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.

Estimation of diffusion time with the Shannon entropy approach.

The present work revisits and improves the Shannon entropy approach when applied to the estimation of an instability timescale for chaotic diffusion in multidimensional Hamiltonian systems. This formulation has already been proved efficient in deriving the diffusion timescale in 4D symplectic maps and planetary systems, when the diffusion proceeds along the chaotic layers of the resonance's web. Herein the technique is used to estimate the diffusion rate in the Arnold model, i.e., of the motion along the homoclinic tangle of the so-called guiding resonance for several values of the perturbation parameter such that the overlap of resonances is almost negligible. Thus differently from the previous studies, the focus is fixed on deriving a local timescale related to the speed of an Arnold diffusion-like process. The comparison of the current estimates with determinations of the diffusion time obtained by straightforward numerical integration of the equations of motion reveals a quite good agreement.

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.

Diffusion and Lyapunov timescales in the Arnold model.

In the present work, we focus on two dynamical timescales in the Arnold Hamiltonian model: the Lyapunov time and the diffusion time when the system is confined to the stochastic layer of its dominant resonance (guiding resonance). Following Chirikov's formulation, the model is revisited, and a discussion about the main assumptions behind the analytical estimates for the diffusion rate is given. On the other hand, and in line with Chirikov's ideas, theoretical estimations of the Lyapunov time are derived. Later on, three series of numerical experiments are presented for various sets of values of the model parameters, where both timescales are computed. Comparisons between the analytical estimates and the numerical determinations are provided whenever the parameters are not too large, and those cases are in fact in agreement. In particular, the case in which both parameters are equal is numerically investigated. Relationships between the diffusion time and the Lyapunov time are established, like an exponential law or a power law in the case of large values of the parameters.

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 COVID-19 pandemic on 2-[18F]FDG PET/CT imaging work-flow in a single medical institution: comparison among the three Italian waves.

PURPOSE: To compare the impact of COVID-19 pandemic on 2-[18F]FDG PET/CT imaging work-flow during the three waves in a medical institution of southern of Italy. METHODS: We retrospectively reviewed the numbers and results of 2-[18F]FDG PET/CT studies acquired during the following three periods of the COVID-19 waves: 1) February 3-April 30, 2020; 2) October 15, 2020-January 15, 2021; and 3) January 18-April 16, 2021. RESULTS: A total of 861 PET/CT studies in 725 patients (388 men, mean age 64 ± 4 years) was acquired during the three waves of COVID-19 pandemic. The majority (94%) was performed for diagnosis/staging (n = 300) or follow-up (n = 512) of neoplastic diseases. The remaining 49 studies (6%) were acquired for non-oncological patients. The distribution of number and type of clinical indications for PET/CT studies in the three waves were comparable (p = 0.06). Conversely, the occurrence of patients positive for COVID-19 infection progressively increased (p < 0.0001) from the first to third wave; in particular, patients with COVID-19 had active infection before PET/CT study as confirmed by molecular oro/nasopharyngeal swab. CONCLUSION: Despite the restrictive medical measures for the emergency, the number of 2-[18F]FDG PET/CT studies was unchanged during the three waves guaranteeing the diagnostic performance of PET/CT imaging for oncological patients.

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.

Considerations on antimicrobial prophylaxis in patients with lymphoproliferative diseases: A SEIFEM group position paper.

The therapeutic armamentarium for the treatment of patients with lymphoproliferative diseases has grown considerably over the most recent years, including a large use of new immunotherapeutic agents. As a consequence, the epidemiology of infectious complications in this group of patients is poorly documented, and even more importantly, the potential benefit of antimicrobial prophylaxis remains a matter of debate when considering the harmful effect from the emergence of multidrug resistant pathogens. The present position paper is addressed to all hematologists treating patients affected by lymphoproliferative malignancies with the aim to provide clinicians with a useful tool for the prevention of bacterial, fungal and viral infections.

Sjögren Syndrome in Primary Salivary Gland Lymphoma.

OBJECTIVES: Sjögren syndrome (SS) is considered as a major etiologic factor for primary salivary gland lymphoma (SGL). However, the percentage of SGL that is caused by SS (and thus the real impact of SS on SGL epidemiology) is unclear. We aimed to assess the prevalence of SS in patients with SGL through a systematic review and meta-analysis. METHODS: Electronic databases were searched for studies assessing the presence of SS in patients with SGL. Pooled prevalence of SS in SGL was calculated, with a subgroup analysis based on histotype (mucosa-associated lymphoid tissue [MALT] vs non-MALT). RESULTS: Sixteen studies with 665 SGLs were included. Pooled prevalence of SS in SGL was 18.2%, with high heterogeneity among studies. In MALT SGL, the prevalence of SS was 29.5%, with moderate heterogeneity. In non-MALT SGL, the prevalence of SS was 0%, with null heterogeneity. CONCLUSIONS: SS seems to be responsible for a significant but minor portion of SGLs. SS appears involved in MALT-type SGL but not in other histotypes.

Hashimoto Thyroiditis in Primary Thyroid Non-Hodgkin Lymphoma.

OBJECTIVES: To assess the prevalence of Hashimoto thyroiditis (HT) in primary thyroid lymphoma (PTL) and whether it differs between mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL). METHODS: Electronic databases were searched for studies assessing HT prevalence in PTL, based on antithyroid antibodies, clinical history, or pathology. Pooled prevalence of HT and its association with histotype (MALT or DLBCL) were calculated. RESULTS: Thirty-eight studies with 1,346 PTLs were included. Pooled prevalence results were 78.9% (any HT evidence), 65.3% (antithyroid antibodies), 41.7% (clinical history), and 64% (pathology). HT prevalence was significantly higher in MALT lymphoma than in DLBCL (P = .007) and in mixed DLBCL/MALT than in pure DLBCL (P = .002). CONCLUSIONS: Overall, 78.9% of patients with PTL have any HT evidence, but only half of these had been clinically followed. The difference in HT prevalence suggests that a subset of DLBCL may not derive from MALT lymphoma.