Alberto Biggi

Early Interim 2-[18F]Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography Is Prognostically Superior to International Prognostic Score in Advanced-Stage Hodgkin's Lymphoma: A Report From a Joint Italian-Danish Study

PURPOSE Starting from November 2001, 260 newly diagnosed patients with Hodgkins lymphoma (HL) were consecutively enrolled in parallel Italian and Danish prospective trials to evaluate the prognostic role of an early interim 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scan and the International Prognostic Score (IPS) in advanced HL, treated with conventional ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) therapy. PATIENTS AND METHODS Most patients (n = 190) presented with advanced disease (stages IIB through IVB), whereas 70 presented in stage IIA with adverse prognostic factors. All but 11 patients were treated with standard ABVD therapy followed by consolidation radiotherapy in case of bulky presentation or residual tumor mass. Conventional radiologic staging was performed at baseline. FDG-PET scan was performed at baseline and after two courses of ABVD (PET-2). No treatment change was allowed on the basis of the PET-2 results. RESULTS After a median follow-up of 2.19 years (range, 0.32 to 5.18 years), 205 patients were in continued complete remission and two patients were in partial remission. Forty-three patients progressed during therapy or immediately after, whereas 10 patients relapsed. The 2-year progression-free survival for patients with positive PET-2 results was 12.8% and for patients with negative PET-2 results was 95.0% (P < .0001). In univariate analysis, the treatment outcome was significantly associated with PET-2 (P < .0001), stage IV (P < .0001), WBC more than 15,000 (P < .0001), lymphopenia (P < .001), IPS as a continuous variable (P < .0001), extranodal involvement (P < .0001), and bulky disease (P = .012). In multivariate analyses, only PET-2 turned out to be significant (P < .0001). CONCLUSION PET-2 overshadows the prognostic value of IPS and emerges as the single most important tool for planning of risk-adapted treatment in advanced HL.

Role of Imaging in the Staging and Response Assessment of Lymphoma: Consensus of the International Conference on Malignant Lymphomas Imaging Working Group

PURPOSE Recent advances in imaging, use of prognostic indices, and molecular profiling techniques have the potential to improve disease characterization and outcomes in lymphoma. International trials are under way to test image-based response–adapted treatment guided by early interim positron emission tomography (PET)–computed tomography (CT). Progress in imaging is influencing trial design and affecting clinical practice. In particular, a five-point scale to grade response using PET-CT, which can be adapted to suit requirements for early- and late-response assessment with good interobserver agreement, is becoming widely used both in practice- and response-adapted trials. A workshop held at the 11th International Conference on Malignant Lymphomas (ICML) in 2011 concluded that revision to current staging and response criteria was timely. METHODS An imaging working group composed of representatives from major international cooperative groups was asked to review the literature, share knowledge about research in progress, and identify key areas for research pertaining to imaging and lymphoma. RESULTS A working paper was circulated for comment and presented at the Fourth International Workshop on PET in Lymphoma in Menton, France, and the 12th ICML in Lugano, Switzerland, to update the International Harmonisation Project guidance regarding PET. Recommendations were made to optimize the use of PET-CT in staging and response assessment of lymphoma, including qualitative and quantitative methods. CONCLUSION This article comprises the consensus reached to update guidance on the use of PET-CT for staging and response assessment for [18F]fluorodeoxyglucose-avid lymphomas in clinical practice and late-phase trials.

International Validation Study for Interim PET in ABVD-Treated, Advanced-Stage Hodgkin Lymphoma: Interpretation Criteria and Concordance Rate Among Reviewers

At present, there are no standard criteria that have been validated for interim PET reporting in lymphoma. In 2009, an international workshop attended by hematologists and nuclear medicine experts in Deauville, France, proposed to develop simple and reproducible rules for interim PET reporting in lymphoma. Accordingly, an international validation study was undertaken with the primary aim of validating the prognostic role of interim PET using the Deauville 5-point score to evaluate images and with the secondary aim of measuring concordance rates among reviewers using the same 5-point score. This paper focuses on the criteria for interpretation of interim PET and on concordance rates. Methods: A cohort of advanced-stage Hodgkin lymphoma patients treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) were enrolled retrospectively from centers worldwide. Baseline and interim scans were reviewed by an international panel of 6 nuclear medicine experts using the 5-point score. Results: Complete scan datasets of acceptable diagnostic quality were available for 260 of 440 (59%) enrolled patients. Independent agreement among reviewers was reached on 252 of 260 patients (97%), for whom at least 4 reviewers agreed the findings were negative (score of 1–3) or positive (score of 4–5). After discussion, consensus was reached in all cases. There were 45 of 260 patients (17%) with positive interim PET findings and 215 of 260 patients (83%) with negative interim PET findings. Thirty-three interim PET–positive scans were true-positive, and 12 were false-positive. Two hundred three interim PET–negative scans were true-negative, and 12 were false-negative. Sensitivity, specificity, and accuracy were 0.73, 0.94, and 0.91, respectively. Negative predictive value and positive predictive value were 0.94 and 0.73, respectively. The 3-y failure-free survival was 83%, 28%, and 95% for the entire population and for interim PET–positive and –negative patients, respectively (P < 0.0001). The agreement between pairs of reviewers was good or very good, ranging from 0.69 to 0.84 as measured with the Cohen kappa. Overall agreement was good at 0.76 as measured with the Krippendorf α. Conclusion: The 5-point score proposed at Deauville for reviewing interim PET scans in advanced Hodgkin lymphoma is accurate and reproducible enough to be accepted as a standard reporting criterion in clinical practice and for clinical trials.

The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five-point scale

A retrospective, international, multicenter study was undertaken to assess: (i) the prognostic role of ‘interim’ positron emission tomography performed during treatment with doxorubicin, bleomycin, vinblastine and dacarbazine in patients with Hodgkin lymphoma; and (ii) the reproducibility of the Deauville five-point scale for the interpretation of interim positron emission tomography scan. Two hundred and sixty patients with newly diagnosed Hodgkin lymphoma were enrolled. Fifty-three patients with early unfavorable and 207 with advanced-stage disease were treated with doxorubicin, bleomycin, vinblastine and dacarbazine ± involved-field or consolidation radiotherapy. Positron emission tomography scan was performed at baseline and after two cycles of chemotherapy. Treatment was not changed according to the results of the interim scan. An international panel of six expert reviewers independently reported the scans using the Deauville five-point scale, blinded to treatment outcome. Forty-five scans were scored as positive (17.3%) and 215 (82.7%) as negative. After a median follow up of 37.0 (2–110) months, 252 patients are alive and eight have died. The 3-year progression-free survival rate was 83% for the whole study population, 28% for patients with interim positive scans and 95% for patients with interim negative scans (P<0.0001). The sensitivity, specificity, and negative and positive predictive values of interim positron emission tomography scans for predicting treatment outcome were 0.73, 0.94, 0.94 and 0.73, respectively. Binary concordance amongst reviewers was good (Cohen’s kappa 0.69–0.84). In conclusion, the prognostic role and validity of the Deauville five-point scale for interpretation of interim positron emission tomography scans have been confirmed by the present study.

Early chemotherapy intensification with BEACOPP in advanced-stage Hodgkin lymphoma patients with a interim-PET positive after two ABVD courses

Interim 2‐[18F]Fluoro‐2‐deoxy‐D‐glucose Positron Emission Tomography performed after two chemotherapy cycles (PET‐2) is the most reliable predictor of treatment outcome in ABVD‐treated Hodgkin Lymphoma (HL) patients. We retrospectively analysed the treatment outcome of a therapeutic strategy based on PET‐2 results: positive patients switched to BEACOPP, while negative patients continued with ABVD. Between January 2006 and December 2007, 219 newly diagnosed HL patients admitted to nine centres were enrolled; 54 patients, unfit to receive this treatment were excluded from the analysis. PET‐2 scans were reviewed by a central panel of nuclear medicine experts, according to the Deauville score ( Meignan, 2009 ). After a median follow up of 34 months (12–52) the 2‐year failure free survival (FFS) and overall survival for the entire cohort of 165 patients were 88% and 98%; the FFS was 65% for PET‐2 positive and 92% for PET‐2 negative patients. For 154 patients in which treatment was correctly given according to PET‐2 review, the 2‐year FFS was 91%: 62% for PET‐2 positive and 95% for PET‐2 negative patients. Conclusions: this strategy, with BEACOPP intensification only in PET‐2 positive patients, showed better results than ABVD‐treated historic controls, sparing BEACOPP toxicity to the majority of patients (Clinical Trials.gov Identifier NCT00877747).

Acute renal cortical scintigraphy in children with a first urinary tract infection

Abstract. This prospective study, performed in 101 children with a first symptomatic urinary tract infection (UTI), evaluates the diagnostic value of clinical, biological, and ultrasound parameters in detecting children with acute renal infection documented by dimercaptosuccinic acid (DMSA) scintigraphy. In children with a positive DMSA scan, mean C-reactive protein (CRP) was higher than in children with a normal DMSA scan (114±64 vs. 67±38 mg/dl, mean±SD, P=0.0002). The sensitivity and specificity of CRP was 64% and 68%, respectively. In children with severe kidney involvement, mean CRP and white blood count (WBC) were higher than in children with mild/moderate disease (151±83 vs. 92±55 mg/dl for CRP, P=0.0149; 20,100±6,854 vs. 15,023±6,145 WBC/ mm3 for WBC, P=0.0131). The sensitivity and specificity was 85% and 20% for CRP, and 77% and 18% for WBC, respectively. One or more areas of abnormal cortical echogenicity were documented in 3% of kidneys with positive DMSA scans. Dilatation of the collecting system was observed in 24% of kidneys. The sensitivity and specificity of ultrasonography was 27% and 89%, respectively. In conclusion, clinical, biological, and ultrasound parameters do not accurately distinguish cystitis from pyelonephritis in children with UTI and do not identify children with severe renal damage. Accordingly, we recommend that DMSA scan should be added to the initial work-up of children with UTI.

Cardiotoxicity after anthracycline chemotherapy in breast carcinoma: Effects on left ventricular ejection fraction, troponin I and brain natriuretic peptide

UNLABELLED Anthracyclines are among the most active drugs in breast cancer patients. We planned to evaluate the early and 2-year modification of left ventricular ejection fraction (LVEF) and the effects of chemotherapy on troponin I and neurohormonal assessment. METHODS Patients with early breast cancer surgically treated and eligible to adjuvant chemotherapy were enrolled. All patients underwent clinical assessment, radionuclide ventriculography, troponin I and brain natriuretic peptide (BNP) measurements at baseline and one-month (T1), one year (T2) and 2-year (T3) after chemotherapy. Reductions of LVEF ≥ 10% or an overt heart failure were considered cardiovascular events. RESULTS 53 patients, 52 females and 1 male, age 55.3 years were included and followed at T3. A significant reduction of LVEF was observed (from 62 ± 5.5% to 59.3 ± 8.6%, p=0.04) at T3; BNP increased (from 33.4 ± 41.5 pg/ml to 62.7 ± 94.7 pg/ml, p=0.005) at T1. Troponin I augmented at T1 (from 0.006 ± 0.01 ng/ml to 0.05 ± 0.04 ng/ml, p=0.0001) but normalized at T2 (0.005 ± 0.08 ng/ml; p=0.9). Only baseline BNP was nearly to be significantly correlated with T3 LVEF (p=0.07 HR 0.96-1) at multivariate analysis. In 13/53 patients (32.1%) LVEF showed ≥ 10% reduction at T3 (group A); in 40/53 patients (67.9%) LVEF was unchanged (group B). Patients in group A demonstrated higher baseline plasma BNP (p=0.02) and lower haemoglobin concentration (p=0.007) compared to patients in group B. CONCLUSIONS LVEF and BNP modified early after anthracycline chemotherapy and LVEF did not recover at T3. In patients who developed left ventricular systolic dysfunction, a subclinical activation of neurohormonal profile was observed.

Positron emission tomography in the staging of patients with Hodgkin's lymphoma. A prospective multicentric study by the Intergruppo Italiano Linfomi.

In this prospective multicentric study, we investigated the contribution of positron emission tomography (PET) scanning to the staging of Hodgkin’s lymphoma (HL) by computed tomography (CT) and attempted to determine whether it has any impact on therapeutic approach. One hundred eighty six consecutive patients with HL from six Italian centers were enrolled in this study. They were staged with conventional methods; 2-[fluorine-18]fluoro-2-deoxy-d-glucose PET scanning were prospectively compared to CT. CT and FDG-PET stages were concordant in 156 patients (84%) and discordant in 30 patients (16%). PET stage in comparison to CT stage was higher in 27 patients (14%) and lower in 3 patients (1%). The programmed treatment strategy was modified in 11 out of 30 patients (37%) after the definition of final stage. If we considered the 123 CT staged patients with localized stage, ten patients (8%) with a change of stage from localized to advanced after PET evaluation were treated with different strategy. FDG-PET was shown to be a relevant, non-invasive method that supplements conventional procedures and should therefore be used routinely to stage HL, particularly in early stage patients, where a change in stage may modify disease management.

In Vivo Treatment Sensitivity Testing With Positron Emission Tomography/Computed Tomography After One Cycle of Chemotherapy for Hodgkin Lymphoma

PURPOSE Negative [(18)F]fluorodeoxyglucose (FDG) -positron emission tomography (PET)/computed tomography (CT) after two cycles of chemotherapy indicates a favorable prognosis in Hodgkin lymphoma (HL). We hypothesized that the negative predictive value would be even higher in patients responding rapidly enough to be PET negative after one cycle. This prospective study aimed to assess the prognostic value of PET after one cycle of chemotherapy in HL and to assess the dynamics of FDG uptake after one cycle (PET1) and after two cycles (PET2). PATIENTS AND METHODS All PET scans were read by two blinded, independent reviewers in different countries, according to the Deauville five-point scale. The main end point was progression-free survival (PFS) after 2 years. RESULTS A total of 126 patients were included, and all had PET1; 89 patients had both PET1 and PET2. The prognostic value of PET1 was statistically significant with respect to both PFS and overall survival. Two-year PFS for PET1-negative and PET1-positive patients was 94.1% and 40.8%, respectively. Among those with both PET1 and PET2, 2-year PFS was 98.3% and 38.5% for PET1-negative and PET1-positive patients and 90.2% and 23.1% for PET2-negative and PET2-positive patients, respectively. No PET1-negative patient was PET2 positive. CONCLUSION PET after one cycle of chemotherapy is highly prognostic in HL. No other prognostic tool identifies a group of patients with HL with a more favorable outcome than those patients with a negative PET1. In the absence of precise pretherapeutic predictive markers, PET1 is the best method for response-adapted strategies designed to select patients for less intensive treatment.

Prognostic value of the acute DMSA scan in children with first urinary tract infection

Abstract. We attempted to verify in a group of 101 children with first urinary tract infection whether it was possible to identify groups of patients with different risks of developing renal scarring by taking into account both the extent of kidney involvement documented in the acute phase of infection using a dimercaptosuccinic acid (DMSA) scan, and the presence or absence of vesicoureteral reflux (VUR). The frequency of persistent lesions in kidneys with mild-moderate lesions (less than 50% of kidney involvement) in the presence of VUR or in non-refluxing kidneys was similar (P=0.1447), while the frequency of persistent lesions in kidneys with severe lesions in the presence of VUR was significantly higher than the frequency of persistent lesions in non-refluxing kidneys (P=0.0089). The extent of kidney involvement and the presence of VUR make possible the identification of different categories of risk of scarring: in the ”low risk group” (normal kidney with/without VUR) the risk of scarring is 0%; in the ”intermediate risk group” (mild lesions with/without VUR; extensive lesions without VUR) the risk of scarring is between 14% and 38%, while in the ”high risk group” (extensive lesions with VUR) the risk of scarring is 88%. Quantifying the risk of scarring could help in planning the treatment or in modifying the later strategy.