Liquid biopsy for molecular characterization of diffuse large B-cell lymphoma and early assessment of minimal residual disease.

Circulating tumour DNA (ctDNA) allows genotyping and minimal residual disease (MRD) detection in lymphomas. Using a next-generation sequencing (NGS) approach (EuroClonality-NDC), we evaluated the clinical and prognostic value of ctDNA in a series of R-CHOP-treated diffuse large B-cell lymphoma (DLBCL) patients at baseline (n = 68) and after two cycles (n = 59), monitored by metabolic imaging (positron emission tomography combined with computed tomography [PET/CT]). A molecular marker was identified in 61/68 (90%) ctDNA samples at diagnosis. Pretreatment high ctDNA levels significantly correlated with elevated lactate dehydrogenase, advanced stage, high-risk International Prognostic Index and a trend to shorter 2-year progression-free survival (PFS). Valuable NGS data after two cycles of treatment were obtained in 44 cases, and 38 achieved major molecular response (MMR; 2.5-log drop in ctDNA). PFS curves displayed statistically significant differences among those achieving MMR versus those not achieving MMR (2-year PFS of 76% vs. 0%, p < 0.001). Similarly, more than 66% reduction in ΔSUVmax by PET/CT identified two subgroups with different prognosis (2-year PFS of 83% vs. 38%; p < 0.001). Combining both approaches MMR and ΔSUVmax reduction, a better stratification was observed (2-year PFS of 84% vs. 17% vs. 0%, p < 0.001). EuroClonality-NDC panel allows the detection of a molecular marker in the ctDNA in 90% of DLBCL. ctDNA reduction at two cycles and its combination with interim PET results improve patient prognosis stratification.

[18F]DCFPyL PET/CT versus [18F]fluoromethylcholine PET/CT in Biochemical Recurrence of Prostate Cancer (PYTHON): a prospective, open label, cross-over, comparative study.

PURPOSE: Primary objective was to compare the per-patient detection rates (DR) of [18F]DCFPyL versus [18F]fluoromethylcholine positron emission tomography/computed tomography (PET/CT), in patients with first prostate cancer (PCa) biochemical recurrence (BCR). Secondary endpoints included safety and impact on patient management (PM). METHODS: This was a prospective, open label, cross-over, comparative study with randomized treatment administration of [18F]DCFPyL (investigational medicinal product) or [18F]fluoromethylcholine (comparator). Men with rising prostate-specific antigen (PSA) after initial curative therapy were enrolled. [18F]DCFPyL and [18F]fluoromethylcholine PET/CTs were performed within a maximum time interval of 12 days. DR was defined as the percentage of positive PET/CT scans identified by 3 central imaging readers. PM was assessed by comparing the proposed pre-PET/CT treatment with the local treatment", defined after considering both PET/CTs. RESULTS: A total of 205 patients with first BCR after radical prostatectomy (73%; median PSA = 0.46 ng/ml [CI 0.16;27.0]) or radiation therapy (27%; median PSA = 4.23 ng/ml [CI 1.4;98.6]) underwent [18F]DCFPyL- and/or [18F]fluoromethylcholine -PET/CTs, between July and December 2020, at 22 European sites. 201 patients completed the study. The per-patient DR was significantly higher for [18F]DCFPyL- compared to [18F]fluoromethylcholine -PET/CTs (58% (117/201 patients) vs. 40% (81/201 patients), p < 0.0001). DR increased with higher PSA values for both tracers (PSA ≤ 0.5 ng/ml: 26/74 (35%) vs. 22/74 (30%); PSA 0.5 to ≤ 1.0 ng/ml: 17/31 (55%) vs. 10/31 (32%); PSA 1.01 to < 2.0 ng/ml: 13/19 (68%) vs. 6/19 (32%);PSA > 2.0: 50/57 (88%) vs. 39/57 (68%) for [18F]DCFPyL- and [18F]fluoromethylcholine -PET/CT, respectively). [18F]DCFPyL PET/CT had an impact on PM in 44% (90/204) of patients versus 29% (58/202) for [18F]fluoromethylcholine. Overall, no drug-related nor serious adverse events were observed. CONCLUSIONS: The primary endpoint of this study was achieved, confirming a significantly higher detection rate for [18F]DCFPyL compared to [18F]fluoromethylcholine, in men with first BCR of PCa, across a wide PSA range. [18F]DCFPyL was safe and well tolerated.

Accuracy and prognostic impact of FDG PET/CT and biopsy in bone marrow assessment of follicular lymphoma at diagnosis: A Nation-Wide cohort study.

BACKGOUND: In the workup of follicular lymphoma (FL), bone marrow biopsy (BMB) assessment is a key component of FLIPI and FLIPI2, the most widely used outcome scores. During the previous decade, several studies explored the role of FDG-PET/CT for detecting nodal and extranodal disease, with only one large study comparing both techniques. METHODS: The aim of our study was to evaluate the diagnostic accuracy and the prognostic impact of both procedures in a retrospective cohort of 299 FL patients with both tests performed at diagnosis. In order to avoid a collinearity bias, FLIPI2 was deconstructed in its founding parameters, and the bone marrow involvement (BMI) parameter separately included as: a positive BMB, a positive PET/CT, the combined "PET/CT and BMB positive" or "PET/CT or BMB positive". These variables were also confronted independently with the POD24 in 233 patients treated with intensive regimens. RESULTS: In the total cohort, bone marrow was involved in 124 and 60 patients by BMB and PET/CT, respectively. In terms of overall survival, age > 60 y.o. and the combined "PET/CT or BMB positive" achieved statistical independence as a prognostic factor. In patients treated with an intensive regimen, only the combined "PET/CT or BMB positive" added prognostic value for a shorter overall survival, when confronted with the POD24. CONCLUSION: Our results show that in FL both BMB and PET/CT should be considered at diagnosis, as their combined assessment provides independent prognostic value in the context of the most widely use clinical scores.

18F-FDG PET/CT in ovarian cancer recurrence: Clinical impact, correlation with ceCT and CA-125, and prognostic value.

AIM: To evaluate 18F-FDG-PET/CT for suspected ovarian cancer relapse with negative/inconclusive conventional imaging, or restaging potentially resectable ovarian cancer relapse. MATERIAL AND METHODS: Thirty-six cases and 140 locations were studied. PET/CT, ceCT and serum CA-125 was conducted in all cases. Nineteen cases were requested for restaging, 17 for suspected relapse. We compared ceCT and PET/CT, assessed by histopathology or radiological follow-up, calculating sensitivity (S) and positive predictive value (PPV) by cases and lesions. We evaluated the correlation between size, number, uptake of the lesions and CA-125. We conducted survival analysis, using ROC curves to calculate the optimal cut-off of SUVmax for survival prediction. We checked whether PET/CT modify the therapeutic attitude vs. conventional imaging. RESULTS: PET/CT and ceCT were concordant in 12 cases: 11 positives (30 lesions), all confirmed. There was 1 FN. In the 24 non-concordant, PET/CT was positive in 19 (97 lesions); ceCT in 21 (59 lesions); 54% of the lesions were concordant. Overall, PET/CT detected 127 lesions, with S=97% and PPV=100%. ceCT detected 89 lesions, with S=61% and PPV=90%. No significant correlation was found between CA-125 and the other parameters. PET/CT detected 10 positive cases, with normal CA-125. PET/CT modified therapeutic management in 15 cases. Significant differences were found in survival with SUVmax=11.8 CONCLUSIONS: PET/CT plays an important role in ovarian cancer relapse, with sensitivity and PPV higher than ceCT, modified therapeutic management in up to 42% of cases, and could be a valuable tool for predicting survival.

Liquid biopsy: a non-invasive approach for Hodgkin lymphoma genotyping.

The Hodgkin lymphoma (HL) genomic landscape is hardly known due to the scarcity of tumour cells in the tissue. Liquid biopsy employing circulating tumour DNA (ctDNA) can emerge as an alternative tool for non-invasive genotyping. By using a custom next generation sequencing (NGS) panel in combination with unique molecule identifiers, we aimed to identify somatic variants in the ctDNA of 60 HL at diagnosis. A total of 277 variants were detected in 36 of the 49 samples (73·5%) with a good quality ctDNA sample. The median number of variants detected per patient was five (range 1-23) with a median variant allele frequency of 4·2% (0·84-28%). Genotyping revealed somatic variants in the following genes: SOCS1 (28%), IGLL5 (26%), TNFAIP3 (23%), GNA13 (23%), STAT6 (21%) and B2M (19%). Moreover, several poor prognosis features (high LDH, low serum albumin, B-symptoms, IPI ≥ 3 or at an advanced stage) were related to significantly higher amounts of ctDNA. Variant detection in ctDNA by NGS is a feasible approach to depict the genetic features of HL patients at diagnosis. Our data favour the implementation of liquid biopsy genotyping for the routine evaluation of HL patients.

Biological Features and Prognostic Impact of Bone Marrow Infiltration in Patients with Diffuse Large B-Cell Lymphoma.

The biology and clinical impact of bone marrow (BM) infiltration in patients with diffuse large B-cell lymphoma (DLBCL) remains unclear in the rituximab era. We retrospectively analyzed 232 patients diagnosed with DLBCL at our center between 1999 and 2014. Concordant-presence of large cells similar to those of the lymph node biopsy- and discordant-infiltration by small cells forming lymphoid aggregates, lacking cytological atypia-BM infiltration was defined by histological criteria and further characterized by flow cytometry (FCM). Cell of origin (COO) was determined using Hans' algorithm. For the clonal relationship between tumor and discordant BM, the VDJH rearrangement was analyzed. Survival analyses were restricted to 189 patients treated with rituximab and chemotherapy. Thirty-six (16%) had concordant, and 37 (16%) discordant BM infiltration. FCM described different indolent lymphomas among discordant cases, clonally related with DLBCL in 10/13 available samples. Median follow-up was 58 months. 5-year-progression-free survival (PFS) for non-infiltrated, discordant and concordant groups was 68%, 65% and 30%, respectively (p < 0.001). Combining COO and BM infiltration, patients with discordant BM and non-germinal center B-cell COO also had decreased 5-year-PFS (41.9%). In multivariate analysis, concordant BM had an independent effect on PFS (HR 2.5, p = 0.01). Five-year cumulative incidence of central nervous system (CNS) relapse was 21%, 4% and 1% in concordant, discordant and non-infiltrated groups, respectively (p < 0.001). In conclusion, concordant BM infiltration represents a subset with poor prognosis, whereas the prognostic impact of discordant BM infiltration could be limited to non-CGB cases.

Immunoglobulin gene rearrangement IGHV3-48 is a predictive marker of histological transformation into aggressive lymphoma in follicular lymphomas.

Follicular lymphoma (FL) is a heterogeneous disease whose pathogenesis remains partially unknown. Around 20% of FL patients experience early progression or treatment-refractory disease and 2-3% of patients per year experience histological transformation (HT) into a more aggressive lymphoma (tFL). Here, we evaluate the immunoglobulin heavy chain variable (IGHV) gene usage and mutational status in 187 FL cases to assess its impact on clinical outcome and histological transformation. The IGHV gene repertoire was remarkably biased in FL. The IGHV4-34 (14%), IGHV3-23 (14%), IGHV3-48 (10%), IGHV3-30 (9%) and IGHV3-21 (7%) genes accounted for more than half of the whole cohort. IGHV3-48 was overrepresented in cases of tFL (19%) compared with non-transformed FL at 5 years (5%, P = 0.05). Patients with the IGHV3-48 gene were significantly more likely to have had HT after 10 years than those who used other genes (71% vs. 25%, P < 0.05), irrespective of the therapy they received. Moreover, IGHV3-30 was also overrepresented in cases of FL (9%) and tFL (13%) compared with diffuse large B-cell lymphoma in which it was nearly absent. In conclusion, our results indicate a role for antigen selection in the development of FL, while the use of IGHV3-48 could help predict histological transformation.

18F-FDG PET/CT of Lung Adenocarcinoma With Ovarian Metastases.

Patient was a 52-year-old woman with medical history of lung adenocarcinoma operated in 2009 (stage I, T2 N0 M0), showing increasing levels of tumor markers and a doubtful retrocrural adenopathy by means of CT scan with intravenous contrast. An F-FDG PET/CT was performed, which showed 2 hypermetabolic foci in both annexes. The anatomopathological study detected bilateral ovarian adenocarcinoma compatible with metastases of pulmonary origin.

Bone marrow biopsy superiority over PET/CT in predicting progression-free survival in a homogeneously-treated cohort of diffuse large B-cell lymphoma.

Several studies have reported uneven results when evaluating the prognostic value of bone marrow biopsy (BMB) and PET/CT as part of the staging of diffuse large B-cell lymphoma (DLBCL). The heterogeneity of the inclusion criteria and not taking into account selection and collinearity biases in the analysis models might explain part of these discrepancies. To address this issue we have carried a retrospective multicenter study including 268 DLBCL patients with a BMB and a PET/CT available at diagnosis where we estimated both the prognosis impact and the diagnostic accuracy of each technique. Only patients treated with R-CHOP/21 as first line (n = 203) were included in the survival analysis. With a median follow-up of 25 months the estimated 3-year progression-free survival (PFS) and overall survival (OS) were 76.3% and 82.7% respectively. In a multivariate analysis designed to avoid a collinearity bias with IPI categories, BMB-BMI [bone marrow involvement](+) (HR: 3.6) and ECOG PS > 1 (HR: 2.9) were independently associated with a shorter PFS and three factors, age >60 years old (HR: 2.4), ECOG PS >1 (HR: 2.4), and abnormally elevated B2-microglobulin levels (HR: 2.2) were independently associated with a shorter OS. In our DLBCL cohort, treated with a uniform first-line chemotherapy regimen, BMI by BMB complemented performance status in predicting those patients with a higher risk for relapse or progression. In this cohort BMI by PET/CT could not independently predict a shorter PFS and/or OS.

Estimation of the total effective dose from low-dose CT scans and radiopharmaceutical administrations delivered to patients undergoing SPECT/CT explorations.

UNLABELLED: Hybrid imaging, such as SPECT/CT, is used in routine clinical practice, allowing coregistered images of the functional and structural information provided by the two imaging modalities. However, this multimodality imaging may mean that patients are exposed to a higher radiation dose than those receiving SPECT alone. OBJECTIVES: The study aimed to determine the radiation exposure of patients who had undergone SPECT/CT examinations and to relate this to the Background Equivalent Radiation Time (BERT). METHODS: 145 SPECT/CT studies were used to estimate the total effective dose to patients due to both radiopharmaceutical administrations and low-dose CT scans. The CT contribution was estimated by the Dose-Length Product method. Specific conversion coefficients were calculated for SPECT explorations. RESULTS: The radiation dose from low-dose CTs ranged between 0.6 mSv for head and neck CT and 2.6 mSv for whole body CT scan, representing a maximum of 1 year of background radiation exposure. These values represent a decrease of 80-85% with respect to the radiation dose from diagnostic CT. The radiation exposure from radiopharmaceutical administration varied from 2.1 mSv for stress myocardial perfusion SPECT to 26 mSv for gallium SPECT in patients with lymphoma. The BERT ranged from 1 to 11 years. CONCLUSIONS: The contribution of low-dose CT scans to the total radiation dose to patients undergoing SPECT/CT examinations is relatively low compared with the effective dose from radiopharmaceutical administration. When a CT scan is only acquired for anatomical localization and attenuation correction, low-dose CT scan is justified on the basis of its lower dose.

Limbic hyperactivity associated to verbal memory deficit in schizophrenia.

In schizophrenia there seems to be an inefficient activation of prefrontal and hippocampal regions. Patients tend to show worse cognitive performance in functions subserved by those regions as compared to healthy controls in spite of higher regional activation. However, the association between activation abnormalities and cognitive deficits remains without being understood. In the present study, we compared cerebral perfusion using single-photon emission tomography (SPECT) in patients and controls to study the association between activation patterns and cognitive performance in this disease. The SPECT studies were simultaneously obtained with an electrophysiological recording during a P300 paradigm to elicit P3a and P3b components. We included 23 stable patients with paranoid schizophrenia and 29 healthy controls that underwent clinical and cognitive assessments. Patients with schizophrenia showed an increased perfusion in the right hippocampus with respect to healthy controls, they also displayed a statistically significant inverse association between perfusion in the left hippocampus and verbal memory performance. Healthy controls showed an inverse association between perfusion in the left dorsolateral prefrontal (DLPFC) region and working memory performance. P3b but not P3a amplitude was significantly lower in patients. The limbic overactivation in the patients may contribute to their cognitive deficits in verbal memory.

Prognostic impact of pretransplantation computed tomography and gallium scans in patients with Hodgkin lymphoma with poor prognosis undergoing hematopoietic stem cell transplantation.

BACKGROUND: The present study evaluated computed tomography (CT) and Gallium-67 scanning (67Ga) before transplantation as prognostic factors for overall survival (OS) and event-free survival (EFS) in patients with relapsed or primary refractory Hodgkin lymphoma undergoing high-dose chemotherapy and stem cell transplantation. PATIENTS AND METHODS: Forty-five patients were included. Of these, 10 (22%) had positive CT and 67Ga scan results, 21 (47%) had negative results of both techniques, 12 (27%) had positive CT/negative 67Ga scan results, and 2 (5%) had negative CT/positive 67Ga scan results. RESULTS: Patients with positive CT/67Ga scan results had a significantly worse EFS and OS at 5 years than those with negative 67Ga scan results, whether it was associated with positive or negative CT scan results (0 and 25% vs. 83% and 90% vs. 74% and 83%, respectively; P < 0.001). With a median follow-up of 59 months (range, 6-150 months), no differences were observed between patients with negative CT/67Ga scan results and those with positive CT/negative 67Ga scan results, with an EFS and OS at 5 years of 74% vs. 83% and 83% vs. 90%, respectively. In multivariate analysis, the presence of pretransplantation positive CT/67Ga scan results adversely influenced EFS and OS (hazard ratio, 39; 95% confidence interval, 8-202 [P < 0.001] and hazard ratio, 24; 95% confidence interval, 4-135 [P < 0.001], respectively). CONCLUSION: Gallium-67 scans help to identify pretransplantation CT-positive patients with a different outcome. A group of patients with positive CT/negative 67Ga scan results before transplantation who showed a favorable outcome with a low rate of relapse and another group of patients with positive CT/67Ga scan results before transplantation who showed poor prognosis did not benefit from autologous stem cell transplantation. They should be offered other therapeutic strategies.