Thromboprophylaxis in multiple myeloma: a case-based review with practical guidelines.

Venous thromboembolism (VTE) poses a significant challenge in the context of multiple myeloma, with an incidence of up to 10% in newly diagnosed patients and varying frequency in the relapsed/refractory setting. Accurate VTE risk assessment and personalized thromboprophylaxis strategies are important parts of supportive care in myeloma. There are three validated risk assessment models for prediction of VTE risk in newly diagnosed myeloma-SAVED, IMPEDE-VTE, and PRISM. In this review, we delve into the practical applications of VTE risk prediction models in the context of current therapies. By emphasizing the necessity of a tailored approach, we underscore the importance of considering patient-specific, disease-specific, and treatment-specific risk factors in each clinical scenario, and using that data to complement the output from risk assessment models. We also provide a summary of currently available data on VTE thromboprophylaxis in myeloma, and highlight specific situations where direct oral anticoagulants should be strongly considered. Our objective is to fill the critical gaps in VTE prophylaxis and management through the analysis of specific patient cases and provide a practical overview for clinicians.

Outcomes of patients with multiple myeloma refractory to standard dose vs low dose lenalidomide.

Refractoriness to lenalidomide is an important factor determining the choice of therapy at first relapse in multiple myeloma (MM). It remains debatable if resistance to lenalidomide varies among MM refractory to standard doses vs low dose maintenance doses. In this study, we assessed the outcomes with subsequent therapies in patients with MM refractory to standard dose vs low dose lenalidomide. We retrospectively reviewed all patients with MM at our institution who received first line therapy with lenalidomide containing regimens, and assessed progression free survival (PFS) and overall survival for these patients for second line therapy, and with lenalidomide retreatment. For second line therapy, we found no difference in the PFS between standard dose refractory and low dose refractory groups (median PFS 14 months vs 14 months, p = 0.95), while the PFS for both these groups was inferior to the not refractory group (median PFS 30 months, p < 0.001 for both pairs). Similar trends were seen among these groups on lenalidomide retreatment, and on multivariable analysis. These data suggest that refractoriness to lenalidomide is not dose dependent, and definition of lenalidomide refractoriness should not depend on the dose of lenalidomide to which the disease was considered refractory.

Traumatic vertebral artery injury: Denver grade, bilaterality, and stroke risk. A systematic review and meta-analysis.

OBJECTIVE: Vertebral artery injury (VAI), a complication of blunt trauma, may cause posterior circulation stroke. An association of disease severity, classified in Denver grades, with stroke risk has not been shown. Using a literature-based analysis, the authors estimated the incidence of VAI following blunt trauma with the aim to investigate the impact of Denver grade and bilateral VAI on stroke occurrence. METHODS: A systematic review of the literature on VAI following blunt trauma was conducted, and data on its incidence, the severity per Denver grade, and stroke occurrence were collected. The incidence of VAI and stroke occurrence were analyzed cumulatively and between Denver grades. A meta-analysis with random-effects models was performed. RESULTS: Fifty-six studies including 2563 patients were identified. The overall incidence of VAI was 0.49% among blunt trauma cases and 14.5% among patients screened via any type of angiography. The incidence rates of bilateral VAI and concurrent carotid injury among all VAIs were 12.3% and 19.2%, respectively. VAI severity by Denver grade was as follows: grade I, 23.4%; grade II, 28.2%; grade III, 5.8%; grade IV, 42.1%; and grade V, 0.5%. The overall stroke risk was 5.32%, differing significantly among lesions of different Denver grades (p = 0.02). Grade III and IV lesions had the highest stroke prevalence (9.8% and 10.9% respectively), while strokes occurred significantly less frequently in patients with grade I and II lesions (1.9% and 3.0%, respectively). Denver grade V cases were too rare for meaningful analysis. Bilateral VAI was associated with a 33.2% stroke prevalence. The association between Denver grade and stroke occurrence persisted in a sensitivity subanalysis including only unilateral cases (p = 0.03). CONCLUSIONS: VAI complicates a small yet nontrivial fraction of blunt trauma cases, with Denver grade IV lesions being the most common. This is the first study to document a significantly higher stroke prevalence among grade III and IV VAIs compared with grade I and II VAIs independently from bilaterality. Bilateral VAIs carry a significantly higher stroke rate.

A proteomic atlas of kidney amyloidosis provides insights into disease pathogenesis.

The mechanisms of tissue damage in kidney amyloidosis are not well described. To investigate this further, we used laser microdissection-mass spectrometry to identify proteins deposited in amyloid plaques (expanded proteome) and proteins overexpressed in plaques compared to controls (plaque-specific proteome). This study encompassed 2650 cases of amyloidosis due to light chain (AL), heavy chain (AH), leukocyte chemotactic factor-2-type (ALECT2), secondary (AA), fibrinogen (AFib), apo AIV (AApoAIV), apo CII (AApoCII) and 14 normal/disease controls. We found that AFib, AA, and AApoCII have the most distinct proteomes predominantly driven by increased complement pathway proteins. Clustering of cases based on the expanded proteome identified two ALECT2 and seven AL subtypes. The main differences within the AL and ALECT2 subtypes were driven by complement proteins and, for AL only, 14-3-3 family proteins (a family of structurally similar phospho-binding proteins that regulate major cellular functions) widely implicated in kidney tissue dysfunction. The kidney AL plaque-specific proteome consisted of 24 proteins, including those implicated in kidney damage (α1 antitrypsin and heat shock protein ß1). Hierarchical clustering of AL cases based on their plaque-specific proteome identified four clusters, of which one was associated with improved kidney survival and was characterized by higher overall proteomic content and 14-3-3 proteins but lower levels of light chains and most signature proteins. Thus, our results suggest that there is significant heterogeneity across and within amyloid types, driven predominantly by complement proteins, and that the plaque protein burden does not correlate with amyloid toxicity.

Outcomes of patients with primary refractory multiple myeloma in the era of triplet and quadruplet induction therapy.

Patients with multiple myeloma (MM) who do not respond to initial therapy have worse outcomes than primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not yet been studied. We reviewed patients with MM treated with triplet/quadruplet therapy at our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. We identified 1127 patients, of whom 1086 were evaluated for hematologic responses after 4 to 6 cycles. Of these, 93.3% (1013) had evidence of response, whereas 6.7% (73) had primary refractory disease. With a median overall survival (OS) of 51.3 months, patients with primary refractory disease had an increased risk of shorter survival in univariable and multivariable analyses (hazard ratio [HR], 3.5 [95% confidence interval (CI), 2.5-4.9]; HR, 4.3 [95% CI, 2.6-6.9], respectively). In the subgroup analysis of patients with primary refractory disease, those who received second-line autologous stem cell transplantation (ASCT) had increased second progression-free survival (20.9 vs 8.1 months; P < .01) and second OS (74.7 vs 31.3 months; P = .02) compared with patients who did not. We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population.

Navigating paediatric virology through the COVID­19 era (Review).

The present review article presents the key messages of the 8th Workshop on Paediatric Virology organised virtually by the Institute of Paediatric Virology based on the island of Euboea in Greece. The major topics covered during the workshop were the following: i) New advances in antiviral agents and vaccines against cytomegalovirus; ii) hantavirus nephropathy in children; iii) human rhinovirus infections in children requiring paediatric intensive care; iv) complications and management of human adenovirus infections; v) challenges of post­coronavirus disease 2019 (COVID­19) syndrome in children and adolescents; and vi) foetal magnetic resonance imaging in viral infections involving the central nervous system. The COVID­19 era requires a more intensive, strategic, global scientific effort in the clinic and in the laboratory, focusing on the diagnosis, management and prevention of viral infections in neonates and children.

Thrombosis in multiple myeloma: Risk estimation by induction regimen and association with overall survival.

Lenalidomide-containing (R) triplet and quadruplet regimens are the standard of care for multiple myeloma (MM) and have been shown to increase the risk of thrombosis. The association between thromboembolism (TE) and survival in the novel multidrug era is not yet delineated. In this study, we evaluated the incidence of TE during the first year of MM diagnosis, its association with the type of induction regimen, and its impact on overall survival. We studied 672 newly diagnosed MM (NDMM) patients who received a triplet or quadruplet lenalidomide-based induction at the Mayo Clinic, Rochester. TE was diagnosed in 83 patients (12.4%). Of these, 56 (8.3%) had a deep venous thrombosis (DVT), 23 (3.4%) had a pulmonary embolism (PE) with or without the DVT, and 4 (0.6%) patients had a stroke. Carfilzomib-Rd (KRd) had the highest risk of TE (21.1%, 18/85), followed by quadruplets (11.1%, 5/45), bortezomib-Rd (9.6%, 51/531), and 0/11 (0%), treated with other lenalidomide-containing regimens. The difference in TE risk between KRd and the other regimens was statistically significant (OR = 2.6, p < .01). Nine patients developed a TE before being exposed to any treatment. Survival was significantly lower among patients that developed a TE (66 vs. 133 months, p < .01). The association of TE with reduced survival demonstrated in univariate analysis (HR = 2.2, 95% CI = 1.6-3.3) was maintained in the multivariable analysis adjusted for high-risk interphase fluorescence in situ hybridization (FISH), sex, age, receipt of an upfront transplant, the response at induction, and the International Staging System (ISS) (HR = 2.61, CI = 1.74-3.9). We conclude that TE is an important aspect of MM management, and effective management is especially relevant in the novel treatment era.

Impact of the time interval between end of induction and autologous hematopoietic transplantation in newly diagnosed patients with multiple myeloma.

Multiple Myeloma patients eligible for autologous hematopoietic transplantation (AHT) typically receive 3-6 cycles of induction therapy before transplant. The last induction cycle is completed 2-4 weeks prior to mobilization. We evaluated the impact of the time interval between end of induction and AHT on progression-free survival (PFS) and overall survival (OS). A total of 1055 patients who underwent AHT were identified. The median time to transplant (TTT) was 33 days (27-42 quartile range). Patients with less than 33 days of TTT had significantly prolonged PFS (35.6 vs. 32.1 months, p < 0.03) but non-significant OS differences compared to those with more than 33 days. Quartile comparisons showed that patients in the 1st quartile (less than 27 days) had significantly prolonged PFS (36.7 vs. 30.9 months, p < 0.01) compared to the 4th quartile group (more than 42 days). In a subgroup analysis of patients with partial or worse biochemical response prior to transplant, patients in the 1st quartile had significantly prolonged PFS (37.7 vs. 28.7 months, p < 0.04) compared to the 4th quartile group. In conclusion, we showed that a prolonged TTT is associated with inferior outcomes compared to tighter chemotherapy schedules. This finding was especially prevalent in patients with partial response at induction.

Utility of PET/CT in assessing early treatment response in patients with newly diagnosed multiple myeloma.

Multiple myeloma (MM) is a plasma cell malignancy that is characterized by diverse clinical presentations. Although biochemical assessment of disease activity is commonly used to monitor treatment response, findings on magnetic resonance imaging and positron emission tomography (PET)/computed tomography (CT), among other imaging modalities, have proven to harbor prognostic value. We sought to corroborate these findings by examining the prognostic significance of fluorodeoxyglucose PET/CT scanning in the setting of newly diagnosed MM. We retrospectively analyzed 195 patients with a PET/CT available at diagnosis and at 6 months posttreatment to examine their value as an adjuvant metric to conventional hematologic responses in terms of time to next treatment (TTNT) and overall survival (OS). The median TTNT and OS for the entire cohort were 24.6 months (95% confidence interval [CI], 20.4-29.1) and 79 months (95% CI, 63.1-119.1), respectively. When comparing PET/CT negative (-) with PET/CT positive (+) patients, we found significantly prolonged median TTNT (55.2 vs 17.8 months, P < .0001) and OS (unreached vs 60.8 months, P < .0001) in the former group. We then examined the additive value of PET/CT on the hematologic response achieved at 6 months and found that PET/CT (-) is associated with significantly increased median TTNT and OS for the very good partial response (VGPR) group and the less than VGPR group. Importantly, PET/CT retained prognostic significance after adjusting for multiple other predictive variables. We conclude that a PET/CT (-) at 6 months confers a significant prognostic advantage for patients with newly diagnosed MM and adds significant value to the hematologic response assessment.

Minimal Residual Disease Assessment in Multiple Myeloma Patients: Minimal Disease With Maximal Implications.

Multiple Myeloma (MM), the second most common hematologic malignancy, has been the target of many therapeutic advances over the past two decades. The introduction of novel agents, such as proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, along with autologous hematopoietic stem cell transplantation (ASCT) in the current standard of care, has increased the median survival of myeloma patients significantly. Nevertheless, a curative treatment option continues to elude us, and MM remains an incurable disease, with patients relapsing even after achieving deep conventionally defined responses, underscoring the need for the development of sensitive methods that will allow for proper identification and management of the patients with a higher probability of relapse. Accurate detection of Minimal Residual Disease (MRD) from a bone marrow biopsy represents a relatively new approach of evaluating response to treatment with data showing clear benefit from obtaining MRD(-) status at any point of the disease course. As life expectancy for patients with MM continues to increase and deep responses are starting to become the norm, establishing and refining the role of MRD in the disease course is more relevant than ever. This review examines the different methods used to detect MRD and discusses future considerations regarding the implementation in day-to-day clinical practice and as a prospective primary endpoint for clinical trials.

Endocardial late potentials during sinus rhythm define the re-entry circuit of ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiomyopathy characterized by progressive fibro-fatty replacement of the right ventricular myocardium. We report a case where mapping of endocardial potentials during sinus rhythm identified the re-entry circuit of a recurrent ventricular tachycardia in a patient with ARVC. The tachycardia was subsequently ablated successfully.

The impact of vagotonic, adrenergic, and random type of paroxysmal atrial fibrillation on left atrial ablation outcomes.

BACKGROUND: Accumulating data have shown that the autonomic nervous system is strongly implicated in the genesis of atrial fibrillation (AF). The aim of this study was to assess the efficacy of a single ablation procedure in patients with vagotonic, adrenergic and random type of paroxysmal AF. METHODS AND RESULTS: The clinical records of consecutive patients with symptomatic, drug-refractory paroxysmal AF who underwent pulmonary vein antral isolation were analysed. The study population consisted of 104 patients (64 males, mean age 57.9 ± 10.9 years) with paroxysmal AF. Based on AF triggers, patients were classified in those with vagotonic (31.7%), adrenergic (17.3%) and random AF (51%). Subjects with adrenergic and random AF tended to be older (p: 0.104) and displayed a higher incidence of hypertension (p: 0.088) compared with those with vagotonic AF. Following a mean follow-up period of 14.7 ± 7.4 months, 74 patients were free from arrhythmia recurrence (71.2%). Late arrhythmia recurrence (>3 months from the index procedure) occurred in 33.3%, 16.7% and 30.2% of patients with vagotonic, adrenergic and random AF, respectively (p: 0.434). Cox regression analysis showed that early AF recurrence [hazard ratio (HR) 15.76; 95% confidence interval (CI) 5.456-45.566, p: <0.001], left atrial volume (HR 0.969; 95% CI 0.942-0.996, p: 0.025) and statin use (HR 6.828; 95% CI 2.078-22.437 p: 0.002) were independent predictors of late arrhythmia recurrence. CONCLUSIONS: In this study cohort, the type of paroxysmal AF was not associated with arrhythmia recurrence following left atrial ablation.

Hyponatremic renal pseudofailure and massive ascites following normal vaginal delivery: a diagnostic and therapeutic challenge.

We report the fifth, to our knowledge, published case of spontaneous intraperitoneal bladder rupture after normal, vacuum-assisted in this occasion, vaginal delivery of a 29-year-old female patient. Diagnosis was established not by imaging or intraoperative findings, but, rather, by the examination and comparison of patient's blood, urine, and peritoneal fluid urea and creatinine levels, which, due to the patient's delayed referral and sequent development of uroperitoneum and hyponatremic renal pseudofailure, were abnormal and characteristic of her medical condition. The patient was successfully managed conservatively and was discharged the sixth day after admission. Due to the rare nature of such medical condition and based on the relative literature, we propose a diagnostic and management algorithm for such cases.

Novel indexes of heterogeneity of ventricular repolarization in subjects with early repolarization pattern.

AIM: The presence of early repolarization (ER) in inferior or inferolateral leads has been associated with malignant arrhythmias and increased mortality. Transmural dispersion of repolarization (TDR) has been proposed to underlie arrhythmogenesis in J-wave syndromes. The present study investigated specific electrocardiographic (ECG) markers including Tpeak-Tend interval and (Tpeak-Tend)/QT ratio that reflect TDR in subjects with ER. METHODS AND RESULTS: The ECGs of 47 healthy individuals (43 males, mean age: 45.7 ± 13.1 years) with an ER pattern in lateral (n = 15) or infero-lateral leads (n = 32) who successfully completed an exercise stress test were analysed at rest, peak workload, and recovery. The ER pattern was defined as slurring or notching of the terminal part of the QRS complex (J-point) ≥ 1 mm, in at least two contiguous leads. Thirty-five age- and sex-matched healthy subjects without ER (28 males, mean age: 48.6 ± 10.2 years) served as comparative controls. Subjects with ER displayed increased Tpeak-Tend interval in lead V(2), Tpeak-Tend dispersion of the precordial leads, and (Tpeak-Tend)/QT ratio in lead V(2) compared with those without ER in all three phases of the exercise test (P < 0.05). In addition, Tpeak-Tend dispersion and the (Tpeak-Tend)/QT ratio in lead V(2) were significantly increased at recovery phase compared with peak exercise only in subjects with ER (P< 0.05). There were no significant differences among the studied ECG parameters regarding the ER location (lateral vs. infero-lateral), the ER type (slurring or notching), or the maximum J-point amplitude (≥ 1.5 vs. <1.5 mm) at baseline ECGs. CONCLUSIONS: Individuals with ER display an increased TDR that may be related to an increased arrhythmic risk.

Current ablation strategies for persistent and long-standing persistent atrial fibrillation.

Atrial fibrillation (AF) is associated with an increased risk of cardiac and overall mortality. Restoration and maintenance of sinus rhythm is of paramount importance if it can be accomplished without the use of antiarrhythmic drugs. Catheter ablation has evolved into a well-established treatment option for patients with symptomatic, drug-refractory AF. Ablation strategies which target the pulmonary veins are the cornerstone of AF ablation procedures, irrespective of the AF type. Ablation strategies in the setting of persistent and long-standing persistent AF are more complex. Many centers follow a stepwise ablation approach including pulmonary vein antral isolation as the initial step, electrogram-based ablation at sites exhibiting complex fractionated atrial electrograms, and linear lesions. Up to now, no single strategy is uniformly effective in patients with persistent and long-standing persistent AF. The present study reviewed the efficacy of the current ablation strategies for persistent and long-standing persistent AF.

Long-term prognosis of asymptomatic individuals with spontaneous or drug-induced type 1 electrocardiographic phenotype of Brugada syndrome.

BACKGROUND: Risk stratification of asymptomatic individuals with type 1 electrocardiogram (ECG) phenotype of Brugada syndrome (BS) still remains controversial. This study investigated the long-term prognosis of asymptomatic subjects with spontaneous or drug-induced type 1 ECG pattern of BS. METHODS AND RESULTS: Data from 33 apparently healthy individuals (30 males; age, 43.6 ± 13.4 years) with spontaneous (n = 12) or drug-induced (n = 21) type 1 ECG pattern of BS were retrospectively analyzed. Thirteen subjects (39.4%) displayed a positive family history of BS and/or sudden cardiac death. Electrophysiologic study was performed in 16 subjects, and programed right ventricular stimulation induced polymorphic ventricular tachycardia in 9 (56.3%) of them. A cardioverter defibrillator was implanted in 6 cases. During a mean follow-up period of 5.3 ± 2.8 years, all subjects remained asymptomatic. None of them had syncope or cardioverter defibrillator discharges due to ventricular arrhythmias. CONCLUSIONS: Asymptomatic individuals with spontaneous or drug-induced type 1 ECG phenotype of BS display a benign clinical course during long-term follow-up.

A case of severe asymptomatic aortic coarctation in an adult female.

Coarctation of the aorta is typically a disease of childhood and early adulthood, and there is a reduced life expectancy in patients who have not undergone correction. Survival to older age is rare, due to severe cardiovascular complications. We describe the case of a woman first diagnosed with coarctation of aorta at an advanced age.