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The definition and role of bulky disease in young patients (ie, aged 18–60 years) with good-prognosis diffuse large-B-cell lymphoma (DLBCL), who have been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-like chemotherapy with or without rituximab, remain controversial. We aimed to assess the effect of maximum tumour diameter (MTD) in these patients. Patients from the MInT (Mabthera International Trial Group) study were eligible. We analysed event-free (EFS) and overall survival (OS) after CHOP-like chemotherapy with or without rituximab, according to MTD, by Martingale residual analyses and Cox regression models. Radiotherapy was given to sites of primary bulky disease according to national standards, and to primary extranodal disease at physician discretion. The primary endpoint was EFS and the secondary endpoint was OS. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT 00064116. Of the 824 patients enrolled in the MInT study, the informed-consent form of one patient was missing, leaving 823 patients evaluable for intention-to-treat analysis. Data on MTD of involved sites were available for 802 patients. Martingale residual analysis showed an adverse prognostic effect of MTD on EFS and OS, which increased linearly. In a multivariable analysis with MTD as a linear regression variable, the effect of MTD was significant after CHOP-like treatment alone for EFS (hazard ratio 1·090 [95% CI 1·051–1·130], p<0·0001) and OS (1·119 [1·057–1·184], p=0·0001), and after CHOP-like treatment and rituximab for OS (1·089 [1·003–1·183], p=0·043), but not for EFS (1·044 [0·991–1·099], p=0·103). For CHOP-like treatment alone, 3-year EFS ranged from 78·2% (MTD <5·0 cm, 95% CI 68·3–85·4) to 41·3% (MTD ≥10·0 cm, 31·8–50·4). For CHOP-like treatment and rituximab, 3-year EFS ranged from 83·2% (MTD <5·0 cm, 72·8–89·9) to 72·7% (MTD ≥10·0 cm, 63·8–79·7). With CHOP-like treatment alone, 3-year OS decreased from 92·9% (MTD <5·0 cm, 84·9–96·8) to 73·5% (MTD ≥10·0 cm, 63·9–81·0); for CHOP-like treatment and rituximab, 3-year OS decreased from 98·0% (MTD <5·0 cm, 92·2–99·5) to 85·2% (MTD ≥10·0 cm, 77·0–90·6). For CHOP-like treatment, any cut-off point between 5·0 cm and 10·0 cm separated two populations with a significant EFS difference (p<0·0001 for all log-rank tests) and OS difference (p≤0·003 for all log-rank tests). For CHOP-like treatment and rituximab, only a cut-off point of 10·0 cm separated two populations with a significant EFS difference (log-rank p=0·047), but any cut-off point of 6·0 cm or more separated two populations with a significant OS difference (log-rank p values 0·0009–0·037). Rituximab decreased, but did not eliminate the adverse prognostic effect of MTD in young patients with good-prognosis DLBCL. Due to the linear prognostic effect of MTD on outcome, arbitrary cut-off points for bulky disease can be set between 5·0 cm and 10·0 cm, depending on clinical considerations. Based on this study, a cut-off point of 10·0 cm might be a suitable margin in the rituximab era to delineate those patients with bulky disease. Roche, Basel, Switzerland (M39045).

Aberrant DNA methylation is considered an important epigenetic mechanism for gene inactivation. Monoclonal gammopathy of undetermined significance (MGUS) is believed to be a precursor of multiple myeloma (MM). We have analyzed methylation status of p15 INK⁴B , p16 INK⁴A , ARF, SOCS-1, p27 KIP¹ , RASSF1A, and TP73 genes in bone marrow DNA samples from 21 MGUS and 44 MM patients, in order to determine the role of aberrant promoter methylation as one of the steps involved in the progression of MGUS to MM. Methylation specific polymerase chain reaction assay followed by DNA sequencing of the resulting product was performed. SOCS-1 gene methylation was significantly more frequent in MM (52%) than in MGUS (14%; p = 0,006). Methylation frequencies of TP73, ARF, p15 INK⁴B , p16 INK⁴A , and RASSF1A were comparable in MGUS: 33%, 29%, 29%, 5%, and 0%, to that observed in MM: 45%, 29%, 32%, 7%, and 2%. All patients lacked methylation at p27 KIP¹ gene. In both entities, a concurrent methylation of p15 INK⁴B and TP73 was observed. The mean methylation index of MGUS was lower (0.16) than that of MM (0.24; p < 0.05). Correlations with clinicopathologic characteristics showed a higher mean age in MGUS patients with SOCS-1 methylated (p < 0.001); meanwhile in MM, methylation of p15 INK⁴B was more frequent in males (p = 0.009) and IgG isotype (p = 0.038). Our findings suggest methylation of TP73, ARF, p15 INK⁴B , and p16 INK⁴A as early events in the pathogenesis and development of plasma cell disorders; meanwhile, SOCS-1 methylation would be an important step in the clonal evolution from MGUS to MM.

Plitidepsin is a cyclic depsipeptide of marine origin in clinical development in cancer patients. Previously, some depsipeptides have been linked to increased cardiac toxicity. Clinical databases were searched for cardiac adverse events (CAEs) that occurred in clinical trials with the single-agent plitidepsin. Demographic, clinical and pharmacological variables were explored by univariate and multivariate logistic regression analysis. Forty-six of 578 treated patients (8.0%) had at least one CAE (11 patients (1.9%) with plitidepsin-related CAEs), none with fatal outcome as a direct consequence. The more frequent CAEs were rhythm abnormalities (n = 31; 5.4%), mostly atrial fibrillation/flutter (n = 15; 2.6%). Of note, life-threatening ventricular arrhythmias did not occur. Myocardial injury events (n = 17; 3.0%) included possible ischemic-related and non-ischemic events. Other events (miscellaneous, n = 6; 1.0%) were not related to plitidepsin. Significant associations were found with prostate or pancreas cancer primary diagnosis (p = 0.0017), known baseline cardiac risk factors (p = 0.0072), myalgia present at baseline (p = 0.0140), hemoglobin levels lower than 10 g/dL (p = 0.0208) and grade ≥2 hypokalemia (p = 0.0095). Treatment-related variables (plitidepsin dose, number of cycles, schedule and/or total cumulative dose) were not associated. Electrocardiograms performed before and after plitidepsin administration (n = 136) detected no relevant effect on QTc interval. None of the pharmacokinetic parameters analyzed had a significant impact on the probability of developing a CAE. In conclusion, the most frequent CAE type was atrial fibrillation/atrial flutter, although its frequency was not different to that reported in the age-matched healthy population, while other CAEs types were rare. No dose-cumulative pattern was observed, and no treatment-related variables were associated with CAEs. Relevant risk factors identified were related to the patient’s condition and/or to disease-related characteristics rather than to drug exposure. Therefore, the current analysis supports a safe cardiac risk profile for single-agent plitidepsin in cancer patients.

The role of rituximab in combination with different CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy regimens in young patients with good-prognosis diffuse large-B-cell lymphoma remains to be defined. We aimed to compare CHOP-like chemotherapy and rituximab with CHOP-like chemotherapy alone in these patients. 824 patients who were from 18 countries; aged 18–60 years; and who had no risk factors or one risk factor according to age-adjusted International Prognostic Index (IPI), stage II–IV disease, or stage I disease with bulk were enrolled. These patients were randomly assigned to six cycles of CHOP-like chemotherapy and rituximab (n=413) or to six cycles of CHOP-like chemotherapy alone (n=411). Bulky and extranodal sites received additional radiotherapy. The primary endpoint was event-free survival; secondary endpoints were response, progression under therapy, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat and per protocol. This trial is registered at http://www.clinicaltrials.gov, NCT 00064116. After a median follow-up of 34 months (range 0·03–61), patients assigned chemotherapy and rituximab had increased 3-year event-free survival compared with those assigned chemotherapy alone (79% [95% CI 75–83] vs 59% [54–64]; difference between groups 20% [13–27], log-rank p<0·0001), and had increased 3-year overall survival (93% [90–95] vs 84% [80–88]; difference between groups 9% [3–13], log-rank p=0·0001). Event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI: after chemotherapy and rituximab, a favourable subgroup (ie, IPI=0, no bulk) could be defined from a less-favourable subgroup (ie, IPI=1 or bulk, or both). Groups did not differ in the frequency of adverse events. Rituximab added to six cycles of CHOP is an effective treatment for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows for a more refined therapeutic approach for these patients.

Purpose Panobinostat, a potent pan-deacetylase inhibitor, improved progression-free survival (PFS) in patients with relapsed and refractory multiple myeloma when combined with bortezomib and dexamethasone in a phase 3 trial, PANORAMA-1. This study aims to explore exposure–response relationship for panobinostat in this combination in a phase 1 trial, B2207 and contrast with data from historical single-agent studies. Methods Panobinostat plasma concentration–time profiles were obtained in patients from PANORAMA-1 ( n  = 12) and B2207 ( n  = 12) trials. Overall response rates (ORR) and major adverse events (AE) by panobinostat exposure were investigated in the B2207 trial. Panobinostat PK data from combination trials were contrasted with data from single-agent studies. Results At maximum tolerated dose (MTD), the geometric mean of panobinostat area under curve from 0 to 24 h (AUC0-24) was 47.5 ng h/mL (77 % CV), and maximum plasma concentration (Cmax) was 8.1 ng/mL (90 % CV). These values were comparable with exposure data obtained in PANORAMA-1, but were 20 % lower than those without dexamethasone, and ∼50 % lower from single-agent trials, likely due to enzyme induction by dexamethasone. Higher levels of panobinostat exposure were associated with higher response rates and higher incidences of diarrhea and thrombocytopenia. Conclusions Apparent panobinostat exposure–AE and exposure–ORR relationships were observed when combined with bortezomib and dexamethasone in the treatment of patients with relapsed and refractory multiple myeloma. The addition of dexamethasone facilitated best response even though plasma exposure of panobinostat was reduced. Combination with a strong enzyme inducer should be avoided in future trials to prevent further reduction of panobinostat exposure.

Asthma is a heterogeneous respiratory disease characterized by usually reversible bronchial obstruction, which is clinically expressed by different phenotypes driven by complex pathobiological mechanisms (endotypes). Within this context, during the last years several molecular effectors and signalling pathways have emerged as suitable targets for biological therapies of severe asthma, refractory to standard treatments. Indeed, various therapeutic antibodies currently allow to intercept at different levels the chain of pathogenic events leading to type 2 (T2) airway inflammation. In addition to pro-allergic immunoglobulin E (IgE), that chronologically represents the first molecule against which an anti-asthma monoclonal antibody (omalizumab) was developed, today other targets are successfully exploited by biological treatments of severe asthma. In particular, pro-eosinophilic interleukin 5 (IL-5) can be targeted by mepolizumab or reslizumab, whereas benralizumab is a selective blocker of IL-5 receptor. Moreover, dupilumab behaves as a dual receptor antagonist of pleiotropic interleukins 4 (IL-4) and 13 (IL-13). Besides these drugs that are already available in medical practice, other biologics are under clinical development such as those targeting innate cytokines, also including the alarmin thymic stromal lymphopoietin (TSLP), which plays a key role in the pathogenesis of type 2 asthma. Therefore, ongoing and future biological therapies are significantly changing the global scenario of severe asthma management. These new therapeutic options make it possible to implement phenotype/endotype-specific treatments, that are delineating personalized approaches precisely addressing the individual traits of asthma pathobiology. Such tailored strategies are thus allowing to successfully target the immune-inflammatory responses underlying uncontrolled T2-high asthma.

Interleukins (IL)-4 and -13 play a pivotal role in the pathobiology of type-2 asthma. Indeed, IL-4 is crucially involved in Th2 cell differentiation, immunoglobulin (Ig) class switching and eosinophil trafficking. IL-13 cooperates with IL-4 in promoting IgE synthesis, and also induces nitric oxide (NO) production, goblet cell metaplasia and fibroblast proliferation, as well as elicits contractile responses and hyperplasia of airway smooth muscle cells. IL-4 and IL-13 share common signaling pathways, activated by the binding of both cytokines to receptor complexes including the α-subunit of the IL-4 receptor (IL-4Rα). Therefore, the subsequent receptor dimerization is responsible for the pathophysiologic effects of IL-4 and IL-13. By selectively blocking IL-4Rα, the fully human IgG4 monoclonal antibody dupilumab behaves as a dual receptor antagonist of both IL-4 and IL-13. Through this mechanism of action, dupilumab exerts effective therapeutic actions in type-2 inflammation, thus decreasing asthma exacerbations, FeNO (fractional exhaled NO) levels, and the intake of oral corticosteroids (OCS). In addition to being approved for the add-on biological therapy of severe asthma, dupilumab has also been licensed for the treatment of nasal polyposis and atopic dermatitis.

Background Abdominoplasty is a common surgical procedure performed under general anesthesia, and although the use of TLA combined with subdural anesthesia has never been reported in abdominoplasty, it offers several benefits such as safe and effective local anesthesia and vasoconstriction. We outline our experience with the TLA technique for primary abdominoplasty over the last 7 years. Methods From 2014 to 2021, TLA and subdural anesthesia have been used in primary abdominoplasty surgeries for 106 patients. The TLA solution consisted of 25 mL of 2% lidocaine, 8 mEq of sodium bicarbonate, and 1 mL of epinephrine (1 mg/1 mL) diluted in 1000 mL of 0.9% saline solution. The solution was then injected with a 2-mm cannula into the subcutaneous adipose tissue in the suprafascial plane. The subdural anesthesia was performed at intervertebral level L1–L2 using Ropivacaine 15/18 mg in 4 ml. Results Patients aged from 32 to 75 years. The amount of tumescent solution infiltrated ranged between 500 and 1000 mL. Mean surgery time was 70 minutes, and recovery room time averaged at 240 minutes. Major complications related to the surgery were observed in 12.26% of patients, including eight hematomas and five seromas. Two patients experienced wound dehiscence, and no dystrophic scar formation was observed. Eventually, there was no need for a conversion to general anesthesia. Conclusions Tumescent local anesthesia combined with subdural anesthesia is a highly effective and safe method for performing abdominoplasty. This technique has proven to be an excellent choice for primary abdominoplasty, providing significant benefits to patients and surgeons alike due to its safe administration, precise pain management during and after surgery, and minimal postoperative side effects. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .