The detection of a low amount of viral RNA is crucial to identify a SARS-CoV-2 positive individual harboring a low level of virus, especially during the convalescent period. However, the detection of ...one gene at high Cycle threshold (Ct) has to be interpreted with caution.
In this study we address this specific issue and report our real-life experience.
A total of 1639 nasopharyngeal swabs (NPS) were analyzed with Xpert® Xpress SARS-CoV-2. Positive samples showing high Ct values (Ct>35) were concentrated by centrifugation and re-tested with Cepheid or other methods (RealStar SARS-CoV2 RT-PCR, Altona Diagnostics; GeneFinder COVID-19 Plus RealAmp Kit, Elitech).
1599 (97.5%) negative samples, 36 (2.3%) positive samples and 4 (0.2%) presumptive positive samples were detected. In 17 out of 36 positive patients, very low viral RNA copies were suspected since positivity was detected at high Ct. We confirmed positivity for patients who showed both E and N genes detected and for patients with only N detected but with Ct <39. On the contrary, samples with only gene N detected with Ct values >39 were found negative. NPS taken 24 hours after the first collection confirmed the negativity of the 12 samples. Clinical data sustained these results since only 2 of these 12 patients showed COVID-19-like symptoms.
These data support our consideration that detection of the N2 gene at high Ct needs to be interpreted with caution, suggesting that collaboration between virologists and clinicians is important for better understanding of results.
Venetoclax, an orally bioavailable inhibitor of BCL-2, was approved in 2016 by the United States Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) patients ...with 17p deletion del(17p), who have received at least one prior therapy. Areas covered: We focus on the mechanism of action of venetoclax and on the clinical trial data that led to the approval of venetoclax for CLL patients. We also review the studies in which this drug has being explored in combination with other anti-CLL drugs. Expert opinion: Data from early clinical trials have shown that venetoclax, as a single agent, is highly effective for relapsed/refractory CLL patients, including those cases with high-risk features. Furthermore, venetoclax seems to be an appropriate option for patients who progress on B-cell receptor (BCR) pathway kinase inhibitors. Venetoclax is also safe, with the most common serious adverse events being neutropenia. The risk of tumor lysis syndrome (TLS) can be reduced by a slow dose ramp-up, careful monitoring, and adequate prophylaxis. Ongoing trials will further clarify the safety and efficacy of venetoclax in combination with other drugs in both relapsed/refractory and untreated CLL patients.
The human
TP53
locus, located on the short arm of chromosome 17, encodes a tumour suppressor protein which functions as a tetrameric transcription factor capable of regulating the expression of a ...plethora of target genes involved in cell cycle arrest, apoptosis, DNA repair, autophagy, and metabolism regulation.
TP53
is the most commonly mutated gene in human cancer cells and
TP53
germ-line mutations are responsible for the cancer-prone Li-Fraumeni syndrome. When mutated, the
TP53
gene generally presents missense mutations, which can be distributed throughout the coding sequence, although they are found most frequently in the central DNA binding domain of the protein.
TP53
mutations represent an important prognostic and predictive marker in cancer. The presence of a
TP53
mutation does not necessarily imply a complete P53 inactivation; in fact, mutant P53 proteins are classified based on the effects on P53 protein function. Different models have been used to explore these never-ending facets of
TP53
mutations, generating abundant experimental data on their functional impact. Here, we briefly review the studies analysing the consequences of
TP53
mutations on P53 protein function and their possible implications for clinical outcome. The focus shall be on Chronic Lymphocytic Leukemia (CLL), which also has generated considerable discussion on the role of
TP53
mutations for therapy decisions.
Background
International guidelines suggest hepatitis C virus (HCV) eradication by direct‐acting antivirals (DAAs) after first‐line immunochemotherapy (I‐CT) in patients with HCV‐positive diffuse ...large B‐cell lymphoma (DLBCL), although limited experiences substantiate this recommendation. Moreover, only a few data concerning concurrent administration of DAAs with I‐CT have been reported.
Subjects, Materials, and Methods
We analyzed hematological and virological outcome and survival of 47 consecutive patients with HCV‐positive DLBCL treated at 23 Italian and French centers with DAAs either concurrently (concurrent cohort ConC: n = 9) or subsequently (sequential cohort SeqC: n = 38) to first‐line I‐CT (mainly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone R‐CHOP‐like).
Results
Median age was 61 years, 89% of patients had stage III/IV, and 25% presented evidence of cirrhosis. Genotype was 1 in 56% and 2 in 34% of cases. Overall, 46 of 47 patients obtained complete response to I‐CT. All patients received appropriate DAAs according to genotype, mainly sofosbuvir‐based regimens (n = 45). Overall, 45 patients (96%) achieved sustained virological response, 8 of 9 in ConC and 37 of 38 in SeqC. DAAs were well tolerated, with only 11 patients experiencing grade 1–2 adverse events. Twenty‐three patients experienced hepatic toxicity (grade 3–4 in seven) following I‐CT in SeqC, compared to only one patient in ConC. At a median follow‐up of 2.8 years, two patients died (2‐year overall survival, 97.4%) and three progressed (2‐year progression‐free survival, 93.1%).
Conclusion
Excellent outcome of this cohort of HCV‐positive DLBCL suggests benefit of HCV eradication by DAAs either after or during I‐CT. Moreover, concurrent DAAs and R‐CHOP administration appeared feasible, effective, and ideally preferable to deferred administration of DAAs for the prevention of hepatic toxicity.
Implications for Practice
Hepatitis C virus (HCV)‐associated diffuse large B‐cell lymphomas (DLBCLs) represent a great therapeutic challenge, especially in terms of hepatic toxicity during immune‐chemotherapy (I‐CT) and long‐term hepatic complications. The advent of highly effective and toxicity‐free direct‐acting antivirals (DAAs) created an exciting opportunity to easily eradicate HCV shortly after or in concomitance with first‐line immunochemotherapy (usually R‐CHOP). This retrospective international study reports the real‐life use of the combination of these two therapeutic modalities either in the concurrent or sequential approach (DAAs after I‐CT) in 47 patients. The favorable reported results on long‐term outcome seem to support the eradication of HCV with DAAs in all patients with HCV‐positive DLBCL. Moreover, the results from the concurrent approach were effective and safe and displayed an advantage in preventing hepatic toxicity during I‐CT.
Epidemiological studies have established that hepatitis C virus (HCV) is associated with diffuse large B‐cell lymphoma (DLBCL). This article reports on patients with HCV‐positive DLBCL treated with direct‐acting antivirals either concurrently or subsequently to a curative‐intent first‐line immunochemotherapy.
n the EMN01 trial, the addition of an alkylator (melphalan or cyclophosphamide) to lenalidomide-steroid induction therapy was prospectively evaluated in transplant-ineligible patients with multiple ...myeloma. After induction, patients were randomly assigned to maintenance treatment with lenalidomide alone or with prednisone continuously. The analysis presented here (median follow-up of 71 months) is focused on maintenance treatment and on subgroup analyses defined according to the International Myeloma Working Group Frailty Score. Of the 654 evaluable patients, 217 were in the lenalidomide-dexamethasone arm, 217 in the melphalan-prednisone-lenalidomide arm and 220 in the cyclophosphamide-prednisone-lenalidomide arm. With regards to the Frailty Score, 284 (43%) patients were fit, 205 (31%) were intermediate-fit and 165 (25%) were frail. After induction, 402 patients were eligible for maintenance therapy (lenalidomide arm, n=204; lenalidomide-prednisone arm, n=198). After a median duration of maintenance of 22.0 months, progression-free survival from the start of maintenance was 22.2 months with lenalidomide-prednisone
18.6 months with lenalidomide (hazard ratio 0.85,
=0.14), with no differences across frailty subgroups. The most frequent grade ≥3 toxicity was neutropenia (10% of lenalidomide-prednisone and 21% of lenalidomide patients;
=0.001). Grade ≥3 non-hematologic adverse events were rare (<15%). In fit patients, melphalan-prednisone-lenalidomide significantly prolonged progression-free survival compared to cyclophosphamide-prednisone-lenalidomide (hazard ratio 0.72,
=0.05) and lenalidomide-dexamethasone (hazard ratio 0.72,
=0.04). Likewise, a trend towards a better overall survival was noted for patients treated with melphalan-prednisone-lenalidomide or cyclophosphamide-prednisone-lenalidomide, as compared to lenalidomide-dexamethasone. No differences were observed in intermediate-fit and frail patients. This analysis showed positive outcomes of maintenance with lenalidomide-based regimens, with a good safety profile. For the first time, we showed that fit patients benefit from a full-dose triplet regimen, while intermediate-fit and frail patients benefit from gentler regimens. ClinicalTrials.gov registration number: NCT01093196.
The multisystem inflammatory syndrome (MIS) is a rare and sometime life-threatening post-infectious complication of coronavirus disease 2019 (Covid-19) in children and adults. To date, only a very ...few reports have associated such systemic reaction with SARS-CoV-2 vaccination.
we describe a case that resembled MIS, in a 46-year-old White man, 12 days after vaccination with Ad26. COV2. S vaccine (Johnson &Johnson/Janssen), a recombinant adenovirus serotype 26 vector encoding the SARS-CoV-2 spike glycoprotein. The patient experienced high grade fever, cutaneous rash, severe weakness, pericardial effusion and raised inflammatory markers, which met the criteria for definition of MIS. The symptoms improved with steroidal therapy.
Our case suggests that MIS could occur after SARS-CoV-2 vaccination.
Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by a multi-step evolutionary path, which starts with an early asymptomatic stage, defined as monoclonal ...gammopathy of undetermined significance (MGUS) evolving to overt disease in 1% of cases per year, often through an intermediate phase known as “smoldering” MM (sMM). Interestingly, while many genomic alterations (translocation, deletions, mutations) are usually found at early stages, they are not sufficient (alone) to determine disease evolution. The latter, indeed, relies on significant “epigenetic” alterations of different normal cell populations within the bone marrow (BM) niche, including the “evasion” from immune-system control. Additionally, MM cells could “educate” the BM immune microenvironment (BM-IM) towards a pro-inflammatory and immunosuppressive phenotype, which ultimately leads to disease evolution, drug resistance, and patients’ worse outcome. Indeed, it is not a case that the most important drugs for the treatment of MM include immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide) and monoclonal antibodies (daratumumab, isatuximab, and elotuzumab). On these bases, in this review, we describe the most recent advances in the comprehension of the role of the different cells composing the BM-IM, and we discuss the potential molecular targets, which could represent new opportunities to improve current treatment strategies for MM patients.
The treatment of chronic lymphocytic leukemia (CLL) currently relies on the use of chemo-immunotherapy, Bruton's tyrosine kinase inhibitors, or BCL2 inhibitors alone or combined with an anti-CD20 ...monoclonal antibody. However, the availability of multiple choices for the first-line setting and a lack of direct head-to-head comparisons pose a challenge for treatment selection. To overcome these limitations, we performed a systematic review and a network meta-analysis on published randomized clinical trials performed in the first-line treatment setting of CLL. For each study, we retrieved data on progression-free survival (according to del17/P53 and IGHV status), overall response rate, complete response, and incidence of most frequent grade 3-4 adverse event. We identified nine clinical trials encompassing 11 different treatments, with a total of 5288 CLL patients evaluated. We systematically performed separated network meta-analyses (NMA) to evaluate the efficacy/safety of each regimen in the conditions previously described to obtain the surface under the cumulative ranking curve (SUCRA) score, which was subsequently used to build separated ranking charts. Interestingly, the combination of obinutuzumab with acalabrutinib reached the top of the chart in each sub-analysis performed, with the exception of the del17/P53mut setting, where it was almost on par with the aCD20 mAbs/ibrutinib combination (SUCRA aCD20-ibrutinib and O-acala: 93.5% and 91%, respectively) and of the safety evaluation, where monotherapies (acalabrutinib in particular) gave better results. Finally, considering that NMA and SUCRA work for single endpoints only, we performed a principal component analysis to recapitulate in a cartesian plane the SUCRA profiles of each schedule according to the results obtained in each sub-analysis, confirming again the superiority of aCD20/BTKi or BCL2i combinations in a first-line setting. Overall, here we demonstrated that: (1) a chemotherapy-free regimen, such as the combination of aCD20 with a BTKi or BCL2i, should be the preferred treatment choice despite biological/molecular characteristics (preferred regimen O-acala); (2) there is less and less room for chemotherapy in the first line treatment of CLL.