The role of the WNT/ß-catenin pathway in central nervous system primitive neuroectodermal tumours (CNS PNETs).

BACKGROUND: Central nervous system primitive neuroectodermal tumours (CNS PNETs) are embryonal tumours occurring predominantly in children. Current lack of knowledge regarding their underlying biology hinders development of more effective treatments. We previously identified WNT/ß-catenin pathway activation in one-third of CNS PNETs, which was potentially linked to a better prognosis. In this study, we have extended our cohort, achieving a statistically significant correlation with prognosis. We additionally investigated the biological effects of WNT/ß-catenin pathway activation in tumour pathogenesis. METHODS: A total of 42 primary and 8 recurrent CNS PNETs were analysed for WNT/ß-catenin pathway status using ß-catenin immunohistochemistry. Genomic copy number and mRNA expression data were analysed to identify a molecular profile linked to WNT/ß-catenin pathway activation. RESULTS: Pathway activation was seen in 26% of CNS PNETs and was significantly associated with longer overall survival. Genes displaying a significant difference in expression levels, between tumours with and without WNT/ß-catenin pathway activation, included several involved in normal CNS development suggesting aberrant pathway activation may be disrupting this process. CONCLUSION: We have identified WNT/ß-catenin pathway status as a marker, which could potentially be used to stratify disease risk for patients with CNS PNET. Gene expression data suggest pathway activation is disrupting normal differentiation in the CNS.

Reassessment of Prostate Biopsy Specimens for Patients Referred for Robot-assisted Radical Prostatectomy Rarely Influences Surgical Planning.

BACKGROUND: The minimum volume standard is 100 robot-assisted radical prostatectomy (RARP) procedures per hospital in the Netherlands, so patients have to be referred to high-volume surgical centers for RARP. During preoperative work-up, prostate biopsies taken elsewhere are reassessed, with upgrading or downgrading of the initial Gleason grade group a possible consequence. OBJECTIVE: To determine if prostate biopsy reassessment leads to adjustment of the surgical plan regarding a nerve-sparing approach and extended pelvic lymph node dissection (ePLND) during RARP. DESIGN SETTING AND PARTICIPANTS: For 125 men who were referred to the Prosper prostate center at Canisius Wilhelmina Hospital (CWH) in the Netherlands between 2013 and 2016, results for the initial assessment of prostate biopsy by a local uropathologist were compared to results for biopsy reassessment by dedicated uropathologists at CWH. RESULTS AND LIMITATIONS: The pathologists reached agreement in 80% of the cases. In cases for which there was disagreement (n = 25), biopsy revision involved upgrading of the initial grade group in 68% and downgrading in 32%. Biopsy reassessment led to a change in surgical plan in ten cases (8%). As a result of upgrading, ePLND was performed in three patients (2%). ePLND was omitted in one patient (1%) because of downgrading. For three patients (2%) a non-nerve-sparing procedure was planned after upgrading of the initial grade group. For four patients (3%), a unilateral nerve-sparing procedure was performed after downgrading. CONCLUSIONS: This study shows that there is large interobserver agreement between uropathologists in the assessment of Gleason grade group in prostate biopsy specimens. Reassessment rarely leads to a change in surgical plan regarding the indication for a nerve-sparing approach and ePLND. Therefore, reassessment of prostate biopsy before radical prostatectomy can be omitted when the initial pathological assessment was performed by a dedicated uropathologist. PATIENT SUMMARY: Reassessment of the initial prostate biopsy specimen for patients referred to a specialist center for robot-assisted removal of the prostate rarely influences surgical planning and can be omitted.

Inheritance of proliferative breast disease in breast cancer kindreds.

Previous studies have emphasized that genetic susceptibility to breast cancer is rare and is expressed primarily as premenopausal breast cancer, bilateral breast cancer, or both. Proliferative breast disease (PBD) is a significant risk factor for the development of breast cancer and appears to be a precursor lesion. PBD and breast cancer were studied in 103 women from 20 kindreds that were selected for the presence of two first degree relatives with breast cancer and in 31 control women. Physical examination, screening mammography, and four-quadrant fine-needle breast aspirates were performed. Cytologic analysis of breast aspirates revealed PBD in 35% of clinically normal female first degree relatives of breast cancer cases and in 13% of controls. Genetic analysis suggests that genetic susceptibility causes both PBD and breast cancer in these kindreds. This study supports the hypothesis that this susceptibility is responsible for a considerable portion of breast cancer, including unilateral and postmenopausal breast cancer.

Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy.

An interferon-gamma, tumor necrosis factor, and interleukin-1-inducible, high-output pathway synthesizing nitric oxide (NO) from L-arginine was recently identified in rodents. High-dose interleukin-2 (IL-2) therapy is known to induce the same cytokines in patients with advanced cancer. Therefore, we examined renal cell carcinoma (RCC; n = 5) and malignant melanoma (MM; n = 7) patients for evidence of cytokine-inducible NO synthesis. Activity of this pathway was evaluated by measuring serum and urine nitrate (the stable degradation product of NO) during IL-2 therapy. IL-2 administration caused a striking increase in NO generation as reflected by serum nitrate levels (10- and 8-fold increase [P less than 0.001, P less than 0.003] for RCC and MM patients, respectively) and 24-h urinary nitrate excretion (6.5- and 9-fold increase [both P less than 0.001] for RCC and MM patients, respectively). IL-2-induced renal dysfunction made only a minor contribution to increased serum nitrate levels. Metabolic tracer studies using L-[guanidino-15N2]arginine demonstrated that the increased nitrate production was derived from a terminal guanidino nitrogen atom of L-arginine. Our results showing increased endogenous nitrate synthesis in patients receiving IL-2 demonstrate for the first time that a cytokine-inducible, high-output L-arginine/NO pathway exists in humans.

A large kindred with 17q-linked breast and ovarian cancer: genetic, phenotypic, and genealogical analysis.

BACKGROUND: Mutation of a specific, but as yet unidentified, gene BRCA1 on chromosome 17q results in increased susceptibility to breast and ovarian cancer. It is important to know the effects of this gene in terms of the age-specific risks of these cancers and the potential interaction of this gene with other known risk factors. PURPOSE: We performed detailed studies on a large multigenerational family, in which there is known 17q-linked breast and ovarian cancer, in order to characterize the effects of the BRCA1 mutation on development of breast and ovarian cancer. METHODS: Data from the Utah Population Database were used to identify a family (identified as K2082) with a cluster of premenopausal breast cancer and ovarian cancer at any age. Blood samples from 195 members of the family were obtained and these individuals were genotyped for a series of four chromosome 17q polymorphic markers. Information on reproductive history, cancer incidence and treatment, and lifestyle factors was collected on 72 women in the family by questionnaire or through contact with living relatives. RESULTS: Odds in favor of linkage of breast and ovarian cancer in this family to the BRCA1 region of chromosome 17q are greater than 10(8) to 1. The estimated risks for breast or ovarian cancer because of the BRCA1 mutation in this family are 40% by age 50 years and 90% by age 70. No differences between affected and unaffected older BRCA1 gene carriers were observed for a number of known epidemiologic risk factors for these cancers. The gender of the parent from whom the mutant BRCA1 allele was inherited was significantly associated with phenotypic expression (P = .04). A recombinant which places BRCA1 distal to the marker Mfd191 was observed. CONCLUSIONS: Women with the BRCA1 mutation are at increased risk of developing breast and ovarian cancer. In our study population, the mutation appears to confer a lower risk of cancer at younger ages than found in previous studies. Continued interaction with family K2082 will be useful in longitudinal follow-up studies and in studies of the psychosocial implications of providing DNA diagnosis of BRCA1.

Hypocholesterolemia in patients treated with recombinant interleukin-2: appearance of remnant-like lipoproteins.

Reversible acute hypocholesterolemia was observed during treatment of metastatic cancer with high-dose intravenous recombinant interleukin-2 (IL-2). Further analysis revealed virtual disappearance of high-density lipoproteins (HDLs) and marked reduction in the concentration of low-density lipoproteins (LDL); the remaining LDL and intermediate-density lipoproteins (IDL) were enriched in triglyceride relative to cholesterol and had broad-beta electrophoretic mobility, properties reminiscent of remnant lipoproteins. These changes differ qualitatively and quantitatively from those previously reported for other cytokines such as tumor necrosis factor (TNF) or the interferons (IFNs).

Combination chemotherapy using adriamycin, DTIC, cyclophosphamide, and actinomycin D for advanced soft tissue sarcomas: a randomized comparative trial. A phase III, Southwest Oncology Group Study (7613).

The term soft tissue sarcoma refers to a large variety of malignant tumors arising in extraskeletal connective tissues that connect, support, and surround discrete anatomic structures. All visceral organs also contain a connective stroma that can undergo malignant transformation. Because of the histological similarities of this group of tumors and their relative rarity, treatment prescriptions for patients that have disseminated disease are most often uniform. In this study, we asked the question whether adding a third drug (cyclophosphamide or actinomycin D) to Adriamycin (Adr [Adria Laboratories, Columbus, OH])-(3,3-dimethyl-1-triazeno)- imidazole-4-carboxamide (DTIC) would improve the response rate and/or survival. A unique feature of this cooperative group clinical trial was the mandatory pathology review of the histological material. All patients of the Southwest Oncology Group between June 1, 1976, and November 17, 1979, who had a biopsy-confirmed diagnosis of a soft tissue sarcoma with convincing clinical or biopsy-documented evidence of metastatic disease were eligible for the study. Patients were randomized to receive (1) Adr, 60 mg/m2 intravenously, day 1, and DTIC, 250 mg/m2 every 3 weeks (104 patients); (2) Adr and DTIC as in (1) and cyclophosphamide, 500 mg/m2, day 1 (112 patients); or (3) Adr and DTIC as in (1) and actinomycin D, 1.2 mg/m2, day 1, (119 patients). There was no statistically significant difference in response rates (33%, 34%, and 24%) (P = .25). Median durations of response were 31 weeks in the Adr-DTIC arm, 26 weeks in the cyclophosphamide-DTIC-Adr arm, and 23 weeks in the Adr-DTIC-Actinomycin D arm (P = .78). Median durations of survival were 37, 42, and 50 weeks, respectively. Again, no statistically significant differences were observed (P = .59). Toxicities from each of these treatment arms were formidable and were equivalent. Prognostic factor analysis showed a prognosis based on bone marrow reserve, sex, and pathology subtype favorable to patients.

Multimodal therapy for limited small-cell lung cancer: a randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders; and with wide-field versus reduced-field radiation in partial responders: a Southwest Oncology Group Study.

In 1979 we initiated a phase III study in the Southwest Oncology Group (SWOG) which was designed to determine the value of chest radiation in limited-stage small-cell lung cancer patients achieving complete response after induction chemotherapy, and to test the use of wide-field v more limited-volume radiation in patients with partial responses (PRs) and patients with stable disease (SD). The induction chemotherapy (VMV-VAC) consisted of vincristine, 2 mg intravenously (IV) every week for six doses; methotrexate, 60 mg/m2 IV days 1 and 43; VP-16, 50 mg/m2/d IV days 1 to 5 and 43 to 47; doxorubicin, 60 mg/m2 IV days 22 and 64; and cyclophosphamide, 1,000 mg/m2 IV days 22 and 64. Four hundred ninety-four patients were registered, of whom 473 were eligible. Of 466 response-evaluable patients, 153 (33%) achieved complete disease remission (CR) with chemotherapy. A total of 387 patients entered the consolidation phase of treatment after chemotherapy and response determination. CR patients were prospectively randomized to receive chest radiation, consisting of 4,800 rad administered in a split-course scheme, or to continue chemotherapy without interruption. The treatment volume was based on tumor extent before the induction chemotherapy. Maintenance chemotherapy consisted of cyclophosphamide and VP-16 administered for four cycles before a period of reinduction chemotherapy consisting of VMV-VAC as described above. Patients receiving chest radiation therapy were given the same maintenance and reinduction chemotherapy programs following completion of the chest radiation. One hundred ninety-one eligible patients achieving PR or SD status after induction chemotherapy were randomized to a preinduction treatment volume or to a postinduction reduced tumor volume, with treatment portals designed according to tumor extent before or after induction chemotherapy, respectively. After completion of the entire treatment plan, there were 218 (47%) CRs and 121 (26%) PRs. These figures represent the greatest response achieved at any point in the treatment program. The median survival for all eligible patients was 57 weeks (74 weeks for CRs). Overall survival for CR patients was not different for patients who did or did not receive chest radiation. However, patterns of tumor relapse were affected by the chest radiation, as 38 of 42 relapsing patients who did not receive radiation had intrathoracic recurrences in comparison to only 20 of 36 radiated patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Hypoprothrombinemia associated with interleukin-2 therapy: correction with vitamin K.

We noted that patients treated with high-dose interleukin (IL)-2 (600,000 IU/kg every 8 h by intravenous bolus) at our institution frequently developed prolongation of their prothrombin time (PT). We therefore performed a prospective study of coagulation function during IL-2 treatment. Since IL-2 treated individuals are known to develop cholestatic liver dysfunction, we hypothesized that the hypoprothrombinemia was due to deficiency of liver-synthesized clotting factors and could be prevented by vitamin K replacement. Alternating patients served as controls or received prophylactic subcutaneous subcutaneous vitamin K. While the nine control patients did not exhibit a significant increase (mean +/- SD) in PT (13.6 +/- 0.6 s pretreatment, 15.0 +/- 2.2 on day 4, and 15.0 +/- 2.5 on day 7, p = 0.77 by repeated measures analysis), three patients developed marked increases in PT (greater than 18 s). Changes in partial thromboplastin time (PTT) over this interval were also not statistically significant. Factor VII levels decreased in all patients from 106 +/- 22 to 59 +/- 16 and 52 +/- 26% on days 4 and 7 (p = 0.0002). Factor VII levels in four patients dropped below the lower limit of normal. Prophylactic treatment of seven patients with vitamin K on days 1-8 of the IL-2 therapy protocol resulted in diminished changes in PT and factor VII compared to control patients (p = 0.02 and 0.003 respectively). No vitamin K-treated patient developed PT or Factor VII levels significantly outside the normal range. Prophylactic vitamin K can prevent hypoprothrombinemia in patients treated with IL-2. This may be of importance in patients with decreased hepatic vitamin K stores, who may be at risk for bleeding complications.

Reduction of testosterone synthesis after high dose interleukin-2 therapy of metastatic cancer.

We have investigated the effect of high dose iv bolus interleukin-2 (IL-2) therapy on sex hormone and adrenal steroid concentrations in six men treated for metastatic renal cell carcinoma or malignant melanoma. Blood concentrations of testosterone, 17 beta-estradiol, LH, FSH, cortisol, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEA-S) were measured before and after a 5-day course of IL-2 therapy. Cortisol levels rose and DHEA-S decreased insignificantly. DHEA declined, reaching a nadir (P less than 0.001) on day 6, and testosterone decreased significantly on day 2 and reached a nadir on day 6 (P less than 0.0001). Concentrations of both steroids then gradually rose. Estradiol rose on day 4 (P less than 0.001) and then declined. Neither LH nor FSH was affected significantly, although there was a rise in the mean level of LH after IL-2 therapy. Our results suggest that high dose IL-2 therapy in men affects both adrenal and testicular androgen production without inhibiting pituitary trophic hormone secretion. These effects of IL-2 on plasma sex steroids may be the result of cytokines stimulated by IL-2 therapy, rather than direct responses to IL-2.

Acute dyslipoproteinemia induced by interleukin-2: lecithin:cholesteryl acyltransferase, lipoprotein lipase, and hepatic lipase deficiencies.

Recombinant human interleukin-2 (rIL-2) is used to treat refractory cancers. During such treatment, patients develop severe hypocholesterolemia along with striking alterations in the concentration and composition of the circulating lipoproteins. The present study was undertaken to gather information about the pathogenesis of these abnormalities. Patients were studied before-, during- and after a 5-day course of high dose i.v. rIL-2. Whole plasma cholesterol was markedly reduced by rIL-2 administration (52%; P < 0.001), whereas the triglyceride concentration did not change. Thus, the lipoproteins became triglyceride enriched (P = 0.004). Low density lipoprotein cholesterol, apolipoprotein B (apoB), high density lipoprotein cholesterol, and apoA-I concentrations all decreased. Esterified cholesterol levels were markedly reduced. Total plasma apoE increased markedly, and two kinds of abnormal particles appeared: 1) beta-migrating, very low density lipoproteins; and 2) discoidal, apoE- and phospholipid-containing particles with abnormal density and electrophoretic mobility. The activities of two lipoprotein triglyceride hydrolases, lipoprotein lipase and hepatic lipase, fell significantly during treatment and returned promptly to pretreatment levels after rIL-2 was discontinued. Lecithin:cholesteryl acyltransferase (LCAT) activity also decreased significantly (64%) during treatment, but in contrast to the lipases, remained low for at least 5 days after the last dose of rIL-2 (P < 0.001). High dose i.v. rIL-2 induces severe dyslipidemia with deficiencies of both postheparin lipases and acute LCAT deficiency. Most, if not all, of the lipoprotein changes observed are explained by the LCAT deficiency that follows IL-2-induced hepatocellular injury and cholestasis.

A 45-year follow-up of kindred 107 and the search for BRCA2.

Interest in the genetics of breast cancer has intensified with the discovery of a breast cancer susceptibility locus, BRCA1, on chromosome 17q. In this paper, we describe updated information on a large breast cancer kindred (K107) that has been extensively studied since 1948. Specifically, we have identified many new cases of cancer in the family and have shown that this family is unlinked to BRCA1 as well as a number of other genes considered as candidates for breast cancer. In a collaborative study between the University of Utah and the Institute of Cancer Research in the United Kingdom, we have collected a set of families with a predisposition to breast and ovarian cancers that have been reliably excluded from linkage to BRCA1 and evaluated their usage in a genomic search for other breast cancer loci. This effort led to the discovery of a second breast cancer locus located on chromosome 13q, BRCA2, which is responsible for the increased incidence of breast cancer in Kindred 107.

Cytologic identification of clinically occult proliferative breast disease in women with a family history of breast cancer.

A cytologic method for sampling the normal breast by fine-needle aspiration (FNA) was used to determine the frequency of clinically inapparent proliferative breast disease (PBD) in women with family histories of breast cancer. The authors attempted to obtain specimens from each quadrant of both breasts in 51 female first-degree relatives of breast cancer patients. The study group had no detectable masses by physical examination or mammography. Samples were prepared on membrane filters, Papanicolaou stained, and evaluated cytomorphologically. Three hundred seventy-eight of 408 (92.6%) possible quadrants were sampled; cellular material was obtained from 290 (76.7%) quadrants. PBD was identified in 20 of the 51 women (39.2%). When epithelium was obtained, nuclear area, perimeter, and diameter were measured with the use of computerized image analysis. Nuclei in samples containing atypical hyperplasia showed significant differences in these parameters when compared with cells from samples containing normal epithelium or benign hyperplasia. The authors' findings indicate that FNA sampling and computerized image analysis are useful in the detection and characterization of clinically inapparent PBD.

Control of water intake: evidence for the role of a hemodynamic pontine pathway.

Hypovolemia increases water intake. Bilateral lesions of a discrete region of the dorsal rostral pons, that contains neurons responding to hypovolemia, markedly increases basal water intake in cats. The critical region appears anteroventral and somewhat medial to the locus coeruleus and is anatomically distinct from a more dorsal region shown previously as essential for compensation of arterial pressure in response to hypovolemia.

Models for early chemoprevention trials in breast cancer.

Several models are being explored for use in the phase I and phase II evaluation of breast cancer chemoprevention agents. The short-term DCIS/small invasive cancer model is probably best used in late phase I trials in conjunction with agents likely to have activity in the progression phase of neoplastic development in addition to activity in earlier phases. The core biopsy or FNA hyperplasia models may be best used with drugs that are likely to have activity primarily in the promotion phase of neoplastic development and that are suitable for longer duration trials lasting several months to years. Morphology currently is the key surrogate endpoint biomarker for assessing efficacy in phase II trials. Other biomarkers that may undergo modulation will have to be validated, in that modulation will have to be shown to be directly related to decreased cancer risk in subsequent phase III trials. Only then can they be considered as validated surrogate endpoint biomarkers and used as stand-alone efficacy markers in phase II trials. Despite accrual challenges and technologic hurdles, interest in phase I and phase II chemoprevention trials is high.

Preparation of controlled release systems by free-radical UV polymerizations in the presence of a drug.

UV free-radical polymerization techniques are often used to synthesize hydrogels for controlled release applications. Numerous techniques exist for immobilizing drugs or solutes in the gel. This work focuses on the entrapment of solute in a hydrogel by conducting a photopolymerization in the presence of the monomer and the solute. A kinetic gelation model has been developed to examine the effect of the solute material on the polymerization process and the ensuing network structure. Kinetic experiments have also been conducted of the polymerization of poly(ethylene glycol) methacrylate in the presence of theophylline. It was found that the presence of the solute led to a more heterogeneous network with numerous microgel regions present. The effect of the size of the solute on the polymerization was also investigated.

NCCN Practice Guidelines for Breast Cancer.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. In many situations, the patient and physician have the responsibility to jointly explore and ultimately select the most appropriate option from among the available alternatives. With rare exception, the evaluation, treatment, and follow-up recommendations contained within these guidelines were based largely on the results of past and present clinical trials. However, there is not a single clinical situation in which the treatment of breast cancer has been optimized with respect to either maximizing cure or minimizing toxicity and disfigurement. Therefore, patient and physician participation in prospective clinical trials allows patients not only to receive state-of-the-art cancer treatment but also to contribute to the improvement of treatment of future patients.

Phase II study of diaziquone in untreated advanced gastric carcinoma. A Southwest Oncology Group Study.

Twenty-nine patients with a diagnosis of advanced adenocarcinoma of the stomach with gross unresectable or measurable residual disease and no prior therapy were entered into a study utilizing diaziquone (AZQ) in an intermittent 3-week schedule of 40 mg/m2. Of 28 eligible patients, 1 (4%) experienced a partial response, 7 (25%) had stable disease of no response, and 18 (64%) developed increasing disease. Two (7%) were unevaluable. Median survival was 3.8 months. Major toxicities were myelosuppression and gastrointestinal, 11 of which were considered to be life-threatening. AZQ used as a single intermittent agent appears to have no significant activity to warrant use in untreated advanced gastric carcinoma. However, recognizing the short plasma half-life of AZQ, significant responses by other schedules of administration are not precluded.

Phase II trial of amonafide in patients with advanced metastatic or recurrent endometrial adenocarcinoma. A Southwest Oncology Group study.

Amonafide, a benzisoquinoline-1,3-dione was administered to 38 patients with recurrent or metastatic, bidimensionally measurable endometrial cancer. There were 34 patients with no prior cytotoxic chemotherapy, performance status of 0-2, and normal bone marrow, renal, and hepatic function were eligible for response and toxicity evaluation. Amonafide, 300 mg/m2, was administered intravenously over 1 hour daily for 5 consecutive days. Courses were repeated every 21 days. The major grade 3 or 4 toxicities were hematologic with granulocytopenia in 18 patients (53%), thrombocytopenia in 6 patients (18%), and anemia in 8 patients (24%). Infectious complications occurred in 3 patients (9%). Other side effects included cardiac dysrhythmias, hypotension, pain and phlebitis at the site of injection, nausea, vomiting, and flu-like symptoms. The overall objective response rate was 6% (95% confidence interval of 1-20%); 2 patients had a complete response (6%), 9 patients had stable disease (26%) and 21 patients had progressive disease (62%). Two patients had insufficient follow-up for response determination and are assumed to be nonresponders. The median survival of the eligible patients was 8 months. With the toxicity observed and the low response rate, amonafide at this dose and schedule has no efficacy in the treatment of endometrial cancer.

Severe myocarditis following high-dose interleukin-2 administration.

We observed a patient who developed unusually severe myocardial dysfunction during therapy for renal cell carcinoma with high-dose interleukin-2 (IL-2). Although cardiac isoenzymes became markedly elevated shortly after the completion of 14 doses of IL-2 (100,000 U/kg of IL-2 every eight hours), serial electrocardiograms revealed only nonspecific changes. Echocardiography documented diffuse myocardial dysfunction, with akinesis of the anteroseptal region, suggestive of myocardial infarction. This anteroseptal hypokinesis persisted over a five-day period. The patient died unexpectedly and postmortem evaluation of the heart revealed a severe, diffuse lymphocytic, and eosinophilic myocarditis with myocyte necrosis, especially prominent in the anteroseptal region. This is the first histologically confirmed case of myocarditis reported, to our knowledge, in association with IL-2 therapy for cancer.