Single-center analysis of biopsy-confirmed posttransplant lymphoproliferative disorder: incidence, clinicopathological characteristics and prognostic factors.

Hematopoietic stem cell and solid organ transplant recipients diagnosed with biopsy-confirmed posttransplant lymphoproliferative disorder (PTLD) at our institution from 1989 to 2010 were identified. Patient-, transplant- and disease-related characteristics, prognostic factors and outcome were collected and analyzed. One hundred and forty biopsy-proven cases of PTLD were included. Overall incidence in the transplant population was 2.12%, with heart transplant recipients carrying the highest risk. Most PTLDs were monomorphic (82%), with diffuse large B-cell lymphoma being the most frequent subtype. The majority of cases (70.7%) occurred > 1 year posttransplant, and 66% were Epstein-Barr virus positive. Following initial therapy the overall response rate was 68.5%. Three-year relapse-free and overall survivals were 59% and 49%, respectively. At last follow-up, 44% of the patients were alive. Multivariable analysis identified several classical lymphoma-specific poor prognostic factors for the different outcome measures. The value of the International Prognostic Index was confirmed in our analysis.

The accuracy of positron emission tomography in the detection of posttransplant lymphoproliferative disorder.

We investigated sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-fluorodeoxyglucose-positron emission tomography in 170 cases with suspected or biopsy-proven posttransplant lymphoproliferative disorder. All solid organ and hematopoietic stem cell transplant recipients who underwent an 18F-fluorodeoxyglucose-positron emission tomography scan between 2003 and 2010 in our center for the indication posttransplant lymphoproliferative disorder, were retrospectively reviewed and results were compared with tissue biopsy whenever possible. One hundred and seventy positron emission tomography scans in 150 patients were eligible for evaluation. In 45 cases, the patient had a biopsy-confirmed posttransplant lymphoproliferative disorder before positron emission tomography scanning and positron emission tomography was performed for staging purposes. In the remaining 125 cases, positron emission tomography was performed to differentiate between posttransplant lymphoproliferative disorder and other diseases. 18F-fluorodeoxyglucose-uptake was quantitatively expressed by calculation of maximum and mean standardized uptake value in the most intense lesion or, in the absence of attenuation corrected positron emission tomography scans, by comparing uptake in target lesion to liver and mediastinal uptake. We found an overall sensitivity of 89%, specificity of 89%, positive predictive value of 91% and negative predictive value of 87% for posttransplant lymphoproliferative disorder detection by 18F-fluorodeoxyglucose-positron emission tomography. In a subanalysis of the 125 scans performed for differentiating posttransplant lymphoproliferative disorder from other diseases, sensitivity, specificity, positive predictive value and negative predictive value were 90%, 89%, 85% and 93%, respectively. 18F-fluorodeoxyglucose-uptake in posttransplant lymphoproliferative disorder was generally high with a median mean and maximum standardized uptake value of 9.0 (range 2.0-18.6) and 17.4 (range 2.6-26.4). Posttransplant lymphoproliferative disorder often had an atypical presentation on positron emission tomography with high incidence of extranodal involvement. In conclusion, from these data, we can conclude that 18F-fluorodeoxyglucose-positron emission tomography is highly sensitive for detecting posttransplant lymphoproliferative disorder and has an excellent ability to differentiate posttransplant lymphoproliferative disorder from non-malignant diseases.

Molecular imaging of therapy response with (18)F-FLT and (18)F-FDG following cyclophosphamide and mTOR inhibition.

PURPOSE: Evaluation and comparison of 3'-[(18)F]-fluoro-3'-deoxy-L-thymidine (FLT) and 2-[(18)F]-fluoro-2-deoxyglucose (FDG)-PET to monitor early response following both cyclophosphamide and temsirolimus treatment in a mouse model of Burkitt lymphoma. METHODS: Daudi xenograft mice were treated with either cyclophosphamide or temsirolimus and imaged with FLT-PET and FDG-PET on appropriate days post therapy inititiation. Immunohistochemical (IHC) studies (H&E, TUNEL, CD20, PCNA and ki-67) and DNA flow cytometry studies were performed. RESULTS: FDG tumor uptake decreased immediately after cyclophosphamide treatment while FLT-PET showed only a late and less pronounced decrease. A fast induction of apoptosis was observed together with an early accumulation of cells in the S-phase of the cell cycle, suggesting DNA repair. Temsirolimus treatment reduced both FDG and FLT tumor uptake immediately after therapy and resulted in a fast induction of apoptosis and G(0)-G(1) phase accumulation. CONCLUSION: FLT response was less distinct than FDG response and may be controlled by DNA repair early after cyclophosphamide. Nevertheless, FLT-PET was able to reflect decreased proliferation following temsirolimus.

Breast cancer in pregnancy: recommendations of an international consensus meeting.

PURPOSE: To provide guidance for clinicians about the diagnosis, staging and treatment of breast cancer occurring during an otherwise uncomplicated pregnancy. METHODS: An international expert Panel convened to address a series of questions identified by a literature review and personal experience. Issues relating to the diagnosis and management of breast cancer after delivery were outside the scope. RESULTS: There is a paucity of large and/or randomized studies. Based on cohort studies, case series and case reports, the recommendations represent the best available evidence, albeit of a lower grade than is optimal. RECOMMENDATIONS: In most circumstances, serious consideration should be given to the option of treating breast cancer whilst continuing with the pregnancy. Each woman should ideally be referred to a centre with sufficient expertise, given a clear explanation of treatment options. Most diagnostic and staging examinations can be performed adequately and safely during pregnancy. Treatment should however be adapted to the clinical presentation and the trimester of the pregnancy: surgery can be performed during all trimesters of pregnancy; radiotherapy can be considered during the first and second trimester but should be postponed during the third trimester; and standard chemotherapies can be used during the second and third trimester. Since neonatal morbidity mainly appears to be related to prematurity, delivery should not be induced before 37 weeks, if at all possible. CONCLUSIONS: The treatment of breast cancer in pregnancy should be executed by experienced specialists in a multidisciplinary setting and should adhere as closely as possible to standard protocols.

Dose-response relationship in cyclophosphamide-treated B-cell lymphoma xenografts monitored with [18F]FDG PET.

PURPOSE: Although [(18)F]FDG PET can measure therapy response sooner and more accurately than morphological imaging techniques, there is still some debate as to whether [(18)F]FDG uptake really reflects changes in the viable cell fraction. In this study changes in [(18)F]FDG uptake were investigated in a lymphoma model at several time-points after treatment and with different doses of chemotherapy. Data were analysed in terms of several parameters. METHODS: SCID mice were subcutaneously inoculated with 5x10(6) Daudi cells in the right thigh. One group was not treated (control group). The other groups received cyclophosphamide 75 mg/kg (low-dose group), 125 mg/kg (medium-dose group) and 175 mg/kg (high-dose group) on day 0. Sequential [(18)F]FDG small-animal PET (microPET) scans were performed on days 0, 2, 6, 9, 13 and 16 after treatment. The mean and maximum standardized uptake value (SUV(mean) and SUV(max)), metabolic tumour volume (Vol(metab)) and total lesion glycolysis (TLG) were calculated. RESULTS: A significant decrease in [(18)F]FDG uptake was observed on day 2 in the medium-dose and high-dose groups and on day 6 in the low-dose group, all preceding morphological changes. SUV(mean) and SUV(max) formed a plateau from day 6 to day 9, corresponding to the known influx of inflammatory cells. No obvious plateau was observed with TLG which was found to be the most sensitive parameter clearly differentiating the low-dose group from the medium- and high-dose groups early after therapy. CONCLUSION: [(18)F]FDG uptake was able to reflect the dose-response relationship for cyclophosphamide. TLG was the best parameter for dose-related response assessment in this tumour model.

Gynaecologic cancer complicating pregnancy: an overview.

Cancer complicating pregnancy endangers two lives. Any approach should look at both maternal and foetal safety. Maternal prognosis will not improve by terminating the pregnancy. Imaging for staging purposes is possible, and sonar and magnetic resonance imaging are the preferred examinations. Abdominopelvic computed tomography exposes the foetus to the highest doses radiation and should be avoided. Provided a thorough maternal monitoring to ensure a stable uteroplacental blood flow and foetal oxygenation, surgical techniques that are used in non-pregnant patients are also safe for pregnant patients. Radiotherapy of the upper part of the body is possible during pregnancy, but during the third trimester the close distance may put the foetus at risk. Chemotherapy during the second or third trimester can be administered without increasing the incidence of congenital malformations. A systematic analysis, especially on the long-term outcome of the offspring after cancer treatment during pregnancy is still lacking. Here, we present a summary of issues related to the diagnosis and treatment of gynaecological malignancies during pregnancy. Firstly, we describe general diagnostic and cancer-treatment-related problems. In the second part, organ pathology including breast, cervical, ovarian, endometrial and vulvar cancer is discussed.

FDG positron emission tomography/computed tomography scan may identify mantle cell lymphoma patients with unusually favorable outcome.

OBJECTIVE: Patients diagnosed with mantle cell lymphoma (MCL) have generally poor prognosis, but a minority have a longer survival. There are no markers to identify this group and no generally established prognostic index for MCL. Our objective was to assess the prognostic value of the staging FDG PET/computed tomography (CT) scan. METHODS: We retrospectively analyzed initial scans performed at three institutions on biopsy-proven, cyclin D (+) MCL patients. The association of the SUVmax of the 'hottest focus' with overall survival (OS) and failure-free survival (FFS) was evaluated. Receiver operating characteristic analysis of SUVmax versus survival was used to establish a cut-off point of 4.83. In addition, PET findings were compared with contrast-enhanced CT performed within 3 weeks in patients from one institution. RESULTS: Both the OS and FFS for patients with SUVmax greater than 5 were significantly decreased (P<0.01 and <0.001, respectively) as compared with the patients with SUV < or = 5. The 5-year OS for group with SUVmax < or = 5 was 87.7% and for SUVmax greater than 5 it was 34%. For SUVmax < or = 5, the median FFS was 45.3 months as compared with 10.6 months for SUVmax greater than 5. PET changed the stage as compared with CT alone in 45% of patients. CONCLUSION: Staging FDG PET/CT is superior to CT and may be used in the future for identification of a subset of MCL patients with a better outcome than otherwise expected.

(18)F-FDG and (18)F-FLT uptake early after cyclophosphamide and mTOR inhibition in an experimental lymphoma model.

UNLABELLED: To be a reliable predictor of response, tracer uptake should reflect changes in the amount of active tumor cells. However, uptake of (18)F-FDG, the most commonly used PET tracer, is disturbed by the inflammatory cells that appear early after cytotoxic therapy. The first aim of this study was to investigate whether 3'-(18)F-fluoro-3'-deoxy-l-thymidine ((18)F-FLT), a marker of cellular proliferation, is a better tracer for response assessment early after cytotoxic therapy. A second objective of this study was to investigate whether (18)F-FDG and (18)F-FLT responses were comparable early after mammalian target of rapamycin (mTOR) inhibition, as an example of proliferation-targeting therapies. METHODS: Severe combined immunodeficient mice were subcutaneously inoculated with Granta-519 cells, a human cell line derived from a leukemic mantle cell lymphoma. Half the mice were treated with cyclophosphamide and the other half with mTOR inhibition. (18)F-FDG and (18)F-FLT uptake was evaluated by small-animal PET on day 0 (D0; before treatment), D+1, D+2, D+4, D+7, D+9, D+11, and D+14. At each time point, 2 mice of each treatment condition were sacrificed, and tumors were excised for histopathology. RESULTS: After cyclophosphamide, (18)F-FDG and (18)F-FLT uptake decreased, with a maximum reduction of -29% for (18)F-FDG and -25% for (18)F-FLT uptake at D+2, compared with baseline. Although (18)F-FDG uptake increased from D+4 on, with a maximum on D+7, (18)F-FLT uptake remained virtually stable. Histology showed an increase in apoptotic or necrotic tumor fraction, followed by an influx of inflammatory cells. In mTOR-inhibited mice, (18)F-FDG uptake dropped until D+2 after therapy (-43%) but increased at D+4 (-27%) to form a plateau on D+7 and D+9 (-14% and -16%, respectively). Concurrently, (18)F-FLT uptake decreased to -31% on D+2, followed by an increase with a peak value of +12% on D+7, after which (18)F-FLT uptake decreased again. Cyclin D1 expression dropped from D+1 until D+4 and returned to baseline at D+7. CONCLUSION: Because (18)F-FLT uptake is not significantly influenced by the temporary rise in inflammatory cells early after cyclophosphamide, it more accurately reflects tumor response. However, a formerly unknown temporary rise in (18)F-FLT uptake a few days after the administration of mTOR inhibition was defined, which makes it clear that drug-specific responses have to be considered when using PET for early treatment monitoring.

Performance of MAP reconstruction for hot lesion detection in whole-body PET/CT: an evaluation with human and numerical observers.

For positron emission tomography (PET) imaging, different reconstruction methods can be applied, including maximum likelihood (ML ) and maximum a posteriori (MAP) reconstruction. Postsmoothed ML images have approximately position and object independent spatial resolution, which is advantageous for (semi-) quantitative analysis. However, the complex object dependent smoothing obtained with MAP might yield improved noise characteristics, beneficial for lesion detection. In this contribution, MAP and postsmoothed ML are compared for hot spot detection by human observers and by the channelized Hotelling observer (CHO). The study design was based on the "multiple alternative forced choice" approach. For the MAP reconstruction, the relative difference prior was used. For postsmoothed ML, a Gaussian smoothing kernel was used. Both the human observers and the CHO performed slightly better on MAP images than on postsmoothed ML images. The average CHO performance was similar to the best human performance. The CHO was then applied to evaluate the performance of priors with reduced penalty for large differences. For these priors, a poorer detection performance was obtained.

PET scanning and prognosis in Hodgkin's lymphoma.

PURPOSE OF REVIEW: Risk-adapted treatment strategies are currently under investigation in the management of patients with lymphoma. This review presents the latest evidence for the use of early interim [(18)F]-fluorodeoxyglucose-positron emission tomography for risk-adapted treatment in Hodgkin's lymphoma. RECENT FINDINGS: In recent years, PET after two cycles of ABVD (adriamycin, bleomycin, vincristin, and dexamethasone) was shown to be the only independent prognostic factor for the prediction of relapse in Hodgkin's lymphoma and to have at least the same prognostic accuracy as end-of-treatment PET. A high prognostic value of PET was reported even earlier, before the second cycle of chemotherapy. The earlier PET becomes negative, the more chemosensitive the disease, which may offer opportunities toward the limitation of the therapy. However, more false-positive lesions occur at earlier time points, and preliminary results indicate that accuracy of PET results differs after BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and immunotherapy. SUMMARY: [(18)F]-Fluorodeoxyglucose-positron emission tomography after two cycles of ABVD is now recognized as the single most important factor in defining disease-specific outcome and is highly promising for investigation of response-adapted treatment strategies. It is now recognized that the optimal time point of PET for response evaluation is crucial and dependent on the administered treatment. Standardization of PET-response is essential and should be adapted to time-dependent and therapy-dependent changes.

Positron emission tomography in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a rare but aggressive non-Hodgkin lymphoma subtype with a poor prognosis; most patients relapse despite initial response to therapy. Response was traditionally evaluated by computed tomography (CT), but the introduction of [(18)F]Fluorine-Deoxyglucose Positron Emission Tomography (PET) changed response assessment in aggressive lymphoma. However, the value of PET-evaluation in MCL has not been studied yet. Therefore, PET- and CT-findings were investigated in 37 patients with MCL (239 scans) and categorised following standardised response criteria for CT-evaluation (IWC-criteria), PET-evaluation (EORTC-criteria) and combined PET/CT-evaluation (IWC + PET-criteria). FDG-PET showed a high sensitivity for the detection of deposits of MCL and a higher FDG-uptake was shown in patients with the more aggressive blastoid-variant of MCL versus common MCL. However, routine use of PET for end-of-treatment response assessment in MCL cannot be recommended because CT- and PET-based designation systems had equivalent prognostic value. PET-based end-of-treatment response assessment only provided additional information over CT-based response assessment in a subpopulation of patients with highly FDG-avid MCL. PET allowed early detection of preclinical relapse during post-therapy surveillance, but the therapeutic consequences of such information are currently unclear.

Is [(18)F]fluorodeoxyglucose positron emission tomography the ultimate tool for response and prognosis assessment?

[(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) is currently the most accurate and reliable tool for the assessment of response in Hodgkin's lymphoma (HL). FDG-PET is superior to conventional imaging techniques for detection of residual disease at the end of treatment, especially in the presence of a residual mass, a frequent finding in HL. FDG-PET response assessment has also a high predictive value early after the initiation of therapy. However, whether risk-adapted treatment strategies based on FDG-PET may also improve patient outcome remains to be proved.

Aggressive and indolent non-Hodgkin's lymphoma: response assessment by integrated international workshop criteria.

Until recently, response assessment in patients with lymphoma was primarily performed by computed tomography (CT). Based on CT, International Workshop Criteria (IWC) were developed and widely used. Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is a more sensitive and specific imaging technique for the detection of residual disease in lymphoma, and Revised Integrated International Workshop Criteria (IWC + PET) were recently proposed by the members of the International Harmonization Project (IHP), which combine both imaging techniques. We determined whether these new IWC + PET-criteria, can more accurately predict outcome compared to IWC-criteria in aggressive and indolent non-Hodgkin's lymphoma (NHL), and therefore correlated IWC and IWC + PET response with time-to-next-treatment (TNT) in 69 patients with NHL. We demonstrated that IWC + PET-guidelines are highly recommended over IWC-guidelines for patients with potentially-curable and routinely FDG-avid lymphoma. In contrast, no additional value of IWC + PET was demonstrated in a small group of patients with incurable histological subtypes.

Hodgkin lymphoma: Response assessment by revised International Workshop Criteria.

Until recently, response assessment in patients with Hodgkin's lymphoma (HL) was primarily performed by computed tomography (CT). Based on CT, International Workshop Criteria (IWC) were developed and widely used. Fluorodeoxyglucose positron emission tomography (FDG-PET) has a higher sensitivity and specificity compared with that of CT, and Revised International Workshop Criteria (IWC + PET) were recently proposed, which combine both imaging techniques. We determined whether these integrated IWC + PET-criteria can more accurately predict outcome compared with IWC-criteria in 56 patients with HL. Of the original 56 patients, nine patients relapsed and 47 are still in remission after a median follow-up of 9 years. Based on IWC-criteria, 15 patients had a complete remission (CR) after chemotherapy, 20 had complete remission unconfirmed (CRu), 19 had partial remission (PR) and two had stable disease (SD). In comparison, by IWC + PET, 47 had CR, seven had PR and two had SD. For IWC, outcome was not significantly different in patients with CR/CRu compared to PR (P = 0.61), while for IWC + PET criteria, time-to-next-treatment was significantly shorter in patients with PR compared to CR (P = 0.01). Therefore, IWC + PET-guidelines provide a more accurate response classification compared with that of IWC-guidelines, and are the preferred method for response assessment in patients with Hodgkin's lymphoma.

Effect of corticosteroids on 18F-FDG uptake in tumor lesions after chemotherapy.

UNLABELLED: To be a reliable predictor of response, (18)F-FDG uptake should reflect changes in the amount of viable tumor cells. However, (18)F-FDG also accumulates in inflammatory cells. Shortly after treatment, the influx of inflammatory cells in the tumor can therefore interfere with early response evaluation. The aim of this study was to investigate whether this inflammation is suppressed by the administration of corticosteroids and, in turn, can improve the correlation of (18)F-FDG uptake with tumor cell kill. METHODS: Severe combined immunodeficiency mice were inoculated subcutaneously with Daudi cells. When the tumor measured 15 mm, mice were divided in 2 groups treated with 1 single dose of cyclophosphamide, 125 mg/kg (group A) or cyclophosphamide followed by hydrocortisone (0.2 mg/d) for 5 d (group B). The change in (18)F-FDG uptake was evaluated with small-animal PET (5 mice/group) on D+6, D+9, D+13, and D+16 (days after treatment). At each time point, 4 mice per group were sacrificed for quantification of the different tumor cell fractions by flow cytometry and histopathology. Changes in (18)F-FDG uptake were correlated with inflammation and viable tumor cells. RESULTS: Cyclophosphamide administration resulted in a steady reduction in viable cell fraction until D+9 (reduction from baseline, -64%). The viable cell fraction increased again on D+13. A transient influx of inflammatory cells was seen from D+6 to D+13 (peak on D+9, 24% of total cell fraction). After hydrocortisone administration, a similar reduction in the viable cell fraction was seen. The inflammatory response was less pronounced but developed with earlier kinetics (peak on D+6 [15% of total cell fraction], almost resolved on D+9) and consisted primarily of granulocytes instead of mononuclear cells in the absence of corticosteroids. In both groups, a significant reduction in (18)F-FDG uptake was seen until D+6. On D+9, a transient increase in (18)F-FDG uptake was seen in group A, whereas a further decrease was observed in group B. CONCLUSION: After corticosteroid administration, the contribution of inflammatory cells to the (18)F-FDG uptake was less important than that in mice treated with chemotherapy alone. The earlier, but weaker, inflammatory response after corticosteroid administration consists primarily of granulocytes instead of mononuclear cells.

PET and PET/CT for response evaluation in lymphoma: current practice and developments.

Positron emission tomography (PET) using the radiolabelled glucose analog 2-[18F]fluoro-2-deoxy-d-glucose (FDG) is increasingly used for response assessment in patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). These patients often present with a residual mass after therapy, but only a minority will relapse as most of these masses consist of inactive fibrosis. However, some patients have residual disease after first-line treatment and they can benefit from additional or early salvage therapy. Special interest for early, but accurate, assessment of response is growing accordingly. Conventional radiological techniques cannot differentiate between active tumoural tissue and fibrosis in these masses. In contrast, FDG-PET has the ability to differentiate between viable tumour and fibrosis and has been evaluated as an initial staging tool, for response assessment after completion of therapy and as a prognostic marker early during treatment. In this review, we will focus especially on the value of PET for response assessment.