Judith M. Joyce

Phase II Trial of Short-Course CHOP-R Followed by 90Y-ibritumomab Tiuxetan and Extended Rituximab in Previously Untreated Follicular Lymphoma

Purpose: Radioimmunotherapy has been approved for relapsed follicular lymphoma (FL), including rituximab-refractory FL. This study was designed to determine the CR rate with short-course chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) followed by 90-Y ibritumomab tiuxetan (RIT) with extended rituximab as first-line treatment. Experimental Design: Between March 2004 and February 2007, 60 patients with stage II to IV symptomatic or bulky FL from a single institution supported by a large community network entered this phase II trial. Patients received CHOP-R for three treatment cycles before RIT followed by four additional weekly treatments with rituximab. Response was determined using fusion [18 F] fluorodeoxyglucose-positron emission tomography (PET)-computed tomography (CT) imaging. Results: Of the 60 patients entering this trial, 55 patients completed all protocol therapy. The median follow up was 19.7 months (range, 0.26-35.9 months). For intent-to-treat analysis, the complete response (CR) rate after CHOP-R, as assessed by CT and PET imaging, was 40% and 46%, respectively. After RIT, the CR rate improved, as assessed by CT and PET imaging, to 82% and 89%, respectively. Ten patients have progressed, including eight from best response of CR. Seven of 18 patients who were PET positive after CHOP-R progressed compared with 3 of 37 patients who were PET negative (P = 0.010). Conclusions: In patients with previously untreated, symptomatic or bulky FL, short-course chemoimmunotherapy and consolidation RIT and extended rituximab resulted in a high CR rate. Failure to achieve an early PET CR after CHOP-R indicated high risk of relapse.

Full-Dose 90Y Ibritumomab Tiuxetan Therapy Is Safe in Patients with Prior Myeloablative Chemotherapy

Purpose: Targeted radioimmunotherapy with yttrium-90 (90Y)–labeled ibritumomab tiuxetan (Zevalin, IDEC-Biogen, San Diego, CA) has shown significant activity in the treatment of relapsed or refractory CD20+ non–Hodgkins lymphoma. Eligibility criteria used in phase I trials, and adopted in phase II and III trials, excluded patients with prior myeloablative therapy. We treated eight patients with 90Y ibritumomab tiuxetan who had prior autologous stem cell transplant, but met all other treatment criteria. Experimental Design: Eight patients with CD20+ non–Hodgkins lymphoma had extensive prior therapy including myeloablative chemotherapy but did not receive total body irradiation. Each had bone marrow cellularity of >15%, platelet count of >100,000/mm3, and one had documented lymphomatous bone marrow involvement of <25%. The standard course of 0.3 to 0.4 mCi/kg of 90Y ibritumomab tiuxetan was administered to patients at full dose. 18-Flouro-deoxyglucose positron emission tomography/computed tomography scans were done at pretreatment and ∼12 weeks after treatment to assess patient response. Maximum toxicities were monitored and classified according to the Common Terminology Criteria for Adverse Events (ver. 3.0). Results: Toxicities observed included grade 4 thrombocytopenia in three of eight evaluable patients and grade 4 neutropenia in one of eight evaluable patients. One patient had a neutropenic fever; all patients were off blood product support 12 weeks post-zevalin. Complete response by 18-flouro-deoxyglucose positron emission tomography/computed tomography imaging occurred in one of seven evaluable patients and one patient treated as consolidation had no evidence of disease. Conclusion: Our experience suggests that 90Y ibritumomab tiuxetan treatment is safe for use in patients with prior myeloablative therapy when the general inclusion criteria are fulfilled. In this small series, the response rates, however, are limited. Nevertheless, 90Y ibritumomab tiuxetan treatment may provide clinical benefit in carefully selected extensively pretreated patients.

Molecular Characterization of Sporadic Pediatric Thyroid Carcinoma with the DNA/RNA ThyroSeq v2 Next-Generation Sequencing Assay

The aim of this study was to test the hypothesis that our 60-gene DNA/RNA ThyroSeq v2 next-generation sequence (NGS) assay would identify additional genetic markers, including gene fusions in sporadic pediatric differentiated thyroid carcinomas (DTC) that had no known molecular alterations. Sporadic pediatric DTCs with informative molecular testing (n = 18) were studied. We previously tested 15 cases by our standard 7-gene (BRAF, NRAS, HRAS, KRAS, RET/PTC1, RET/PTC3, PAX8/PPARg) mutation panel. Three cases were not tested previously. The standard 7-gene panel identified molecular alterations in 9 of 15 tumors (60%). Cases analyzed by ThyroSeq v2 NGS included the six previously negative cases by the standard 7-gene panel and three cases not previously tested. The NGS assay revealed new gene fusions in four of six previously negative cases (67%). These gene fusions included ETV6/NTRK3 (n = 3) and TPR/NTRK1 (n = 1). A point mutation (BRAF-V600E) was detected in one of three untested cases. While standard testing could identify only molecular alterations in 60% of cases, with the addition of the ThyroSeq v2 NGS, this increased to 87% (n = 13/15). Some cases with chromosomal rearrangements, including ETV6/NTRK3, appear to be associated with an aggressive histopathologic phenotype, but had no documented history of radiation exposure. Additional work is needed to investigate if pediatric DTCs could benefit from a reclassification based on molecular subtypes, which may better reflect their underlying biologic potential. Our data support the use of broad gene panels for the molecular diagnostics of pediatric thyroid nodules to aid future classification, treatment, and clinical management recommendations.

Surgeon volume and adequacy of thyroidectomy for differentiated thyroid cancer

INTRODUCTION We aimed to determine influence of surgeon volume on (1) frequency of appropriate initial surgery for differentiated thyroid cancer (DTC) and (2) completeness of resection. METHODS We reviewed all initial thyroidectomies (Tx; lobectomy and total) performed in a health system during 2011; surgeons were grouped by number of Tx cases per year. For patients with histologic DTC ≥ 1 cm, surgeon volume was correlated with initial extent of the operation, and markers of complete resection including uptake on I(123) prescan, thyrotropin-stimulated thyroglobulin levels, and I(131) dose administered. RESULTS Of 1,249 patients who underwent Tx by 42 surgeons, 29% had DTC ≥ 1 cm without distant metastasis. At a threshold of ≥ 30 Tx per year, surgeons were more likely to perform initial total Tx for DTC ≥ 1 cm (P = .01), and initial resection was more complete as measured by all 3 quantitative markers. For patients with advanced stage disease, a threshold of ≥ 50 Tx per year was needed before observing improvements in I(123) uptake (P = .004). CONCLUSION Surgeons who perform ≥ 30 Tx a year are more likely to undertake the appropriate initial operation and have more complete initial resection for DTC patients. Surgeon volume is an essential consideration in optimizing outcomes for DTC patients, and even higher thresholds (≥ 50 Tx/year) may be necessary for patients with advanced disease.

Anaphylaxis after administration of ibritumomab tiuxetan for follicular non-hodgkin lymphoma.

We report an anaphylactic reaction in a 45-year-old gentleman with an 8-year history of extensively treated, relapsing follicular lymphoma who was receiving a second treatment with ibritumomab tiuxetan. Within seconds of receiving Y-90 ibritumomab, he developed chest tightness, shallow respirations, hypotension, and incontinence. After successful resuscitation, a human antimouse antibody (HAMA) level was found to be elevated, 618 ng/mL (reference 0–188 ng/mL).

Rim of FDG uptake around a pulmonary infarct on PET/CT in a patient with unsuspected pulmonary embolism.

Evaluation of malignancies by positron emission tomography/ computed tomography has revolutionized the noninvasive approach to cancer diagnosis and management. However, demonstration of fluorodeoxyglucose (FDG) avidity is not synonymous with a malignant finding since a wide variety of nonmalignant conditions have been reported which demonstrate FDG uptake. We report an asymptomatic patient with an atypical pattern of moderate FDG uptake along the border of a pleural based opacity at the lung base on positron emission tomography/computed tomography, suggesting the presence of a pulmonary infarct. Awareness of this appearance is important, since this pattern may indicate underlying pulmonary embolism, a potentially life-threatening condition.

Acute cholecystitis detected on a Tc-99m sestamibi myocardial imaging.

The liver, biliary tree, and intestinal activity were seen on a Tc-99m MIBI study, but the gallbladder was not visualized. Similar findings were seen the next day on Tc-99m mebrofenin hepatobiliary imaging. Acute cholecystitis was found at surgery.

Thyroid: nuclear medicine update.

Nuclear medicine has been used in the evaluation and treatment of benign and malignant thyroid disease since the discovery of iodine 131 ((131)I) in the 1930s. Although traditional methods of imaging are routinely used, recent advancements such as SPECT/CT and PET/CT have greatly enhanced the ability of nuclear medicine to accurately detect and localize. Guidelines for the management of thyroid cancer continue to evolve, treatment regimens selected should balance the long-term risk of disease recurrence and cumulative risks of radiation exposure, and physicians should be aware of these updates and guidelines when caring for patients with thyroid disease.

Tc-99m nofetumomab merpentan complements an equivocal bone scan for detecting skeletal metastatic disease from lung cancer

A 56-year-old man with recently diagnosed mixed small-cell and non-small-cell lung carcinoma of the left lung apex was referred for bone scintigraphy to identify possible skeletal metastatic disease. Whole-body planar images showed subtle focal uptake along the lateral portion of the right fifth rib and in the superior L1 vertebra. These findings were suggestive of metastatic disease, but benign post-traumatic or degenerative change could not be excluded. A nofetumomab merpentan scan was performed to help determine whether these bone scan findings represented skeletal metastatic disease. After the injection of 12.9 mCi Tc-99m nofetumomab merpentan, delayed 15-hour whole-body planar images and SPECT images of the chest and abdomen were obtained. These images showed increased uptake in the apical portion of the left upper lobe and left hilum, which corresponded to the known tumor in the left apex with metastatic hilar adenopathy. In addition, increased activity was noted in the lateral right fifth rib and L1 vertebra body, corresponding to the subtle bone scan abnormalities. A lumbar spine CT performed approximately 1 month later revealed a lytic lesion at L1 that confirmed the detection of metastatic disease on the nofetumomab merpentan study.

Possible false-positive metastatic prostate cancer on an In-111 capromab pendetide scan as a result of a pelvic kidney.

A 61-year-old man who had a radical prostatectomy for adenocarcinoma of the prostate 8 months before now had a Gleason score of 9 and a prostate-specific antigen level that had increased to 0.6 since the surgery. An In-111 capromab pendetide scan was ordered to determine the presence and extent of disease. SPECT images of the pelvis showed asymmetric uptake in the left posterior pelvis suggestive of metastatic disease in the left internal iliac nodes. Correlation with the preoperative CT images revealed a low-lying pelvic kidney in this location, which explained this worrisome appearance.