International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

PURPOSE: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS: Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS: We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION: In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Liquid biopsy: A promising tool for driving strategies and predicting failures in patients with classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) consists of a heterogeneous group of haematological disorders that covers undifferentiated B cell neoplasms originating from germinal centre B cells. The HL molecular characterization still represents an ongoing challenge due to the low fraction of tumour Hodgkin and Reed-Sternberg cells mixed with a plethora of non-tumour haematological cells. In this scenario, next generation sequencing of liquid biopsy samples is emerging as a useful tool in HL patients' management. In this review, we aimed to overview the clinical and methodological topics regarding the implementation of molecular analysis in cHL, focusing on the role of liquid biopsy in diagnosis, follow-up, and response prediction.

Multicenter Observational Retrospective Study on Febrile Events in Patients with Acute Myeloid Leukemia Treated with Cpx-351 in "Real-Life": The SEIFEM Experience.

In the present study, we aimed to evaluate the absolute risk of infection in the real-life setting of AML patients treated with CPX-351. The study included all patients with AML from 30 Italian hematology centers of the SEIFEM group who received CPX-351 from July 2018 to June 2021. There were 200 patients included. Overall, 336 CPX-351 courses were counted: all 200 patients received the first induction cycle, 18 patients (5%) received a second CPX-351 induction, while 86 patients (26%) proceeded with the first CPX-351 consolidation cycle, and 32 patients (10%) received a second CPX-351 consolidation. A total of 249 febrile events were recorded: 193 during the first or second induction, and 56 after the first or second consolidation. After the diagnostic work-up, 92 events (37%) were classified as febrile neutropenia of unknown origin (FUO), 118 (47%) were classifiable as microbiologically documented infections, and 39 (17%) were classifiable as clinically documented infections. The overall 30-day mortality rate was 14% (28/200). The attributable mortality-infection rate was 6% (15/249). A lack of response to the CPX-351 treatment was the only factor significantly associated with mortality in the multivariate analysis [p-value: 0.004, OR 0.05, 95% CI 0.01-0.39]. Our study confirms the good safety profile of CPX-351 in a real-life setting, with an incidence of infectious complications comparable to that of the pivotal studies; despite prolonged neutropenia, the incidence of fungal infections was low, as was infection-related mortality.

Ultrasonography-guided core-needle biopsy of lymphadenopathies suspected of lymphoma: Analysis on diagnostic efficacy and safety of 1000 front-line biopsies in a multicenter Italian study.

The reliability and safety of front-line ultrasonography guided core needle biopsy (UG-CNB) performed with specific uniform approach have never been evaluated in a large series of patients with lymphadenopathies suspected of lymphoma. The aim of this study was to assess the overall accuracy of UG-CNB in the lymph node histological diagnosis, using a standard reference based on pathologist consensus, molecular biology, and/or surgery. We retrospectively checked the findings concerning the application of lymph node UG-CNB from four Italian clinical units that routinely utilized 16-gauge diameter modified Menghini needle under power-Doppler ultrasonographic guidance. A data schedule was sent to all centers to investigate the information regarding techniques, results, and complications of lymph node UG-CNB in untreated patients over a 12-year period. Overall, 1000 (superficial target, n = 750; deep-seated target, n = 250) biopsies have been evaluated in 1000 patients; other 48 biopsies (4.5%), screened in the same period, were excluded because inadequate for a confident histological diagnosis. Most patients were suffering from lymphomas (aggressive B-cell non-Hodgkin lymphoma [aBc-NHL], 309 cases; indolent B-cell [iBc]-NHL, 279 cases; Hodgkin lymphoma [HL], 212 cases; and nodal peripheral T-cell [NPTC]-NHL, 30 cases) and 100 cases from metastatic carcinoma; 70 patients had non-malignant disorders. The majority of CNB results met at least one criterion of the composite reference standard. The overall accuracy of the micro-histological sampling was 97% (95% confidence interval: 95%-98%) for the series. The sensitivity of UG-CNB for the detection of aBc-NHL was 100%, for iBc-NHL 95%, for HL 93%, and for NPTC-NHL 90%, with an overall false negative rate of 3.3%. The complication rate was low (6% for all complications); no patient suffered from biopsy-related complications of grade >2 according to the Common Terminology Criteria for Adverse Events. Lymph node UG-CNB as mini-invasive diagnostic procedure is effective with minimal risk for the patient.

Intravascular Complications of Central Venous Catheterization by Insertion Site in Acute Leukemia during Remission Induction Chemotherapy Phase: Lower Risk with Peripherally Inserted Catheters in a Single-Center Retrospective Study.

The basilic/brachial (BBV), internal jugular (IJV), and subclavian veins (SCV) are commonly used as central venous catheter (CVC) sites. A BBV approach [peripherally inserted central catheter (PICC)] is increasingly used for short- to intermediate-term CVCs for acute leukemias undergoing cytotoxic intensive regimens. In this retrospective study, the catheterization of the BBV, IJV, and SCV in patients with previously untreated acute leukemia was assessed. The primary outcome was the composite incidence of catheter-related symptomatic deep-vein thrombosis (sDVT) and bloodstream infection (BSI) from catheterization up to 30 days later. In a 10-year period, 336 CVC were inserted in the BBV (n = 115), IJV (n = 111), and SCV (n = 110) in 336 patients suffering from AML (n = 201) and ALL (n = 135) and undergoing induction chemotherapy. The primary outcome events were 8, 20, and 27 in the BBV, SCV and IJV cohorts (2.6, 6.9, and 9.6 per 1000 catheter-days, respectively; p = 0.002). The primary outcome risk was significantly higher in the IJV-cohort than in the BBV-cohort (HR, 3.6; 95% CI, 1.6 to 7.9; p = 0.001) and in the SCV-cohort than in the BBV-cohort (HR, 2.6; 95% CI, 1.2 to 5.9; p = 0.02). PICC was a valid CVC for the induction chemotherapy of acute leukemia for the lowest risk of sDVT and BSI.

Lamivudine 24-month-long prophylaxis is a safe and efficient choice for the prevention of hepatitis B virus reactivation in HBsAg-negative/HBcAb-positive patients with advanced DLBCL undergoing upfront R-CHOP-21.

Introduction: Occult hepatitis B infection (OBI) is a condition where replication-competent hepatitis B virus-DNA (HBV-DNA) is present in the liver, with or without HBV-DNA in the blood [<200 international units (IU)/ml or absent] in HB surface antigen (HBsAg)-negative/HB core antibody (HBcAb)-positive individuals. In patients with advanced stage diffuse large B-cell lymphoma (DLBCL) undergoing 6 cycles of R-CHOP-21+2 additional R, OBI reactivation is a frequent and severe complication. There is no consensus among recent guidelines on whether a pre-emptive approach or primary antiviral prophylaxis is the best solution in this setting of patients. In addition, questions still unresolved are the type of prophylactic drug against HBV and adequate prophylaxis duration. Methods: In this case-cohort study, we compared a prospective series of 31 HBsAg-/HBcAb+ patients with newly diagnosed high-risk DLBCL receiving lamivudine (LAM) prophylaxis 1 week before R-CHOP-21+2R until 18 months after (24-month LAM series) versus 96 HBsAg-/HBcAb+ patients (from January 2005 to December 2011) undergoing a pre-emptive approach (pre-emptive cohort) and versus 60 HBsAg-/HBcAb+ patients, from January 2012 to December 2017, receiving LAM prophylaxis [1 week before immunochemotherapy (ICHT) start until 6 months after] (12-month LAM cohort). Efficacy analysis focused primarily on ICHT disruption and secondarily on OBI reactivation and/or acute hepatitis. Results: In the 24-month LAM series and in the 12-month LAM cohort, there were no episodes of ICHT disruption versus 7% in the pre-emptive cohort (P = 0.05). OBI reactivation did not occur in any of the 31 patients in the 24-month LAM series versus 7 out of 60 patients (10%) in the 12-month LAM cohort or 12 out of 96 (12%) patients in the pre-emptive cohort (P = 0.04, by χ 2 test). No patients in the 24-month LAM series developed acute hepatitis compared with three in the 12-month LAM cohort and six in the pre-emptive cohort. Discussion: This is the first study collecting data regarding a consistent and homogeneous large sample of 187 HBsAg-/HBcAb+ patients undergoing standard R-CHOP-21 for aggressive lymphoma. In our study, 24-month-long prophylaxis with LAM appears to be the most effective approach with a null risk of OBI reactivation, hepatitis flare-up, and ICHT disruption.

Predictive value on advance hodgkin lymphoma treatment outcome of end-of treatment FDG PET/CT in the HD0607 clinical trial.

The Lugano classification for response assessment in lymphoma recommends the use of the 5-point-scale Deauville Score (DS) to assess response evaluation of end-of-treatment FDG-PET/CT (eotPET) in Hodgkin Lymphoma (HL); nevertheless, there is a paucity of data on its accuracy and reproducibility. We focus here on the cohort of advanced stage IIb-IV HL patients enrolled in the HD0607 clinical trial (NCT identifier 00795613) that having had a negative interim PET performed 6 cycles of ABVD (Doxorubicin, Vinblastine, Vincristine and Dacarbazine) and then performed an eotPET. Negative patients were randomized to radiotherapy and no further treatment while positive patients were treated based on local policies. eotPET was re-evaluated independently by two readers evaluated and progression free survival was analysed (PFS). eotPET of 254 patients were analysed. The median follow-up was 43 months. The best receiver operator characteristics cut-off values to distinguish positive and negative patients was 4. The area-under-the-curve was 0.81 (95%CI, 0.70-0.91). Three-years PFS was 0.95 (95% CI 0.90-0.97) in eotPET negative and 0.22 (95% CI 0.11-0.43) in eotPET positive. DS demonstrated a good reproducibility of positivity/negativity between the readers consensus and local site evaluation where the agreement occurred on 95.0% of patients. The present study demonstrates that eotPET is an accurate tool to predict treatment outcome in HL and confirms the appropriateness of the Lugano classification for eotPET evaluation.

Epidemiology, Mechanisms of Resistance and Treatment Algorithm for Infections Due to Carbapenem-Resistant Gram-Negative Bacteria: An Expert Panel Opinion.

Antimicrobial resistance represents a serious threat for global health, causing an unacceptable burden in terms of morbidity, mortality and healthcare costs. In particular, in 2017, carbapenem-resistant organisms were listed by the WHO among the group of pathogens for which novel treatment strategies are urgently needed. Fortunately, several drugs and combinations have been introduced in recent years to treat multi-drug-resistant (MDR) bacteria. However, a correct use of these molecules is needed to preserve their efficacy. In the present paper, we will provide an overview on the epidemiology and mechanisms of resistance of the most common MDR Gram-negative bacteria, proposing a treatment algorithm for the management of infections due to carbapenem-resistant bacteria based on the most recent clinical evidence.

A roadmap for a comprehensive diagnostic approach to fine needle cytology of lymph node metastases.

OBJECTIVE: Fine needle cytology (FNC) is widely used as a first-line procedure in the diagnostic algorithm of lymphadenopathies. In a metastatic setting, a first-line diagnostic approach identifies non-haematopoietic malignancy; however, cytopathologists could also provide a second diagnostic level, identifying the origin of the primary tumour. This paper outlines a comprehensive and practical approach to the cytological diagnosis of lymph node metastases. METHODS: Cytological diagnoses of lymph node metastases performed over a 10-year period were selected and divided into two groups. The first group, labelled "oncological," comprised patients with a previous history of malignancy; the second group, labelled "naïve," included patients with no relevant history. Pathology records were retrieved to record microscopic findings, namely, background appearance, group architecture, and specific cell features; data from cell block (CB) preparations were also collected. RESULTS: Overall, 982 cases were selected: 497 cases (50.61%) in the naïve group, and 485 (49.39%) in the oncological group. Overall, a second diagnostic level was achieved in 834/982 cases (84.92%); cases diagnosed as carcinoma not otherwise specified were more frequent in the naïve group than in the oncological group (17.51% vs. 8.04%, P < 0.01). Notably, although CB material was available in only 44.87% of the naïve cases, we were able to achieve a second diagnostic level thanks to the integration of clinical and cytomorphological findings, plus lymph node topography, in 82.49% of the cases. CONCLUSION: Our results confirmed that in a metastatic setting, FNC can reliably lead to the identification of the origin of the primary tumour.

Liposomal doxorubicin supercharge-containing front-line treatment in patients with advanced-stage diffuse large B-cell lymphoma or classical Hodgkin lymphoma: Preliminary results of a single-centre phase II study.

We evaluated the impact of liposomal doxorubicin (NPLD) supercharge-containing therapy on interim fluorodeoxyglucose positron emission tomography (interim-FDG-PET) responses in high-risk diffuse large B-cell lymphoma (DLBCL) or classical Hodgkin lymphoma (c-HL). In this phase II study (2016-2021), 81 adult patients with advanced-stage DLBCL (n = 53) and c-HL (n = 28) received front-line treatment with R-COMP-dose-intensified (DI) and MBVD-DI. R-COMP-DI consisted of 70 mg/m2 of NPLD plus standard rituximab, cyclophosphamide, vincristine and prednisone for three cycles (followed by three cycles with NPLD de-escalated at 50 mg/m2 ); MBVD-DI consisted of 35 mg/m2 of NPLD plus standard bleomycin, vinblastine and dacarbazine for two cycles (followed by four cycles with NPLD de-escalated at 25 mg/m2 ). Patients underwent R-COMP-DI and MBVD-DI with a median dose intensity of 91% and 94% respectively. At interim-FDG-PET, 72/81 patients (one failed to undergo interim-FDG-PET due to early death) had a Deauville score of ≤3. At end of treatment, 90% of patients reached complete responses. In all, 20 patients had Grade ≥3 adverse events, and four of them required hospitalisation. At a median 21-months of follow-up, the progression-free survival of the entire population was 77.3% (95% confidence interval 68%-88%). Our data suggest that the NPLD supercharge-driven strategy in high-risk DLBCL/c-HL may be a promising option to test in phase III trials, for improving negative interim-FDG-PET cases incidence.

Sulfur Exafluoride Contrast-Enhanced Ultrasound Showing Early Wash-Out of Marked Degree Identifies Lymphoma Invasion of Spleen with Excellent Diagnostic Accuracy: A Monocentric Study of 260 Splenic Nodules.

Contrast-enhanced ultrasonography (CEUS) use for detecting lymphoma in the spleen was questioned because of the risk of its inadequate diagnostic accuracy. The aim of the present study was to validate CEUS exam for the identification of spleen involvement by lymphoma in patients at risk. A total of 260 nodules from the spleens of 77 patients with lymph node biopsy-proven non-Hodgkin lymphoma (NHL; n = 44) or Hodgkin lymphoma (HL; n = 33) at staging (n = 56) or follow-up (n = 21) were collected in a hematology Italian center and retrospectively analyzed. Nodules were classified as malignant lymphoma if ≥0.5 cm (long axis) with arterial phase isoen-hancement and early (onset <60 s after contrast agent injection) wash-out of marked (≤120 s after contrast agent injection) degree. Other perfusional combinations at CEUS scans qualified lesions as benign or inconclusive. Diagnostic reference standard was clinical laboratory imaging monitoring for 230 nodules, and/or histology for 30 nodules. The median nodule size was 1.5 cm (range 0.5−7 cm). According to the reference standard, 204 (78%) nodules were lymphomas (aggressive-NHL (a-NHL), 122; classic-HL (c-HL), 65; indolent (i)-NHL, 17) and 56 (22%) were benign (inflammation, infection, and/or mesenchymal) lesions. Sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy of CEUS for detecting lymphoma in the spleen were 95%, 100%, 100%, 85%, and 96%, respectively. Marked wash-out range of 55−90 s (median, 74 s), 92−120 s (median, 100 s), and 101−120 s (median, 114.5 s) was 100%, 96.6%, and 77% predictive of a-NHL, c-HL, and i-NHL splenic nodular infiltration, respectively. The CEUS perfusional pattern of arterial phase isoenhancement with early wash-out of marked degree was highly accurate for the detection of lymphomatous invasion of spleen in patients at risk, enabling its use for a confident non-invasive diagnosis.

Impact of a cardio-oncology unit on prevention of cardiovascular events in cancer patients.

AIMS: As the world population grows older, the co-existence of cancer and cardiovascular comorbidities becomes more common, complicating management of these patients. Here, we describe the impact of a large Cardio-Oncology unit in Southern Italy, characterizing different types of patients and discussing challenges in therapeutic management of cardiovascular complications. METHODS AND RESULTS: We enrolled 231 consecutive patients referred to our Cardio-Oncology unit from January 2015 to February 2020. Three different types were identified, according to their chemotherapeutic statuses at first visit. Type 1 included patients naïve for oncological treatments, Type 2 patients already being treated with oncological treatments, and Type 3 patients who had already completed cancer treatments. Type 2 patients presented the highest incidence of cardiovascular events (46.2% vs. 12.3% in Type 1 and 17.9% in Type 3) and withdrawals from oncological treatments (5.1% vs. none in Type 1) during the observation period. Type 2 patients presented significantly worse 48 month-survival (32.1% vs. 16.7% in Type 1 and 17.9% in Type 3), and this was more evident when in the three groups we focused on patients with uncontrolled cardiovascular risk factors or overt cardiovascular disease at the first cardiologic assessment. Nevertheless, these patients showed the greatest benefit from our cardiovascular assessments, as witnessed by a small, but significant improvement in ejection fraction during follow-up (Type 2b: from 50 [20; 67] to 55 [35; 65]; P = 0.04). CONCLUSIONS: Patients who start oncological protocols without an accurate baseline cardiovascular evaluation are at major risk of developing cardiac complications due to antineoplastic treatments.

Prognostic value of Bcl2 and Bcl6 in primary cutaneous large B-cell lymphoma: A systematic review and meta-analysis.

AIMS: To assess the prognostic value of Bcl2 and Bcl6 in primary cutaneous diffuse large B-cell lymphoma (pcDLBCL), through a systematic review and meta-analysis. METHODS: Electronic databases were searched from their inception to April 2021 for studies reporting Bcl2 and Bcl6 expression and survival outcomes in pcDLBCL series. Kaplan-Meier and Cox regression survival analyses with hazard ratio calculation were performed for overall survival (OS), with a significant p-value< 0.05. RESULTS: Eight studies with 148 patients were included. OS was significantly decreased in Bcl2-pos itive pcDLBCLs (5-year OS= 52.9 ± 5.2%) compared to Bcl2 negative pcDLBCLs (5-year OS= 86.6 ± 7.2%), with a HR of 4.615 (95% CI, 1.827-11.657; p = 0.001); no significant difference in OS was found between Bcl6-positive pcDLBCLs (5-year OS= 61.3 ± 6.5%) and Bcl6-negative pcDLBCLs (5-year OS= 56.8 ± 7.2%), with a HR of 0.789 (95% CI, 0.462-1.350; p = 0.388). CONCLUSIONS: In pcDLBCL, Bcl2 expression is a strong unfavourable prognostic marker; Bcl6 does not seem to be associated with survival instead. Further studies are necessary in this field.

Invasive aspergillosis in relapsed/refractory acute myeloid leukaemia patients: Results from SEIFEM 2016-B survey.

BACKGROUND: In patients with relapsed/refractory acute myeloid leukaemia (R/R AML) who received salvage chemotherapy, limited and not updated studies explored the incidence of invasive aspergillosis (IA) and the role of antifungal prophylaxis (AP). The aims of this multicentre retrospective 'SEIFEM 2016-B' study were as follows: (1) to evaluate the current rate and the outcome of proven/probable IA and (2) to assess the efficacy of AP, in a large 'real life' series of patient with R/R AML submitted to salvage chemotherapy. RESULTS: Of 2250 R/R AML patients, a total of 74 cases of IA (5.1%) were recorded as follows: 10 (0.7%) proven and 64 (4.3%) probable. Information about AP were available in 73/74 (99%) patients. Fifty-eight (79%) breakthrough infections occurred, mainly during AP with posaconazole [25 (43%)]. The patients who received AP during salvage chemotherapy showed a benefit from antifungal therapy (AT) than patients who did not received AP [43 (86%) vs 7 (14%); p < .033]. In a multivariate analysis, AP and absence of severe mucositis had a significant favourable effect on overall response rate. CONCLUSION: Our data demonstrated that the incidence of IA during the salvage chemotherapy is similar to the past. Nevertheless, the attributable mortality rate (AMR) appears to be lower than that previously reported in R/R AML. Further prospective studies should be performed to confirm our preliminary observation and understand and the why a decreased AMR is reported in this setting of high-risk patients.

The impact of MR-based attenuation correction in spinal cord FDG-PET/MR imaging for neurological studies.

PURPOSE: Positron emission tomography (PET) attenuation correction (AC) in positron emission tomography-magnetic resonance (PET/MR) scanners constitutes a critical and barely explored issue in spinal cord investigation, mainly due to the limitations in accounting for highly attenuating bone structures which surround the spinal canal. Our study aims at evaluating the clinical suitability of MR-driven AC (MRAC) for 18-fluorodeoxy-glucose positron emission tomography (18 F-FDG-PET) in spinal cord. METHODS: Thirty-six patients, undergoing positron emission tomography-computed tomography (PET/CT) and PET/MR in the same session for oncological examination, were retrospectively analyzed. For each patient, raw PET data from PET/MR scanner were reconstructed with 4- and 5-class MRAC maps, generated by hybrid PET/MR system (PET_MRAC4 and PET_MRAC5, respectively, where PET_MRAC is PET images reconstructed using MR-based attenuation correction map), and an AC map derived from CT data after a custom co-registration pipeline (PET_rCTAC, where PET_rCTAC is PET images reconstructed using CT-based attenuation correction map), which served as reference. Mean PET standardized uptake values ( SU V m ) were extracted from the three reconstructed PET images by regions of interest (ROIs) identified on T2-weighted MRI, in the spinal cord, lumbar cerebrospinal fluid (CSF), and vertebral marrow at five levels (C2, C5, T6, T12, and L3). SU V m values from PET_MRAC4 and PET_MRAC5 were compared with each other and with the reference by means of paired t-test, and correlated using Pearson's correlation (r) to assess their consistency. Cohen's d was calculated to assess the magnitude of differences between PET images. RESULTS: SU V m values from PET_MRAC4 were lower than those from PET_MRAC5 in almost all analyzed ROIs, with a mean difference ranging from 0.03 to 0.26 (statistically significant in the vertebral marrow at C2 and C5, spinal cord at T6 and T2, and CSF at L3). This was also confirmed by the effect size, with highest values at low spinal levels (d = 0.45 at T12 in spinal cord, d = 0.95 at L3 in CSF). S U V m values from PET_MRAC4 and PET_MRAC5 showed a very good correlation (0.81 < r < 0.97, p < 0.05) in all spinal ROIs. Underestimation of SU V m between PET_MRAC4 and PET_rCTAC was observed at each level, with a mean difference ranging from 0.02 to 0.32 (statistically significant in the vertebral marrow at C2 and T6, and CSF at L3). Although PET_MRAC5 underestimates PET_rCTAC (mean difference ranging from 0.02 to 0.3), an overall decrease in effect size could be observed for PET_MRAC5, mainly at lower spinal levels (T12, L3). SU V m from both PET_MRAC4 and PET_MRAC5 methods showed r value from good to very good with respect to PET_rCTAC (0.67 < r < 0.9 and 0.73 < r < 0.94, p < 0.05, respectively). CONCLUSIONS: Our results showed that neglecting bones in AC can underestimate the FDG uptake measurement of the spinal cord. The inclusion of bones in MRAC is far from negligible and improves the AC in spinal cord, mainly at low spinal levels. Therefore, care must be taken in the spinal canal region, and the use of AC map reconstruction methods accounting for bone structures could be beneficial.

A Novel Approach to Classification and Reporting of Lymph Node Fine-Needle Cytology: Application of the Proposed Sydney System.

Fine-needle cytology (FNC) is a useful diagnostic tool in the first line evaluation of lymphadenopathy of unknown aetiology. Nevertheless, considering the large number of conditions presenting as lymphadenopathy, lymph node cytology represents a challenging scenario. Recently, an expert panel published the proposal of the Sydney system for performing classification and reporting of lymph node cytopathology; the aim of the present study was to evaluate the applicability of this system. Thus, 300 lymph node FNCs performed over 1 year were reviewed and categorized according to the Sydney system classification. Overall, n = 20 cases (6.7%) were categorized as L1-inadequate/non-diagnostic; n = 104 (34.7%) as benign (L2); n = 25 (8.3%) as atypical (L3); n = 13 (4.3%) as suspicious (L4), and n = 138 (46%) as malignant (L5). FNC diagnoses were correlated with histopathologic and clinical follow-up to assess the diagnostic accuracy and the risk of malignancy (ROM) for each diagnostic category. Statistical analysis showed the following results: sensitivity 98.47%, specificity 95.33%, positive predictive value 96.27%, negative predictive value 98.08%, and accuracy 97.06%. The ROM was 50% for the category L1, 1.92% for L2, 58.3% for L3, and 100% for L4 and L5. In conclusion, FNC coupled with ancillary techniques ensures satisfactory diagnostic accuracy and the implementation of the Sydney system may improve the practice of cytopathologists.

Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial.

BACKGROUND: Despite advances in the treatment of Hodgkin lymphoma with the introduction of PET-adapted regimens, practical challenges prevent more widespread use of these approaches. The ECHELON-1 study assessed the safety and efficacy of front-line A+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in patients with stage III or IV classical Hodgkin lymphoma. The primary analysis showed improved modified progression-free survival with A+AVD. We present an updated analysis of ECHELON-1 at 5 years, an important landmark for this patient population. METHODS: ECHELON-1 was an international, open-label, randomised, phase 3 trial done at 218 clinical sites, including hospitals, cancer centres, and community clinics, in 21 countries. Previously untreated patients (≥18 years with an Eastern Cooperative Oncology Group performance status of ≤2) with stage III or IV classical Hodgkin lymphoma were randomly assigned (1:1) to receive A+AVD (brentuximab vedotin, 1·2 mg/kg of bodyweight, doxorubicin 25 mg/m2 of body surface area, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 U/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) intravenously on days 1 and 15 of each 28-day cycle for up to six cycles. Stratification factors included region (Americas vs Europe vs Asia) and International Prognostic Score risk group (low, intermediate, or high risk). The primary endpoint was modified progression-free survival; this 5-year update includes analysis of progression-free survival as per investigator assessment in the intention-to-treat population, which was an exploratory endpoint, although the 5-year analysis was not prespecified in the protocol. This trial is registered with ClinicalTrials.gov (NCT01712490) and EudraCT (2011-005450-60), and is ongoing. FINDINGS: Between Nov 19, 2012, and Jan 13, 2016, 1334 patients were randomly assigned to receive A+AVD (n=664) or ABVD (n=670). At a median follow-up of 60·9 months (IQR 52·2-67·3), 5-year progression-free survival was 82·2% (95% CI 79·0-85·0) with A+AVD and 75·3% (71·7-78·5) with ABVD (hazard ratio [HR] 0·68 [95% CI 0·53-0·87]; p=0·0017). Among PET-2-negative patients, 5-year progression-free survival was higher with A+AVD than with ABVD (84·9% [95% CI 81·7-87·6] vs 78·9% [75·2-82·1]; HR 0·66 [95% CI 0·50-0·88]; p=0·0035). 5-year progression-free survival for PET-2-positive patients was 60·6% (95% CI 45·0-73·1) with A+AVD versus 45·9% (32·7-58·2) with ABVD (HR 0·70 [95% CI 0·39-1·26]; p=0·23). Peripheral neuropathy continued to improve or resolve over time with both A+AVD (375 [85%] of 443 patients) and ABVD (245 [86%] of 286 patients); more patients had ongoing peripheral neuropathy in the A+AVD group (127 [19%] of 662) than in the ABVD group (59 [9%] of 659). Fewer secondary malignancies were reported with A+AVD (19 [3%] of 662) than with ABVD (29 [4%] of 659). More livebirths were reported in the A+AVD group (n=75) than in the ABVD group (n=50). INTERPRETATION: With 5 years of follow-up, A+AVD showed robust and durable improvement in progression-free survival versus ABVD, regardless of PET-2 status, and a consistent safety profile. On the basis of these findings, A+AVD should be preferred over ABVD for patients with previously untreated stage III or IV classical Hodgkin lymphoma. FUNDING: Millennium Pharmaceuticals (a wholly owned subsidiary of Takeda Pharmaceutical Company), and Seagen.

Rituximab-Containing Risk-Adapted Treatment Strategy in Nodular Lymphocyte Predominant Hodgkin Lymphoma: 7-Years Follow-Up.

BACKGROUND: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare variant of HL that accounts for 5% of all HL cases. The expression of CD20 on neoplastic lymphocytes provides a suitable target for novel treatments based on Rituximab. Due to its rarity, consolidated and widely accepted treatment guidelines are still lacking for this disease. METHODS: Between 1 December 2007 and 28 February 2018, sixteen consecutive newly diagnosed adult patients with NLPHL received Rituximab (induction ± maintenance)-based therapy, according to the baseline risk of German Hodgkin Study Group prognostic score system. The treatment efficacy and safety of the Rituximab-group were compared to those of a historical cohort of 12 patients with NLPHL who received Doxorubicin, Bleomycin, Vinblastine, Dacarbazine (ABVD) chemotherapy followed by radiotherapy (RT), if needed, according to a similar baseline risk. The primary outcome was progression-free survival (PFS) and secondary outcomes were overall survival (OS) and side-effects (according to the Common Terminology Criteria for Adverse Events, v4.03). RESULTS: After a 7-year follow-up (range, 1-11 years), PFS was 100% for patients treated with the Rituximab-containing regimen versus 66% for patients of the historical cohort (p = 0.036). Four patients in the latter group showed insufficient response to therapy. The PFS for early favorable and early unfavorable NLPHLs was similar between treatment groups, while a better PFS was recorded for advanced-stages treated with the Rituximab-containing regimen. The OS was similar for the two treatment groups. Short- and long-term side-effects were more frequently observed in the historical cohort. Grade ≥3 neutropenia was more frequent in the historical cohort compared with the Rituximab-group (58.3% vs. 18.7%, respectively; p = 0.03). Long-term non-hematological toxicities were observed more frequently in the historical cohort. CONCLUSION: Our results confirm the value of Rituximab in NLPHL therapy and show that Rituximab (single-agent) induction and maintenance in a limited-stage, or Rituximab with ABVD only in the presence of risk factors, give excellent results while sparing cytotoxic agent- and/or RT-related damage. Furthermore, Rituximab inclusion in advanced-stage therapeutic strategy seems to improve PFS compared to conventional chemo-radiotherapy.