Quantitative assessment of thyroid-to-background ratio improves the interobserver reliability of technetium-99m sestamibi thyroid scintigraphy for investigation of amiodarone-induced thyrotoxicosis.

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) is caused by excessive hormone synthesis and release (AIT I), a destructive thyroiditis (AIT II), or a combination of both (AIT Ind). Although no gold-standard diagnostic test is available, technetium-99m sestamibi thyroid scintigraphy (99mTc-STS) has been previously reported to be an accurate tool for differentiating subtypes with important therapeutic implications. However, the information to guide reporting of 99mTc-STS is qualitative and highly subjective. This study aims to compare the interobserver reliability of 99mTc-STS before and after the use of quantitative thyroid-to-background ratios (TBRs) displayed on a time-activity curve for differentiation of AIT subtypes. METHODS: A retrospective audit of Nuclear Medicine Departments at Royal Melbourne Hospital (Parkville, Victoria, Australia) and Cabrini Hospital (Malvern, Victoria, Australia) identified 15 consecutive 99mTc-STS studies performed for AIT. Four nuclear medicine physicians reported the studies according to previously established criteria (series 1). Quantitative TBR and estimated 'normal' range TBR were subsequently provided before the studies were reordered and reported again (series 2). Interobserver reliability was calculated using Fleiss' κ statistic for each assessment. RESULTS: The overall percentage of agreement (PoA) and κ statistics for use of conventional 99mTc-STS for diagnosis of AIT improved from 47 to 80% and from 0.30 to 0.67 following the use of quantitative TBR displayed on a time-activity curve with reference to a normal population. Interobserver reliability improved substantially under all diagnostic comparisons, particularly for differentiation of either AIT I (PoA 80% to 94%, κ: 0.48 to 0.84) or AIT Ind (PoA 47% to 82%, κ: -0.05 to 0.51) from other types of AIT. CONCLUSION: Use of quantitative TBR improves the interobserver reliability of reporting 99mTc-STS for investigation of different types of AIT. There is 'almost perfect' agreement upon differentiation of AIT I from AIT II and AIT Ind, with important implications for rationalizing the use of corticosteroid therapy. Prospective identification of AIT Ind is improved from 'poor' to a 'moderate' level of agreement to facilitate rational use of combination therapy at diagnosis.

Acceptability of early integration of palliative care in patients with incurable lung cancer.

BACKGROUND: Lung cancer remains the leading cause of cancer death, and it is known many affected will have significant palliative care needs. Evidence suggests that early involvement of palliative care can translate into improvements in quality of care, quality of life, and survival. However, routine early integration is yet to be embraced as standard of care for the majority of patients, and it is unclear what lung cancer clinicians continue to perceive as the barriers to this model of care. METHODS: We performed a qualitative exploration of lung cancer clinicians' perceptions, focusing on current experiences of engaging with palliative care, perceptions of palliative care for patients with lung cancer, and views of barriers and benefits of referring to palliative care. RESULTS: Focus group and targeted interviews were conducted with 28 clinicians, with four key emergent themes: 1) Competence/skill--with referrers needing to be confident in the quality and capability of palliative care provision; 2) Care Coordination--the need to ensure integrated care, with defined lines of responsibility and clear team communication; 3) Ease of referral--the need for ready access to a palliative care provider in the lung cancer clinic; and 4) Perceptions--concerns about loss of hope and fears of negative patient reaction. CONCLUSIONS: Early and routine involvement of palliative care in patients with incurable lung cancer is acceptable to the majority of treating clinicians. To facilitate early integration of palliative care, palliative care providers need to become front-line team members who provide a high-quality service. Lung cancer clinicians need further education as to the role and benefits of early palliative care, and how best to introduce this.

Hypoxia-targeted radiotherapy dose painting for head and neck cancer using (18)F-FMISO PET: a biological modeling study.

BACKGROUND: This study investigates the use of (18)F-fluoromisonidazole (FMISO) PET-guided radiotherapy dose painting for potentially overcoming the radioresistant effects of hypoxia in head and neck squamous cell carcinoma (HNSCC). MATERIAL AND METHODS: The study cohort consisted of eight patients with HNSCC who were planned for definitive radiotherapy. Hypoxic subvolumes were automatically generated on pre-radiotherapy FMISO PET scans. Three radiotherapy plans were generated for each patient: a standard (STD) radiotherapy plan to a dose of 70 Gy, a uniform dose escalation (UDE) plan to the standard target volumes to a dose of 84 Gy, and a hypoxia dose-painted (HDP) plan with dose escalation only to the hypoxic subvolume to 84 Gy. Plans were compared based on tumor control probability (TCP), normal tissue complication probability (NTCP), and uncomplicated tumor control probability (UTCP). RESULTS: The mean TCP increased from 73% with STD plans to 95% with the use of UDE plans (p < 0.001) and to 93% with HDP plans (p < 0.001). The mean parotid NTCP increased from 26% to 44% with the use of UDE plans (p = 0.003), and the mean mandible NTCP increased from 2% to 27% with the use of UDE plans (p = 0.001). There were no statistically significant differences between any of the NTCPs between the STD plans and HDP plans. The mean UTCP increased from 48% with STD plans to 66% with HDP plans (p = 0.016) and dropped to 37% with UDE plans (p = 0.138). CONCLUSION: Hypoxia-targeted radiotherapy dose painting for head and neck cancer using FMISO PET is technically feasible, increases the TCP without increasing the NTCP, and increases the UTCP. This approach is superior to uniform dose escalation.

Positron emission tomography changes management, improves prognostic stratification and is superior to gallium scintigraphy in patients with low-grade lymphoma: results of a multicentre prospective study.

PURPOSE: Positron emission tomography (PET) was evaluated in low-grade non-Hodgkin lymphoma (NHL) to determine its impact on staging and management and to compare PET and gallium scans. METHODS: PET resulted in management plan changes in 74 patients with untreated low-grade NHL stages I to III. Patient outcomes to 12 months were documented. RESULTS: PET identified additional lesions in 50% of patients, led to a change in stage in 32%, and had a significant impact on management in 34%. Inferior progression-free survival was noted in patients with additional lesions detected by PET (p=0.001) and in the 28% of patients upstaged by PET to stage III or IV (p=0.024). In a subset of 16 patients undergoing both PET and gallium scans, PET was found to be superior. CONCLUSION: PET has a major role in the management of low-grade NHL in addition to its proven role in aggressive lymphoma.

Differentiation of tumor recurrence from radiation necrosis in high-grade gliomas using 201Tl-SPECT.

MRI is routinely performed to detect recurrence in patients with primary brain tumors, but it may not differentiate recurrent tumor from radiation-induced necrosis reliably. Thallium-201 single-photon emission computed tomography ((201)Tl-SPECT) might be useful in distinguishing between these two clinical entities. In a retrospective study (201)Tl-SPECT studies with corresponding MRI studies in 19 patients with clinical or radiological suspicion of high-grade tumor recurrence were reviewed. The diagnostic accuracies of both modalities were based on the subsequent histology or clinical course where biopsy was not performed. Post-scan histology was available in nine patients (43%) who underwent re-resection. The SPECT result determined management in six patients (29%). Post-SPECT survival was significantly better in patients with negative (201)Tl-SPECT studies compared to patients with positive studies (median survival 15+vs. 6 months) (p=0.04, log-rank test). The sensitivity and specificity of (201)Tl-SPECT in diagnosing tumor recurrence were 83% and 100%, respectively. (201)Tl-SPECT can accurately differentiate tumor recurrence from radiation necrosis in patients with high-grade gliomas and abnormal MRI findings post irradiation. This is reflected in a significantly longer post-scan survival time in patients with a negative (201)Tl-SPECT result.

PET changes management and improves prognostic stratification in patients with head and neck cancer: results of a multicenter prospective study.

UNLABELLED: The primary aim of this study was to determine the impact of PET in changing initial management plans in patients with untreated head and neck cancer. Secondary aims were to determine the incremental staging information provided by PET and to document the effect of PET on treatment outcomes. METHODS: Patients with untreated head and neck cancer underwent PET scans. Pre-PET management plans were documented by referring clinicians unaware of the PET results, and management plan changes due to PET scan findings were documented. Follow-up to 12 mo after treatment was performed to determine actual management and clinical outcomes. RESULTS: A total of 71 patients (median age, 56 y; 69% male) were studied. PET scans resulted in management change in 33.8% of patients. Moreover, PET was able to detect additional sites of disease in 39.4% of patients. Follow-up data showed that PET improved the classification of patients into curative and palliative categories. Trends toward inferior disease-free survival and lower complete response rates in patients with additional lesions detected on PET were demonstrated. In addition, a trend toward inferior disease-free survival in patients with a higher maximum standardized uptake value was shown. CONCLUSION: These data unequivocally demonstrate the significant impact of PET on management and outcomes in patients with untreated head and neck cancer.

PET changes management and improves prognostic stratification in patients with recurrent colorectal cancer: results of a multicenter prospective study.

UNLABELLED: The aims of our study were to examine the impact of PET in changing management in patients with proven or suspected colorectal cancer recurrence and to assess the impact of management change on disease-free survival. METHODS: Symptomatic patients with a residual structural lesion suggestive of recurrent tumor (group A) or patients with pulmonary or hepatic metastases considered to be potentially resectable (group B) underwent PET scans. Pre-PET management plans were documented by referring clinicians unaware of the PET results, and follow-up to 12 mo was performed to determine actual management and clinical outcomes. RESULTS: A total of 191 patients (118 men and 73 women; mean age, 66 y) were studied. PET detected additional sites of disease in 48.4% of patients in group A and in 43.9% of patients in group B. A change in planned management was documented in 65.6% of group A and in 49.0% of group B patients. These management plans were implemented in 96% of patients. Follow-up data in group A showed progressive disease in 60.5% of patients with additional lesions detected by PET, compared with conventional imaging, and in 36.2% of patients with no additional lesions detected by PET (P=0.04). In group B, progressive disease was identified in 65.9% of patients with additional lesions detected by PET and in 39.2% of patients with no additional lesions detected by PET (P=0.01). PET also provided valuable prognostic information on patients stratified into curative- or palliative-intent groups. CONCLUSION: These data demonstrate the significant impact of PET on management and outcomes in patients with suspected recurrent colorectal cancer.

Fixed defect on rest/stress Tc-99m sestamibi study underestimates myocardial ischemia: comparison with 24-hour thallium-201 study for short- and intermediate-term follow-up.

PURPOSE: We assessed whether a same day rest/stress gated Tc-99m sestamibi (MIBI) SPECT myocardial study underestimates reversible ischemia in patients with fixed perfusion defects compared with a 24-hour thallium-201 (Tl-201) study. The short- and intermediate-term outcome with or without Tl-201 reversibility was assessed. METHODS: Forty-nine consecutive patients with fixed MIBI defects received an additional Tl-201 study and were evaluated. Tl-201 was given to patients with a high clinical suspicion of underestimation of reversibility. Images were interpreted semiquantitatively by 3 nuclear medicine physicians using a 17-segment, 5-point model. A summed stress score (SSS) from stress MIBI images, a summed rest score (SRS) from Tl images, and a summed difference (SDS = SSS - SRS) score were calculated. SDS >3 indicated significant Tl-201 redistribution. Composite end points included acute myocardial infarction, unstable angina needing admission, cardiac death, or revascularization within 3 and 6 months. RESULTS: Fifteen of 49 patients showed no Tl-201 redistribution. Thirty-four of 49 (69%) patients had significant Tl-201 redistribution, and these patients had significantly higher cardiac events (CE) at 3 months (29% vs. 7%; P = 0.039), and higher at 6 months (32% vs. 7%; P = 0.027). These patients with CE had a larger amount of Tl-201 redistribution, mean SDS 8.6 vs. 5.3 (P = 0.047). Patients with significant Tl-201 redistribution had a lower left ventricular ejection fraction (mean 37%; P = 0.001). CONCLUSION: With short- and intermediate-term follow-up, our study shows a significant association towards fixed defects on the rest/stress MIBI study underestimating CE risk when compared with a delayed Tl-201 study, especially in patients with a large amount of Tl-201 redistribution. Hence, the addition of a Tl-201 study may be useful in the management of patients with large fixed MIBI defects, especially with a depressed left ventricular ejection fraction.

Optimizing the approach to patients with potentially resectable liver metastases from colorectal cancer.

Liver metastases are a common event in colorectal carcinoma. Significant advances have been made in managing these patients in the last decade, including improvements in staging and surgical techniques, an increasing armamentarium of chemotherapeutics and multiple local ablative techniques. While combination chemotherapy significantly improves median patient survival, surgical resection provides the only prospect of cure and is the focus of this review. Interpretation of published work in this field is challenging, particularly as there is no consensus to what is resectable disease. Of particular interest recently has been the use of neoadjuvant treatment for downstaging and downsizing disease in patients with initially unresectable liver metastases, in the hope of response leading to potentially curative surgery. This review summarizes the recent developments and consensus guidelines in the areas of staging, chemotherapy, local ablative techniques, radiation therapy and surgery, emphasizing the multidisciplinary approach to this disease and ongoing controversies in this field and examines the changing paradigms in the management of colorectal hepatic metastases.

Radiation dose to PET technologists and strategies to lower occupational exposure.

OBJECTIVE: The use of PET in Australia has grown rapidly. We conducted a prospective study of the radiation exposure of technologists working in PET and evaluated the occupational radiation dose after implementation of strategies to lower exposure. METHODS: Radiation doses measured by thermoluminescent dosimeters over a 2-y period were reviewed both for technologists working in PET and for technologists working in general nuclear medicine in a busy academic nuclear medicine department. The separate components of the procedures for dose administration and patient monitoring were assessed to identify the areas contributing the most to the dose received. The impact on dose of implementing portable 511-keV syringe shields (primary shields) and larger trolley-mounted shields (secondary shields) was also compared with initial results using no shield. RESULTS: We found that the radiation exposure of PET technologists was higher than that of technologists performing general nuclear medicine studies, with doses averaging 771 +/- 147 and 524 +/- 123 microSv per quarter, respectively (P = 0.01). The estimated dose per PET procedure was 4.1 microSv (11 nSv/MBq). Injection of 18F-FDG contributed the most to radiation exposure. The 511-keV syringe shield reduced the average dose per injection from 2.5 to 1.4 microSv (P < 0.001). For the longer period of dose transportation and injection, the additional use of the secondary shield resulted in a significantly lower dose of radiation than did use of the primary shield alone or no shield (1.9 vs. 3.6 microSv [P = 0.01] and 3.4 microSv [P = 0.03], respectively). CONCLUSION: The radiation doses currently received by technologists working in PET are within accepted occupational health guidelines, but improved shielding can further reduce the dose.

Results of strontium-89 therapy in patients with prostate cancer resistant to chemotherapy.

PURPOSE: Strontium-89 (Sr-89) chloride is an effective palliative treatment of the bone metastases of prostate cancer. Chemotherapy has also been shown to have a palliative benefit in this disease. We aimed to determine the benefits and complications of Sr-89 therapy in patients with prostate cancer who had become refractory to chemotherapy. We conducted a retrospective review of 14 treatments administered to 13 patients with chemotherapy-resistant and hormone-resistant prostate cancer. RESULTS: Of the 14 administered treatments, 8 (57%) resulted in improved pain control, with 2 patients able to stop analgesia. The median duration of response was 56 days. No prostate-specific antigen response was seen in the 8 patients tested. There was significant and prolonged bone marrow toxicity, with 6 patients requiring red blood cell transfusion. Prolonged thrombocytopenia was seen, with platelet counts remaining below baseline levels after treatment in all but one patient. Leukopenia was generally mild and not associated with infection. CONCLUSIONS: Sr-89 is an effective treatment of patients with chemotherapy-refractory prostate cancer, but careful and prolonged monitoring of hematologic parameters after therapy is required.

A phase I study of recombinant human leukemia inhibitory factor in patients with advanced cancer.

PURPOSE: Leukemia inhibitory factor (LIF) is a pleiotropic molecule of the interleukin 6 family of cytokines. We aimed to examine the safety, pharmacokinetics, and biological effects of recombinant human LIF (rhLIF, emfilermin) in patients with advanced cancer. EXPERIMENTAL DESIGN: In stage 1 of the study, 34 patients received rhLIF or placebo (3:1 ratio) at doses of 0.25-16.0 micro g/kg/day or 4.0 micro g/kg three times daily for 7 days. In stage 2, 40 patients received rhLIF or placebo, either once daily for 14 days commencing the day after chemotherapy (0.25-8.0 micro g/kg/day) or for 7 days commencing the day before chemotherapy (4.0 micro g/kg three times daily). The chemotherapy was cisplatin 75 mg/m(2) and paclitaxel 135 mg/m(2). RESULTS: In stage 1, platelet counts increased in most patients, including those who received placebo. Blood progenitor cells increased in response to rhLIF. In stage 2, platelet recovery to baseline levels was earlier for patients receiving higher doses of rhLIF (>/=4.0 micro g/kg/day; P = 0.02). The neutrophil nadir after chemotherapy was less severe in patients receiving >/=4.0 micro g/kg/day of rhLIF. In stages 1 and 2, increases in C reactive protein were seen at higher doses. Several patients developed evidence of autonomic dysfunction, in particular impotence and episodic hypotension. The dose-limiting toxicities were hypotension and rigors. Pharmacokinetic studies demonstrated a short half-life (1-5 h) independent of dose. CONCLUSIONS: We demonstrated a biological effect of rhLIF on blood progenitor cells, C reactive protein levels, and hemopoietic recovery after chemotherapy.

Mannan Mucin-1 Peptide Immunization: Influence of Cyclophosphamide and the Route of Injection.

SUMMARY: The mucin MUC1 is greatly increased in breast cancer and is a potential target for immunotherapy. In mice, MUC1 conjugated to oxidized mannan (MUC1-mannan fusion protein [M-FP]) targets the mannose receptor and induces a high frequency of cytotoxic T lymphocytes and anti-tumor responses. On this basis, three phase I trials were performed in patients with adenocarcinoma to evaluate the tnxicity and the immunologic responses to mannan MUC1. Forty-one patients with metastatic or locally advanced carcinoma of the breast (trial 1), colon (trial 2), and various adenocarcinomas (trial 3) received increasing doses of M-FP (1 to 300 &mgr;g). The immunizations were given at weekly intervals (weeks 1 to 3) and repeated in weeks 7 to 9. Cyclophosphamide (to increase cellular immunity) was given on weeks 1 and 4. M-FP was given intramuscularly in trial 1 and intraperitoneally in trial 2. No toxic effects occurred, and delayed-type hypersensitivity responses were present only as a microscopic lymphocytic infiltration. Overall, approximately 60% of the patients had high-titer MUC1 immunoglobulin G1 antibody responses, with the intraperitoneal route yielding approximately 10-fold higher responses. Cellular responses (proliferation, cytotoxic T cells, or CD8 T cells secreting tumor necrosis factor-alpha alphand interferon-gamma in response to MUC1 stimulation in vitro) were found in 28% of the patients, which was similar to that seen without cyclophosphamide. In most patients, disease progressed, but in five it remained stable. In addition, there were no objective responses. M-FP is not toxic and induces immune responses that were amplified by the intraperitoneal route of immunization. Cyclophosphamide was of no benefit.