN, LC was 10 out of 12 with RT and 11 out of 11 without RT; for Stage III with initial N/PN, LC was 8 out of 9 with RT and 1 out of 1 without RT. Initial CT and RT was followed by delayed N/PN for 20 sites; LC was 15 out of 17 in post induction Stage I-II and 1 out of 3 in postinduction Stage III. In 23 sites undergoing biopsy and chemotherapy, LC was 19 out of 20 with RT and 1 out of 3 without RT. Seven of 23 sites had a complete response (CR) after induction CT, and LC was maintained in four out of four with RT and one out of three without RT. Univariate Cox Regression analysis demonstrated that sites receiving two drugs had a statistically significant increase in loco-regional relapse when compared to sites receiving three drugs (p = 0.004). Major morbidities related to multimodality therapy have included renal failure in one patient and small bowel obstruction requiring lysis of adhesions in two patients. CONCLUSIONS: Local control does not seem to be compromised by renal conservation therapy. Local control is excellent in sites treated with radiation therapy in combination with three drug chemotherapy.

Adolescent↗

Postoperative small-bowel intussusception in children with cancer.

The clinical and imaging features of small-bowel intussusception as a complication of abdominal surgery are not well known. Diagnosis may be delayed because symptoms mimic common postoperative complaints. In pediatric cancer patients, the side effects of chemotherapy and symptoms related to the primary malignancy may also obscure the diagnosis. We report the clinical and radiographic features of eight children undergoing evaluation and treatment for solid tumors who developed small-bowel intussusception following laparotomy. These children represent 2.2% of all children and adolescents who underwent laparotomy at a pediatric cancer research and treatment center during a 13-year period. With prompt diagnosis and intervention, morbidity and mortality from this rare but life-threatening postoperative complication can be avoided.

Child↗

Outcome of moderate aplastic anemia in children.

PURPOSE: In order to assist in the management of newly diagnosed children with moderate aplastic anemia (MAA) we reviewed the clinical course and outcome of children with MAA seen at our institution over the past 12 years and compared them with children with severe aplastic anemia (SAA). PATIENTS AND METHODS: MAA was defined as having a hypocellular bone marrow and cytopenia in at least two cell lines not in the severe range. Twelve children met these criteria. Twenty-eight children with SAA were seen during the same interval. Patients with MAA were treated with immunomodulation with antithymocyte globulin and/or cyclosporine if they progressed to SAA. RESULTS: Five patients with MAA progressed to SAA at a median interval of 18 months from diagnosis. The other seven patients required no therapy or only received transfusions for < or = 6 months after diagnosis. The survival of the patients with MAA was significantly better than that of patients with SAA treated with immunomodulation (p = 0.022). All patients with MAA are alive at a median follow up of 7 years and are transfusion independent; only one patient currently receives therapy. Residual hematologic abnormalities in children with MAA included thrombocytopenia, leukopenia, and macrocytosis. CONCLUSIONS: In this small series of children with MAA the outcome was excellent and significantly better than in patients with SAA; more than half recovered with minimal or no therapy. Patients who progressed to SAA responded well to treatment. A larger prospective study is needed to conclusively define the natural history of MAA.

Adolescent↗

Bilateral Wilms tumor. Review of outcome, associated abnormalities, and late effects in 36 pediatric patients treated at a single institution.

BACKGROUND: Patients with bilateral Wilms tumor have an increased incidence of associated abnormalities and nephrogenic rests and require individualized multimodality therapy for cure. The authors reported the associated abnormalities, outcome, complications, and late effects of treatment in a group of children with bilateral Wilms tumor treated at St. Jude Children's Research Hospital, Memphis, Tennessee, over a 28-year period. METHODS: The records of 36 consecutive pediatric patients diagnosed with bilateral Wilms tumor between 1962-1990 were analyzed. Biopsy material was also reviewed, with particular emphasis on characterization of nephrogenic rests and histology. RESULTS: Twenty-nine patients had synchronous tumors and 7 had metachronous lesions. Associated physical abnormalities were present in 12 patients and involved the genitourinary, cardiovascular, integumentary, and musculoskeletal systems. The overall survival for patients with metachronous tumors (71%) was similar to that for those with synchronous tumors (70%). There was no effect of age or the presence of nephroblastomatosis. Two patients with synchronous tumors initially treated with nephrectomy eventually required bilateral nephrectomies for contralateral recurrence after chemotherapy and radiation therapy. Nephrogenic rests were present in 22 of 30 evaluable patients. Two of three patients with metachronous tumors had intralobar nephrogenic rests. Bilateral renal salvage procedures were demonstrated to be technically feasible and effective in controlling disease without compromising renal function or survival. Late effects included scoliosis in three patients treated before 1970, cardiomyopathy in one patient who received 300 mg/m2 doxorubicin and 12 Gy pulmonary irradiation, and benign tumors in two patients, one of whom also had a bowel obstruction. Serum creatinine, urea nitrogen, and blood pressure were normal in 23 of 26 survivors. CONCLUSIONS: The authors' experience supports a favorable outcome with minimal late effects for patients with bilateral Wilms tumor who receive individualized therapy at pediatric oncology centers.

Child↗

Serum intercellular adhesion molecule-1 in childhood malignancy.

Levels of soluble intercellular adhesion molecule-1 (ICAM-1) were measured in serum samples taken at diagnosis from pediatric patients with Hodgkin's disease (n = 69), acute lymphoblastic leukemia (n = 28), Wilms' tumor (n = 20), osteosarcoma (n = 17), rhabdomyosarcoma (n = 18), or Ewing's sarcoma (n = 15). Median levels of serum ICAM-1 were significantly higher in acute lymphoblastic leukemia and Hodgkin's disease than in controls and other malignancies. Levels were positively correlated with disease stage for patients with Hodgkin's disease, Ewing's sarcoma or Wilms' tumor, and with the frequency of relapse in Hodgkin's disease (P = .016). Serum levels were normal in all of 76 patients tested in remission. It remains to be determined whether increased serum ICAM-1 levels simply reflect a greater tumor burden or whether this molecule contributes directly to the progression of childhood malignancies.

Adolescent↗

A phase I study of ifosfamide with Mesna given daily for 3 consecutive days to children with malignant solid tumors.

BACKGROUND: The authors conducted a Phase I dose escalation trial of ifosfamide given daily for 3 consecutive days to 29 children with malignant solid tumors. Twenty-eight of these children had received prior chemotherapy. METHODS: Patients were assigned to dosage cohorts separately on the basis of prior exposure to the platinum alkylating agents cisplatin or carboplatin (n = 20) or the absence of such exposure (n = 9). At least three patients in each category were treated at a starting dosage of 2133 mg/m2/d for 3 days. This dosage represented 80% of the total dose delivered in the prior study of ifosfamide given daily over 5 days with dosage escalation of 20% in subsequent cohorts. RESULTS: Myelosuppression was dose-limiting at the second dosage level (2560 mg/m2/d) for patients previously treated with platinum and at the third dosage level (3072 mg/m2/d) for those not previously treated with platinum. Dose-limiting neurotoxicity was seen at 2560 mg/m2/d for the former group, but was not encountered in the latter group. CONCLUSIONS: Delivery of ifosfamide daily for 3 days is feasible and safe at recommended dosages of 2133 mg/m2/d for children with prior exposure to platinum and 3000 mg/m2/d for those without prior exposure.

Adolescent↗

Efficacy and toxicity of multiagent chemotherapy and low-dose involved-field radiotherapy in children and adolescents with Hodgkin's disease.

PURPOSE: Between May 1980 and September 1990, 85 patients with Hodgkin's disease were treated with a regimen designed to increase cure rates while reducing late toxicity. PATIENTS AND METHODS: Therapy consisted of five cycles of cyclophosphamide, Oncovin (vincristine; Eli Lilly and Co, Indianapolis, IN), and procarbazine (COP), alternated with four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and low-dose (20 Gy) regional radiotherapy. Vincristine and cyclophosphamide were administered as tolerated during irradiation and during the 2- to 4-week rest period between radiation volumes. The need for staging laparotomy was defined by clinical presentation. RESULTS: The median age at diagnosis was 14 years (range, 4 to 20), and 56% of patients were male. The majority (67%) had stage III or IV disease and 68% (19 of 28) of stage II patients had bulky mediastinal disease. Nodular sclerosing histology predominated (67%). Ninety-three percent of patients were alive without disease with a median follow-up of 4.1 years. Abnormalities were detected on chest roentgenograms and/or pulmonary function tests in 58% and 25% of clinically asymptomatic patients who were tested at least 1 year after completion of therapy. The only symptomatic patient had pulmonary fibrosis after treatment with bleomycin (20 U/m2) and mantle (20 Gy)/lung (13 Gy) irradiation, and developed multiple spontaneous pneumothoraces that required cortical stripping. One patient had congestive heart failure 19 months post-treatment, and two had abnormalities on echocardiograms. Thyroid abnormalities occurred in 21 (27%) patients who were assessable for late toxicity. The majority of female patients have had regular menstrual cycles. Six developed ovarian failure, and 10 have had a total of 17 pregnancies. Other than one documented case of oligospermia, information was not available on male fertility. CONCLUSION: The results demonstrate excellent disease control for the COP/ABVD regimen, with acceptable toxicity.

Adolescent↗

Phase I study of escalating targeted doses of carboplatin combined with ifosfamide and etoposide in children with relapsed solid tumors.

PURPOSE: The tolerance of escalating targeted doses of carboplatin combined with ifosfamide (IFOS)/etoposide (VP-16) (ICE) was assessed in children with recurrent solid tumors. PATIENTS AND METHODS: To reduce interpatient variability in carboplatin systemic exposure, 45 children were treated with doses individualized to a target area under the serum concentration versus time curve (AUC) based on renal function, using technetium 99-diethyl-enetriamine pentaacetic acid (99mTc-DTPA) clearance to estimate glomerular filtration rate (GFR). Cohorts of at least three patients received carboplatin at an initial target AUC of 2 mg/mL x min, with escalations of 1 mg/mL x min in subsequent cohorts. Courses consisted of carboplatin on day 1 followed by IFOS 2 g/m2 plus VP-16 100 mg/m2 on days 2 and 3. Patients received at least two courses, with a maximum of eight courses possible in the absence of progressive disease. When only moderate toxicity occurred after escalation to 5 mg/mL x min, a third dose of IFOS plus VP-16 was added. After three patients were treated at this level, carboplatin escalation proceeded. RESULTS: Neutropenia and thrombocytopenia were the dominant toxicities in the 43 assessable patients. At the target AUC of 8 mg/mL x min, 13 of 20 cycles were associated with febrile neutropenia. For phase II trials, we recommend a carboplatin target AUC of 6 mg/mL x min with three doses of IFOS and VP-16 for patients with prior craniospinal irradiation or high-dose cisplatin (CDDP)/VP-16, or 7 mg/mL x min for patients without such histories. There were two complete responses (CRs), 13 partial responses (PRs), and 17 objective responses (ORs). CONCLUSION: The ICE regimen shows promising activity in pediatric solid tumors. The clear relationship between hematologic toxicity and carboplatin systemic exposure supports the use of targeted dosing in further trials of ICE chemotherapy.

Adolescent↗

Acute hypersensitivity reactions to etoposide in a VEPA regimen for Hodgkin's disease.

PURPOSE: We report an unexpectedly high incidence of hypersensitivity to etoposide among 45 patients with newly diagnosed Hodgkin's disease treated with vinblastine, etoposide, prednisone, and doxorubicin (VEPA) plus radiation. PATIENTS AND METHODS: Twenty-three of 45 patients (51%) had one or more acute hypersensitivity reactions to etoposide administration. The 23 patients were 8 to 18 years of age (median, 15 years); 12 were males. Four patients had experienced prior allergic reactions to antibiotics or intravenous contrast media. RESULTS: Hypersensitivity reactions followed the first or second dose of VEPA in most cases. The reactions occurred at a median time of 5 minutes (range, 3 to 120) from the start of the etoposide infusion. Fifteen patients reacted early (within 10 minutes), four midway through the infusion, and four after completion of the infusion. Signs and symptoms included flushing, respiratory problems, changes in blood pressure, and abdominal pain with or without nausea and vomiting. Respiratory problems included dyspnea, chest pain/tightness, bronchospasm, and cyanosis. Symptoms were alleviated by discontinuing the etoposide infusions and administering diphenhydramine and/or hydrocortisone; epinephrine was required to reverse bronchospasm in three cases. All 23 patients recovered without adverse sequelae and were rechallenged with etoposide. Fifteen patients tolerated subsequent etoposide infused at a slower rate, with antihistamine and/or corticosteroid premedication; five had recurrent hypersensitivity despite these measures. Three of these five developed similar symptoms when teniposide was substituted for etoposide. Three patients who had isolated episodes of hypotension on completion of the etoposide infusion successfully received subsequent infusions without premedication or change in infusion rate or concentration. CONCLUSION: Despite this unexpectedly high incidence of hypersensitivity among Hodgkin's disease patients treated with etoposide, rechallenge with the drug was successful in 78% of cases.

Acute Disease↗

Serum interleukin-2 receptor levels in Hodgkin disease and other solid tumors of childhood.

Serum levels of interleukin-2 receptor (IL2R) were determined in children with newly diagnosed Hodgkin disease (n = 68), Wilms tumor (n = 20), osteosarcoma (n = 18), rhabdomyosarcoma (n = 18), or Ewing sarcoma (n = 15). Measurements of soluble IL2R were positively correlated with disease stage in Hodgkin disease but not in other tumors. Very high levels of soluble IL2R (> or = 5000 U/ml) were significantly associated with a poorer treatment outcome in Hodgkin disease (p = 0.006) and retained significance in a multivariate analysis (p = 0.03). The addition of soluble IL2R measurements to existing prognostic models may improve risk assignment in children with Hodgkin disease.

Child↗

Myeloid neoplasia in children treated for solid tumours.

Therapy-related myeloid neoplasia developed 14 to 189 months after diagnosis of the primary malignancy in 12 out of 3365 children treated for malignant solid tumours; 6 of the 12 were in their first complete remission. The 10-year cumulative incidence of myeloid neoplasia was 1.3% (95% Cl 0.5-3.6) for the 447 patients with Hodgkin's disease, 1.3% (0.4-4.3) for the 420 with non-Hodgkin lymphoma, and 1.2% (0.3-5.2) for the 440 with neuroblastoma. This complication appeared in 1 of 180 children with brain tumours and in none of the 1878 with other malignancies. Risk of therapy-related myeloid neoplasia in patients with Hodgkin's disease was associated with recurrence of the primary malignancy, a combination of radiotherapy and chemotherapy with alkylating agents, and age greater than or equal to 12 years at diagnosis of Hodgkin's disease. Of the 8 patients who underwent chromosomal analysis of neoplastic myeloid cells, 2 showed complete loss of chromosome 7 and 4 showed t(9;11) or t(8;21) with or without del(16)(q22). The 2 patients who had received an epipodophyllotoxin had an 11q23 abnormality. The risk of therapy-related myeloid neoplasia is low in children with malignant solid tumours.

Adolescent↗

Wilms' tumor: reduced-dose radiotherapy in advanced-stage Wilms' tumor with favorable histology.

Fifty-two children with favorable histology Wilms' tumor who had residual abdominal disease (Surgical Stages III and IV) were treated from 1979 to 1988 on a protocol designed to assess the effectiveness of reduced radiation doses. All patients received three-agent chemotherapy, beginning within 1 week after surgery. To permit assessment of disease response to initial chemotherapy, radiation therapy was delayed for a median of 28 days after surgery (range, 14-71 days). Total doses of abdominal radiation were limited to 12 Gy, given as 150 cGy daily fractions; 18 patients with Stage IV disease received 12 Gy bilateral pulmonary irradiation. Two year disease-free survival was 85% and 71% for Stage III and IV, respectively (p = .24). Abdominal relapses occurred in 3 cases (5.7%). The interval between surgery and initiation of irradiation was not related to disease-free survival. Of several patient and disease-related factors analyzed, only patient age was related to outcome. Disease-free survival was 100% at 3 years for children under the age of 3 versus 78% for children greater than age 3 (p = .05). Reduced-dose abdominal radiotherapy in conjunction with multi-agent chemotherapy and surgery provided excellent disease control with minimal toxicity in advanced-stage, favorable histology Wilms' tumor.

Antineoplastic Combined Chemotherapy Protocols↗

Extrarenal Wilms' tumor.

The extrarenal location of Wilms' tumor is extremely rare. These tumors can arise from other neoplasms, generally teratomas, or they can present without any associated teratomatous elements. We encountered only 19 well-documented cases of isolated extrarenal nephroblastoma, and we describe three previously unreported patients with this disease. Two of the three children presented also with horseshoe kidneys, an association that may have clinical and embryologic significance. The presence of tumor cephalad to a horseshoe kidney is easier to explain when we consider that they originate from primitive mesodermal tissue, probably mesonephric rests, and not from metanephric remnants. Also, this association should alert physicians to the possible diagnosis of extrarenal nephroblastoma in patients with a retroperitoneal mass and horseshoe kidneys. These patients should be treated according to the same protocols as those for patients with intrarenal Wilms' tumor.

Child↗

Increased serum CD8 antigen level in childhood Hodgkin's disease relates to advanced stage and poor treatment outcome.

Measurement of the soluble form of CD8 antigen, a surface membrane component of suppressor/cytotoxic T cells, has yielded useful information relevant to prognosis in the lymphoid malignancies of childhood. We therefore determined pretreatment levels of serum CD8 antigen in 90 children with newly diagnosed Hodgkin's disease. The findings ranged widely, from 220 to 2,585 U/mL (median, 556 U/mL). In patients with advanced disease (stage III or IV), the median serum CD8 level was significantly higher than in those with less disease extension (stage I or II): 675 v 477 U/mL, P = .003. It was also higher in children with B symptoms compared with all others: 622 v 494 U/mL, P = .005. Cases with a histologic classification of mixed cellularity had a significantly higher median level of the antigen than did those classified as nodular sclerosis: 847 v 509 U/mL, P = .005. Finally, higher serum CD8 levels (greater than 430 U/mL) were significantly associated with an increased probability of treatment failure (P = .02). In a multivariate analysis, serum CD8 level retained its impact on treatment outcome after adjustment for other potentially useful prognostic factors, including disease stage, presence of B symptoms, histology, erythrocyte sedimentation rate, sex, age, and race. The prognostic strength shown by soluble CD8 in this analysis suggests that the antigen has clinical value. We postulate that increased CD8 levels in serum indicate enhanced suppressor T-cell activity, which may compromise the host's antitumor immunity, leading to unusually aggressive disease.

Adolescent↗

High serum interleukin-2 receptor levels correlate with a poor prognosis in children with Hodgkin's disease.

To improve the biologic evaluation of Hodgkin's disease, we determined serum interleukin-2 receptor (IL2R) levels in 88 children with this tumor. In patients with stage III or IV disease, the median receptor level was significantly higher than in patients with lower stages (3195 vs. 1087 U/ml, p = 0.0001). Similarly, the median level for children with stage B disease was 3262 U/ml, compared with 999 U/ml for those lacking constitutional symptoms (p = 0.0001). Patients with very high soluble IL2R levels (greater than or equal to 5000 U/ml) were significantly more likely to fail treatment (p = 0.01), even when the analysis was restricted to groups with advanced disease: stages III and IV (p = 0.0001). When entered in the Cox-proportional hazards model with other potentially useful prognostic factors, soluble IL2R level was found to be an independent predictor of treatment outcome. The relationship of high serum IL2R levels to an adverse clinical outcome in Hodgkin's disease may be explained by a model in which the soluble receptor competes for the ligand with the cellular receptor on normal lymphocytes, thus blocking antitumor immunity dependent on interleukin-2. Alternatively, high serum levels of IL2R may simply reflect increased release of the receptor from activated malignant cells in patients with advanced disease or an otherwise poor prognosis.

Adolescent↗