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Infertility is increasing worldwide, as well as in Italy, and fallopian tube pathology represents one of the most impacting causes of infertility for multiple women. Indeed, tubal patency assessment is a crucial step in medical evaluation for women attending an in vitro fertilization (IVF) center. Currently, different methods for tubal investigation are available, such as chromosalpingoscopy, hysterosalpingography (HSG), and hysterosalpingo-contrast sonography (HyCoSy). This diagnostic exam is performed by ultrasonography and an air-water-based contrast agent represented by air-water, or foam solution (HyFoSy). An additional side benefit of these assessment tests is a fertility-enhancing effect, thanks to a positive effect defined as "tubal flushing," which in current literature is more strongly associated with HyFoSy with respect to HyCoSy. In this report, we present a case of a 34-year-old woman presented to our attention at the Reproductive and Physiopathology Unit of Sandro Pertini Hospital, Rome, in 2023, with unexplained infertility for 3.1 years of free sexual intercourse with a partner who did not report sperm abnormalities. Subsequently, in this exam, the woman spontaneously conceived in the same menstrual cycle that the 4D-HyCoSy was performed, without any additional fertility enhancement interventions. In this case report, we also include an updating review of the current literature regarding the insurgence of spontaneous pregnancy after this technique in order to explore the physiopathological and etiopathogenetic mechanisms underlying the achievement of spontaneous pregnancy and to confront our case with other recent works published. According to our clinical experience and the current literature, 4D-HyCoSy is the easiest, safest, and cheapest diagnostic exam for investigating tubal patency, which can lead to medical success in some cases of "unexplained infertility" as the achievement of a spontaneous pregnancy., Competing Interests: All authors declare no conflict of interest., (Copyright © 2024 Francesco Bisogni et al.)

During the SARS-CoV-2 pandemic, many countries directed substantial resources toward genomic surveillance to detect and track viral variants. There is a debate over how much sequencing effort is necessary in national surveillance programs for SARS-CoV-2 and future pandemic threats. We aimed to investigate the effect of reduced sequencing on surveillance outcomes in a large genomic data set from Switzerland, comprising more than 143k sequences. We employed a uniform downsampling strategy using 100 iterations each to investigate the effects of fewer available sequences on the surveillance outcomes: (i) first detection of variants of concern (VOCs), (ii) speed of introduction of VOCs, (iii) diversity of lineages, (iv) first cluster detection of VOCs, (v) density of active clusters, and (vi) geographic spread of clusters. The impact of downsampling on VOC detection is disparate for the three VOC lineages, but many outcomes including introduction and cluster detection could be recapitulated even with only 35% of the original sequencing effort. The effect on the observed speed of introduction and first detection of clusters was more sensitive to reduced sequencing effort for some VOCs, in particular Omicron and Delta, respectively. A genomic surveillance program needs a balance between societal benefits and costs. While the overall national dynamics of the pandemic could be recapitulated by a reduced sequencing effort, the effect is strongly lineage-dependent-something that is unknown at the time of sequencing-and comes at the cost of accuracy, in particular for tracking the emergence of potential VOCs.IMPORTANCESwitzerland had one of the most comprehensive genomic surveillance systems during the COVID-19 pandemic. Such programs need to strike a balance between societal benefits and program costs. Our study aims to answer the question: How would surveillance outcomes have changed had we sequenced less? We find that some outcomes but also certain viral lineages are more affected than others by sequencing less. However, sequencing to around a third of the original effort still captured many important outcomes for the variants of concern such as their first detection but affected more strongly other measures like the detection of first transmission clusters for some lineages. Our work highlights the importance of setting predefined targets for a national genomic surveillance program based on which sequencing effort should be determined. Additionally, the use of a centralized surveillance platform facilitates aggregating data on a national level for rapid public health responses as well as post-analyses., Competing Interests: The authors declare no conflict of interest.

Introduction: The study aims to compare the efficacy and safety of bulking agents and single-incision slings in the treatment of urinary incontinence in 159 patients during a 29-month follow-up period., Material and Methods: Of the 159 patients suffering from stress urinary incontinence, 64 were treated with bulking agents (PAHG Bulkamid ® ) and 75 with a single-incision sling (Altis ® ). The ICIQ-UI-SF (Incontinence Questionnaire-Urine Incontinence-Short Form), PISQ-12 (Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaires short form), FSFI (Female Sexual Function Index), FSDS (Female Sexual Distress Scale), and PGI-I (Patient Global Improvement Index) were used to assess efficiency and quality of life., Results: The bulking agents showed high efficacy and safety during the 29-month follow-up. Post-operative complications were recorded in both groups, with only two significant differences. The Bulkamid group experienced no pain, while 10.8% of the ALTIS group experienced groin pain and 5% experienced de novo urgency. Furthermore, patients treated with bulking agents experienced reduced nicturia (0.78 vs. 0.92 in patients treated with single-incision slings.). In both groups, we noticed a significant improvement in QoL (quality of life), with a halved ICIQ-UI-SF (International Consultation on Incontinence Questionnaire-Urine Incontinence-Short Form) score which was completed to assess the impact of urine symptoms. After 24 months of therapy, the Bulkamid group saw a decrease from 14.58 ± 5.11 at baseline to 5.67 ± 1.90 ( p < 0.0001), whereas the ALTIS group experience a decrease from 13.75 ± 5.89 to 5.83 ± 1.78. Similarly, we observed an improvement in sexual function, with the number of sexually active patients increasing from 29 to 44 (56.4%) in the Bulkamid group ( p = 0.041) and from 31 to 51 (61.7%) in the ALTIS group ( p = 0.034). According to the most recent statistics, the PISQ-12, FSFI, and FSDS scores all demonstrated an improvement in women's sexual function., Conclusions: In terms of efficacy and safety, bulking agents had notable results over the 29-month follow-up period. Furthermore, the patients treated with bulking agents reported a lower incidence of postoperative complications and a no discernible difference in terms of quality of life and sexual activity compared to the ones treated with single-incision slings. Bulking agents can be considered a very reliable therapeutic option based on accurate patient selection.

Background: The aim of the study was to demonstrate the efficacy of sequential combined treatment with transobturator tape (TOT) followed by posterior tibial nerve stimulation (PTNS) in patients with mixed urinary incontinence (MUI); quality of life and patients' satisfaction was also assessed., Methods: Retrospective analysis on women affected by MUI with prevalent Stress Urinary Incontinence (SUI) component. Women, divided in 2 groups, underwent different treatments, TOT vs. TOT+PTNS. Population was assessed by medical history, previous pelvic surgery, clinical exam, urodynamic exams, pelvic ultrasound examination, and questionnaires (The International Consultation on Incontinence Questionnaire Short Form, Overactive Bladder Questionnaire, Health Related Quality of Life) comparing them before and after 12 weeks after treatment., Results: One hundred twelve women were enrolled in the study. The mean age was 57.96±7.34 in the first group (N.=60) and 58.29±6.14 in the second group (N.=52). Peak flow (mL/s) statistically improved after treatment, 22.23±4.29 (TOT) vs. 24.81±5.8 (TOT+PTNS). First voiding desire (mL) improved significantly between the two groups 108.72±19.24 vs. 142.43±19.98. Maximum cystometric capacity (mL) in the TOT group at 12-weeks was 328.76±82.44 vs. TOT+PTNS group of 396.26±91.21. Detrusor pressure at peak flow(cmH2O) showed a greater improvement in TOT+PTNS than TOT alone 14.45±6.10 vs. 11.89±54.49. At 12-week, urinary diary and quality of life improved in terms of urgent urination events, mean number of voids, urge symptoms and nocturia events. The Patient Impression of Global Improvement (PGI-I) after 3 months was better in combined group., Conclusions: Combined and sequential TOT+PTNS is more effective compared to TOT alone in MUI patients with prevalent SUI component.

Background: Upper limb (UL) motor impairment following stroke is a leading cause of functional limitations in activities of daily living. Robot-assisted therapy supports rehabilitation, but how its efficacy and the underlying neural mechanisms depend on the time after stroke is yet to be assessed., Aim: We investigated the response to an intensive protocol of robot-assisted rehabilitation in sub-acute and chronic stroke patients, by analyzing the underlying changes in clinical scores, electroencephalography (EEG) and end-effector kinematics. We aimed at identifying neural correlates of the participants' upper limb motor function recovery, following an intensive 2-week rehabilitation protocol., Design: Prospective cohort study., Setting: Inpatients and outpatients from the Neurorehabilitation Unit of Pisa University Hospital, Italy., Population: Sub-acute and chronic stroke survivors., Methods: Thirty-one stroke survivors (14 sub-acute, 17 chronic) with mild-to-moderate UL paresis were enrolled. All participants underwent ten rehabilitative sessions of task-oriented exercises with a planar end-effector robotic device. All patients were evaluated with the Fugl-Meyer Assessment Scale and the Wolf Motor Function Test, at recruitment (T0), end-of-treatment (T1), and one-month follow-up (T2). Along with clinical scales, kinematic parameters and quantitative EEG were collected for each patient. Kinematics metrics were related to velocity, acceleration and smoothness of the movement. Relative power in four frequency bands was extracted from the EEG signals. The evolution over time of kinematic and EEG features was analyzed, in correlation with motor recovery., Results: Both groups displayed significant gains in motility after treatment. Sub-acute patients displayed more pronounced clinical improvements, significant changes in kinematic parameters, and a larger increase in Beta-band in the motor area of the affected hemisphere. In both groups these improvements were associated to a decrease in the Delta-band of both hemispheres. Improvements were retained at T2., Conclusions: The intensive two-week rehabilitation protocol was effective in both chronic and sub-acute patients, and improvements in the two groups shared similar dynamics. However, stronger cortical and behavioral changes were observed in sub-acute patients suggesting different reorganizational patterns., Clinical Rehabilitation Impact: This study paves the way to personalized approaches to UL motor rehabilitation after stroke, as highlighted by different neurophysiological modifications following recovery in subacute and chronic stroke patients.

The scarcity of malignant Hodgkin and Reed-Sternberg cells hampers tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). By contrast, liquid biopsies show promise for molecular profiling of cHL due to relatively high circulating tumour DNA (ctDNA) levels 1-4 . Here we show that the plasma representation of mutations exceeds the bulk tumour representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumours, we demonstrate Hodgkin and Reed-Sternberg ctDNA shedding to be shaped by DNASE1L3, whose increased tumour microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R mutations that are dependent on IL-13 signalling and therapeutically targetable with IL-4Rα-blocking antibodies. Finally, using PhasED-seq 5 , we demonstrate the clinical value of pretreatment and on-treatment ctDNA levels for longitudinally refining cHL risk prediction and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL, as well as capturing molecularly distinct subtypes with diagnostic, prognostic and therapeutic potential., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Here we evaluated the epigenomic and transcriptomic profile of XPO1 mutant chronic lymphocytic leukaemia (CLL) and their clinical phenotype. By ATAC-seq, chromatin regions that were more accessible in XPO1 mutated CLL were enriched of binding sites for transcription factors regulated by pathways emanating from the B-cell receptor (BCR), including NF-κB signalling, p38-JNK and RAS-RAF-MEK-ERK. XPO1 mutant CLL, consistent with the chromatin accessibility changes, were enriched with transcriptomic features associated with BCR and cytokine signalling. By combining epigenomic and transcriptomic data, MIR155HG, the host gene of miR-155, and MYB, the transcription factor that positively regulates MIR155HG, were upregulated by RNA-seq and their promoters were more accessible by ATAC-seq. To evaluate the clinical impact of XPO1 mutations, we investigated a total of 957 early-stage CLL subdivided into 3 independent cohorts (N = 276, N = 286 and N = 395). Next-generation sequencing analysis identified XPO1 mutations as a novel predictor of shorter time to first treatment (TTFT) in all cohorts. Notably, XPO1 mutations maintained their prognostic value independent of the immunoglobulin heavy chain variable status and early-stage prognostic models. These data suggest that XPO1 mutations, conceivably through increased miR-155 levels, may enhance BCR signalling leading to higher proliferation and shorter TTFT in early-stage CLL., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Adequate iodine intake is of crucial importance in pregnancy to meet the thyroid hormone needs of both mother and fetus. In the present study, undertaken as a part of the surveillance actions following the introduction in Italy of a national salt iodination program in 2005, the iodine intake was investigated in 123 pregnant women and 49 control women living in the same area of central Italy. All the participants were screened for urinary iodine concentration (UIC), serum level of thyrotropin, free-thyroxine, free-triiodothyronine, and thyroid volume. Moreover, they were provided with a questionnaire on the use of iodine-containing salt or supplements. Control women had a median UIC of 102 µg/L, consistent with an iodine sufficiency, while in pregnant women the median UIC value was 108 µg/L, lower than the endorsed UIC of 150 µg/L. In addition, pregnant women showed a significantly increased median thyroid volume compared to controls. Interestingly, the median UIC did not differ between pregnant women not using iodine-containing salt or supplements and those regularly consuming iodized salt alone, while pregnant women with a daily intake of iodine-containing supplements had an adequate median UIC (168 µg/L). In conclusion, the data reported here showed that pregnant women and their fetuses are still exposed to the detrimental effects of iodine deficiency and that the consumption of iodine-containing supplements should be recommended in pregnancy.

Background: Pharmacovigilance agencies did not collect data regarding menstrual changes after COVID-19 vaccination even if many women experienced it. Our aim was to evaluate whether COVID-19 vaccination is associated with secondary changes in menstrual cycle and to assess both quality of life (QoL) and sexual function (SF)., Methods: This study is a retrospective analysis referred to our Department from January 2021 to December 2021. The study cohort responded to same questionnaires before the second dose of vaccination (referring to previous 3 months) and 3 months after that (referring to three menstrual cycles after full-dose vaccination). The surveys administered were FSFI, FSDS, SF-36, MEDI-Q and the VAS-scale for dysmenorrhea., Results: Four-hundred-nineteen vaccinated women were included in the study. The survey did not show a significant change in menstrual cycle length before and after COVID-19 vaccine (5.88±3.67 vs. 4.97±2.89, P=0.21); the interval between periods was significantly higher after a full-cycle vaccination (28.32±7.34 vs. 32.38±7.45, P<0.02); 32 patients (7.6%) developed amenorrhea after the second dose; VAS Scale did not change significantly (median range 3 (3-5) vs. 4 (3-6), P=0.20). MEDI-Q did not show significant variations before and after the vaccination (43.21±11.65 vs. 40.28±9.88, P=0.35). QoL and SF did not change significantly (FSFI median 27 [24-29] vs. 28 [25-30], P=0.12, FSDS median 9 [5-11] vs. 8 [4-12], P=0.22), SF-36 median 81 [70-85] vs. 82 [72-86], P=0.43)., Conclusions: COVID-19 vaccination is associated with a significant change in intervals between menstrual cycles without other alterations in menstrual characteristics, in QoL or SF.

Background: The aim of this study was to demonstrate that the implementation of remote medical care in the management of patients suffering from specific urogynecological diseases can be a valid alternative to outpatient visits leading to a huge saving of resources which can be used for real emergencies. Therefore, the primary aim of this study was to demonstrate that patients treated with telehealth had the same improvement in symptoms and Quality of Life as those treated with outpatient visits., Methods: Observational analysis on women with urogynecological diseases was performed during restrictive measures period. One group of patients was assessed in the clinic and one group by video consultations. The population answered Female Sexual Function Index (FSFI), Female Sexual Distress Scale (FSDS), the Overactive Bladder Questionnaire Symptoms and Health-Related Quality of Life Short-Form Symptoms (OAB-Q), Prolapse Quality of Life Questionnaire (P-QoL), the Pelvic Pain and Urinary/Frequency Patient Symptom Scale (PUF) scores, the Short Form Health Survey questionnaires (SF-36) during the first visit and after 12 weeks. The primary endpoint was to evaluate the change in symptoms after the outpatient and telemedicine visit. The secondary endpoint was the evaluation of the telemedicine impact on the Quality of Life and sexual function., Results: One hundred twenty-five patients were considered. Symptoms of overactive bladder, genitourinary syndrome, and recurrent urinary infections improved significantly in both groups with no significant differences. Sexual activity increased significantly in both groups with a significant change in FSFI and FSDS values. The SF-36 showed a significant change 12 weeks after the visit in both groups., Conclusions: Telemedicine is equally useful and effective as the outpatient visits in patients suffering from urogynecological diseases.

Background: The aim of this study was to compare the efficacy of vaginal native tissue repair (VNTR) combined with tension-free transobturator tape (TVT-O) or pelvic floor muscle training (PFMT) in terms of quality of life (QoL) and sexual function (SF) in women affected by anterior defect and occult stress urinary incontinence (OSUI)., Methods: One hundred forty-seven patients with symptomatic anterior defect with OSUI underwent VNTR. In 71 patients TVT-O was inserted and 76 underwent PFMT after surgery. Clinical exam, 3-day voiding diary and urodynamic testing were evaluated in preoperative and postoperative times. Specific questionnaires were also administered, in order to indagate disease perception and the impact on QoL and SF., Results: Nine patients had postoperative pain in the TVT-O group vs. 0 patients in the PMFT group (P=0.001) and 7 patients reported de novo urgency vs. 3 in the two groups, respectively. At 12 weeks follow-up (FU), the first voiding desire was at 88.12+19.70 mL in VNTR+TOT vs. 102.29+19.13 (P=0.03); the mean number of voids (24 hours) was 9.95±2.66 vs. 6.14±1.77 (P=0.04), respectively. No significant differences in terms of QoL and SF were shown., Conclusions: This retrospective study suggests that VNTR+TVT-O and VNTR+PMFT have the same efficacy in terms of QoL and SF, with several post-operative complications, even if minor, in patients treated with combined surgery.

Objectives: The aim of the study is to demonstrate the best stress urinary incontinence (SUI) surgical technique for women with a Body mass index higher than 30. The results of Transvaginal Tension Free Vaginal Tape-Obturator and Mini-sling surgery were analyzed and compared through both clinical examination and standardized questionnaires at 36 months of follow-up., Materials and Methods: This is a retrospective multicenter study over 159 women with SUI who underwent surgery. Seventy-eight women underwent TVT-O and 81 Mini-sling technique. Intra and post-operative complications were recorded. Patients were monitored for 36 months by analyzing symptoms, voiding diary, quality of life and sexual activity through standardized questionnaires., Results: Complications had a low incidence in both groups and inter-group differences were superimposable. Only groin pain was statistically higher after TVT-O than after Mini-sling (12.8% vs1.2%, p = 0.03). At 36 months of follow-up, a statistically significant decrease in Positive stress test (%) and Q-Tip test (grade) was observed in both groups with no differences between them (p = 0.54 and p = 0.32 respectively). The mean number of daily voids was higher after TVT-O (p = 0.04) than after Altis (p = 0.22) with a significant difference in favor of the Altis group (p = 0.03). After 36 months, there were no significant differences between groups in terms of quality of life and sexual activity. PGI-I did not show any difference between groups (p = 0.21)., Conclusion: TVT-O and Minisling had the same efficacy and results in the surgical treatment of SUI in obese women. Both techniques relieved their symptoms and improved their quality of life without any significant difference except for a lower incidence of post- Mini-sling complications., Competing Interests: Declaration of competing interest Authors have no relevant conflicts of interest to this article., (Copyright © 2023. Published by Elsevier B.V.)

Background: The aim of this study was to evaluate the effects of breast cancer on the ovarian response and on oocyte quality following controlled ovarian hyperstimulation (COH)., Methods: This retrospective case-control study evaluated the effects of breast cancer on the ovarian response and on the oocyte quality. Oncological patients with breast cancer undergoing controlled ovarian stimulation cycles for fertility preservation, and age- and date-matched controls undergoing COH for in vitro fertilization (IVF) for male or tubal factor infertility were included in the study. Two hundred and ninety-four women were enrolled: 105 affected by breast cancer and 189 healthy women in the control group. Both groups were comparable in terms of age, BMI, and AMH value. Maximal estradiol levels on the triggering day, duration of stimulation, total amount of gonadotropins administered, number of oocytes retrieved, rate of metaphase 2 oocyte production, and numbers of immature and dysmorphic oocytes were analyzed., Results: Considering factors influencing the oocyte quality, such as age, BMI, AMH, duration of stimulation, E2 level on the triggering day, total FSH cumulative dose, stage, histotype, BRCA status, and hormone receptors, the univariate and multivariate analyses identified breast cancer as a risk factor for the presence of dysmorphic oocytes., Conclusions: The diagnosis of breast cancer does not seem to be associated with the impairment of the ovarian reserve, but is linked to a worsening oocyte quality.

Studies conducted in healthy subjects have clearly shown that different hypnotic susceptibility, which is measured by scales, is associated with different functional equivalence between imagery and perception/action (FE), cortical excitability, and information processing. Of note, physiological differences among individuals with high (highs), medium (mediums), and low hypnotizability scores (lows) have been observed in the ordinary state of consciousness, thus independently from the induction of the hypnotic state, and in the absence of specific suggestions. The potential role of hypnotic assessment and its relevance to neurological diseases have not been fully explored. While current knowledge and therapies allow a better survival rate, there is a constant need to optimize rehabilitation treatments and quality of life. The aim of this paper is to provide an overview of hypnotizability-related features and, specifically, to discuss the hypothesis that the stronger FE, the different mode of information processing, and the greater proneness to control pain and the activity of the immune system observed in individuals with medium-to-high hypnotizability scores have potential applications to neurology. Current evidence of the outcome of treatments based on hypnotic induction and suggestions administration is not consistent, mainly owing to the small sample size in clinical trials and inadequate control groups. We propose that hypnotic assessment may be feasible in clinical routine and give additional cues into the treatment and rehabilitation of neurological diseases., (© 2022. The Author(s).)

Background: The incidence of median nerve injuries in pediatric elbow dislocations is approximately 3% and avulsion of the open medial epicondylar epiphysis in the pediatric population is one predisposing factor that may explain this age predilection. These lesions can be difficult to diagnose in the acute phase because symptoms tend to be mild or delayed, consequently their management can be challenging and functional outcome poorer., Methods: We present the case of an unrecognized median nerve entrapment in a 16-year-old boy with posterior dislocation of the elbow and a medial epicondyle fracture, treated initially with close reduction and open stabilization with a cannulated screw. Assessment is supported by a review of similar reported cases available in literature., Results: We discuss the diagnostic approach and the surgical options that can be used for this type of injury., Conclusions: High clinical suspicion of entrapment is imperative in presence of signs of damage to the median nerve in the pediatric patient immediately after the reduction of an elbow dislocation. If diagnosis of entrapment is made the therapeutic choice between neurolysis and nerve graft depends on the lesion severity. In the presence of a Fourrier's type 4 lesion, neurolysis should be avoided, while nerve resection and grafting are recommended., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and in genetically modified mouse models, and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments., (© 2022 by The American Society of Hematology.)

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a new member of the Betacoronaviridae family, responsible for the recent pandemic outbreak of COVID-19. To start exploring the molecular events that follow host cell infection, we queried VirusCircBase and identified a circular RNA (circRNA) predicted to be synthesized by SARS-CoV-2, circ&#95;3205, which we used to probe: (i) a training cohort comprised of two pools of cells from three nasopharyngeal swabs of SARS-CoV-2 infected (positive) or uninfected (negative, UCs) individuals; (ii) a validation cohort made up of 12 positive and 3 negative samples. The expression of circRNAs, miRNAs and miRNA targets was assayed through real-time PCR. CircRNA-miRNA interactions were predicted by TarpMiR, Analysis of Common Targets for circular RNAs (ACT), and STarMir tools. Enrichment of the biological processes and the list of predicted miRNA targets were retrieved from DIANA miRPath v3.0. Our results showed that the predicted SARS-CoV-2 circ&#95;3205 was expressed only in positive samples and its amount positively correlated with that of SARS-CoV-2 Spike (S) mRNA and the viral load (r values = 0.80952 and 0.84867, Spearman's correlation test, respectively). Human (hsa) miR-298 was predicted to interact with circ&#95;3205 by all three predictive tools. KCNMB4 and PRKCE were predicted as hsa-miR-298 targets. Interestingly, the function of both is correlated with blood coagulation and immune response. KCNMB4 and PRKCE mRNAs were upregulated in positive samples as compared to UCs (6 and 8.1-fold, p values = 0.049 and 0.02, Student's t test, respectively) and their expression positively correlated with that of circ&#95;3205 (r values = 0.6 and 0.25, Spearman's correlation test, respectively). We propose that our results convincingly suggest that circ&#95;3205 is a circRNA synthesized by SARS-CoV-2 upon host cell infection and that it may behave as a competitive endogenous RNA (ceRNA), sponging hsa-miR-298 and contributing to the upregulation of KCNMB4 and PRKCE mRNAs., (© 2022. The Author(s).)

Objective: To evaluate the influence of cancer on ovarian response and oocyte quality in controlled ovarian hyperstimulation (COH)., Methods: This prospective study conducted at the Physiopathology of Reproduction and Andrology Unit of Sandro Pertini Hospital enrolled 82 cancer patients undergoing controlled ovarian stimulation (COH) cycles for fertility preservation, and age- and date-matched controls undergoing COH for in vitro fertilization for male-factor infertility from June 2016 to November 2019. The interventions performed were COH, oocyte retrieval, and quality evaluation. Main outcome measures were maximal estradiol levels on the day of human chorionic gonadotropin administration, duration of stimulation, total amount of gonadotropins administered, number of oocytes retrieved, and rates of metaphase 2 oocytes and abnormal oocytes. All data were analyzed using the Statistical Package for the Social Sciences (IBM Corp., Armonk, NY, USA) 22.0., Results: Intergroup comparisons (82 cancer patients and 180 patients in control group) showed a significant difference in ovarian response, especially for a significant higher number of abnormal oocytes in cancer patients (P < 0.0001). Regression analysis to assess the influence of the neoplastic process, regardless of the type, on ovarian response showed an effect on the main outcome measured due to cancer itself., Conclusion: Cancer influences the ovarian response, particularly the oocyte quality, during COH performed for fertility preservation., (© 2021 International Federation of Gynecology and Obstetrics.)

To advance the use of circulating tumor DNA (ctDNA) applications, their broad clinical validity must be tested in different treatment settings, including targeted therapies. Using the prespecified longitudinal systematic collection of plasma samples in the phase 1/2a LYM1002 trial (registered on www.clinicaltrials.gov as NCT02329847), we tested the clinical validity of ctDNA for baseline mutation profiling, residual tumor load quantification, and acquisition of resistance mutations in patients with lymphoma treated with ibrutinib+nivolumab. Inclusion criterion for this ancillary biological study was the availability of blood collected at baseline and cycle 3, day 1. Overall, 172 ctDNA samples from 67 patients were analyzed by the LyV4.0 ctDNA Cancer Personalized Profiling Deep Sequencing Assay. Among baseline variants in ctDNA, only TP53 mutations (detected in 25.4% of patients) were associated with shorter progression-free survival; clones harboring baseline TP53 mutations did not disappear during treatment. Molecular response, defined as a >2-log reduction in ctDNA levels after 2 cycles of therapy (28 days), was achieved in 28.6% of patients with relapsed diffuse large B-cell lymphoma who had ≥1 baseline variant and was associated with best response and improved progression-free survival. Clonal evolution occurred frequently during treatment, and 10.3% new mutations were identified after 2 treatment cycles in nonresponders. PLCG2 was the topmost among genes that acquired new mutations. No patients acquired the C481S BTK mutation implicated in resistance to ibrutinib in CLL. Collectively, our results provide the proof of concept that ctDNA is useful for noninvasive monitoring of lymphoma treated with targeted agents in the clinical trial setting., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The loss of arm function is a common and disabling outcome after stroke. Robot-assisted upper limb (UL) training may improve outcomes. The aim of this study was to explore the effect of robot-assisted training using end-effector and exoskeleton robots on UL function following a stroke in real-life clinical practice., Methods: A total of 105 patients affected by a first-ever supratentorial stroke were enrolled in 18 neurorehabilitation centers and treated with electromechanically assisted arm training as an add-on to conventional therapy. Both interventions provided either an exoskeleton or an end-effector device (as per clinical practice) and consisted of 20 sessions (3/5 times per week; 6-8 weeks). Patients were assessed by validated UL scales at baseline (T0), post-treatment (T1), and at three-month follow-up (T2). The primary outcome was the Fugl-Meyer Assessment for the upper extremity (FMA-UE)., Results: FMA-UE improved at T1 by 6 points on average in the end-effector group and 11 points on average in the exoskeleton group ( p < 0.0001). Exoskeletons were more effective in the subacute phase, whereas the end-effectors were more effective in the chronic phase ( p < 0.0001)., Conclusions: robot-assisted training might help improve UL function in stroke patients as an add-on treatment in both subacute and chronic stages. Pragmatic and highmethodological studies are needed to confirm the showed effectiveness of the exoskeleton and end-effector devices.

Brain lesions caused by cerebral ischemia lead to network disturbances in both hemispheres, causing a subsequent reorganization of functional connectivity both locally and remotely with respect to the injury. Quantitative electroencephalography (qEEG) methods have long been used for exploring brain electrical activity and functional connectivity modifications after stroke. However, results obtained so far are not univocal. Here, we used basic and advanced EEG methods to characterize how brain activity and functional connectivity change after stroke. Thirty-three unilateral post stroke patients in the sub-acute phase and ten neurologically intact age-matched right-handed subjects were enrolled. Patients were subdivided into two groups based on lesion location: cortico-subcortical ( CS , n = 18) and subcortical ( S , n = 15), respectively. Stroke patients were evaluated in the period ranging from 45 days since the acute event (T0) up to 3 months after stroke (T1) with both neurophysiological (resting state EEG) and clinical assessment (Barthel Index, BI) measures, while healthy subjects were evaluated once. Brain power at T0 was similar between the two groups of patients in all frequency bands considered (δ, θ, α, and β). However, evolution of θ-band power over time was different, with a normalization only in the CS group. Instead, average connectivity and specific network measures ( Integration , Segregation , and Small-worldness ) in the β-band at T0 were significantly different between the two groups. The connectivity and network measures at T0 also appear to have a predictive role in functional recovery (BI T1-T0), again group-dependent. The results obtained in this study showed that connectivity measures and correlations between EEG features and recovery depend on lesion location. These data, if confirmed in further studies, on the one hand could explain the heterogeneity of results so far observed in previous studies, on the other hand they could be used by researchers as biomarkers predicting spontaneous recovery, to select homogenous groups of patients for the inclusion in clinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fanciullacci, Panarese, Spina, Lassi, Mazzoni, Artoni, Micera and Chisari.)

Osteoid osteoma is a benign osteoblastic tumor, quite uncommon in the spine. We report a case of an osteoid osteoma involving the atlas in a 6-year-old boy, who presented with suboccipital pain and torticollis. Initial radiological findings were ambiguous as magnetic resonance imaging showed mainly edema of upper cervical soft tissues. The subsequent computed tomography depicted a lesion of left lamina of C1. As conservative treatment failed, the lesion was surgically resected and the patient became pain free. To our knowledge, this is the first case of osteoid osteoma involving the atlas associated with abnormal soft tissue reaction reported in literature., Competing Interests: None., (Thieme. All rights reserved.)

Background and Aims: Gaucher disease (GD) is associated with peculiar metabolic abnormalities (ie hypermetabolic state, peripheral insulin resistance, dyslipidaemia), partially reverted by enzyme replacement therapy (ERT) at the expense of weight gain. Such metabolic alterations together with an unhealthy lifestyle acquired by an ageing GD population may favour the development of liver steatosis. We aimed at evaluating the prevalence of significant liver steatosis and at identifying the factors associated with liver steatosis in a cohort of patients with type 1 GD., Methods: Twenty adult type 1 GD patients from an Italian academic referral centre were prospectively submitted to vibration-controlled transient elastography (Fibroscan®) with controlled attenuation parameter (CAP); significant steatosis was defined as CAP values ≥250 dB/min., Results: Median CAP values were 234 [165-358] dB/min and 8 patients (40%) had significant steatosis. Significant steatosis was associated with indices of adiposity (weight, BMI and waist circumference), high blood pressure, insulin resistance and metabolic syndrome. GD-related variables and dose and duration of ERT were not associated with significant steatosis. In the subgroup of 16 patients on stable ERT for at least 24 months, CAP resulted significantly and positively associated with liver stiffness (rho 0.559, P = .024)., Conclusions: Significant steatosis is highly prevalent in adult type 1 GD patients and is strongly associated with a worse metabolic profile, featuring metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD may determine liver fibrosis progression in GD patients on stable ERT and may be a risk factor for long-term liver-related complications., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The beginning of 2020 was characterized by the COVID-19 pandemic. The world governments have adopted restrictive measures to reduce the spread of infection. These measures could affect the sexual function and quality of life of women living with their partner., Aim: The aim is to assess the impact of the social distancing measures caused by the COVID-19 pandemic on sexual function and quality of life of noninfected reproductive-age women, living with their sexual partner., Methods: Observational analysis on sexually active women, living with their partner, and without COVID-19 infection was performed. The population previously answered FSFI, FSDS, and SF-36 questionnaires. 4 weeks after the introduction of the restrictive measures, these women were invited to complete the same questionnaires by e-mail for an evaluation during the COVID-19 outbreak., Main Outcome Measures: The primary endpoint was the assessment of the women's sex function change during the social restriction period, by analyzing the FSFI and FSDS questionnaires. The secondary endpoint was the evaluation of the impact on the quality of life calculated by the SF-36 questionnaire., Results: 89 patients were considered. The median age was 39 (28-50) years. Mean sexual intercourses/month decreased from 6.3 ± 1.9 to 2.3 ± 1.8, mean difference: -3.9 ± 1.2. FSFI decreased significantly (29.2 ± 4.2 vs 19.2 ± 3.3, mean difference: -9.7 ± 2.6) and FSDS increased significantly (9.3 ± 5.5 vs 20.1 ± 5.2, mean difference: 10.8 ± 3.4). The SF-36 showed a significant change from 82.2 ± 10.2 to 64.2 ± 11.8 4 weeks after the introduction of the restrictive measures; mean difference: -17.8 ± 6.7. The univariable analysis identified working outside the home, university educational level, and parity ≥1 as predictive factors of lower FSFI. In multivariable analysis, working outside the home and combination of working outside the home + university educational level + parity ≥1 were the independent factors of a lower FSFI., Clinical Implication: The negative impact of the COVID-19 epidemic period on sexual function and quality of life in women shows how acute stress might affect the psychological state. Thus, psychological or sexual support could be useful., Strengths and Limitations: To our knowledge, this study is the first that analyzes the change in sexual activity in women during the COVID-19 outbreak period. The limitations were the low number of the analyzed participants, psychological tests were not included, and no data were collected on masturbation, self-heroism, solitary, and nonpenetrative sex., Conclusion: The COVID-19 epidemic and the restrictive social distancing measures have negatively influenced the sexual function and quality of life in not-infected reproductive-age women who live with their sexual partners. Schiavi MC, Spina V, Zullo MA, et al. Love in the Time of COVID-19: Sexual Function and Quality of Life Analysis During the Social Distancing Measures in a Group of Italian Reproductive-Age Women. J Sex Med 2020;17:1407-1413., (Copyright © 2020 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

In recent years, the outcome of mantle cell lymphoma (MCL) has improved, especially in younger patients, receiving cytarabine-containing chemoimmunotherapy and autologous stem cell transplantation. Nevertheless, a proportion of MCL patients still experience early failure. To identify biomarkers anticipating failure of intensive chemotherapy in MCL, we performed target resequencing and DNA profiling of purified tumor samples collected from patients enrolled in the prospective FIL-MCL0208 phase 3 trial (high-dose chemoimmunotherapy followed by autologous transplantation and randomized lenalidomide maintenance). Mutations of KMT2D and disruption of TP53 by deletion or mutation associated with an increased risk of progression and death, both in univariate and multivariate analysis. By adding KMT2D mutations and TP53 disruption to the MIPI-c backbone, we derived a new prognostic index, the "MIPI-genetic" ("MIPI- g"). The "MIPI-g" improved the model discrimination ability compared to the MIPI-c alone, defining three risk groups: i) low-risk patients (4-year progression free survival and overall survival of 72.0% and 94.5%); ii) inter-mediate-risk patients (4-year progression free survival and overall survival of 42.2% and 65.8%) and iii) high-risk patients (4-year progression free survival and overall survival of 11.5% and 44.9%). Our results: i) confirm that TP53 disruption identifies a high-risk population characterized by poor sensitivity to conventional or intensified chemotherapy; ii) provide the pivotal evidence that patients harboring KMT2D mutations share the same poor outcome as patients harboring TP53 disruption; and iii) allow to develop a tool for the identification of high-risk MCL patients for whom novel therapeutic strategies need to be investigated. ( Trial registered at clinicaltrials.gov identifier: NCT02354313 )., (Copyright© 2020 Ferrata Storti Foundation.)

Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials., (© 2020 by The American Society of Hematology.)

Hypnotizability is a psychophysiological trait associated with morphofunctional brain peculiarities and with several cognitive, sensorimotor and cardiovascular correlates. Behavioral and EEG studies indicate stronger functional equivalence (FE) between motor imagery and action in the individuals with high hypnotizability scores (Highs). We hypothesized that stronger FE leading to greater proneness to ideomotor behavior could be due to greater cortical excitability of the motor cortex. The aim of the study was to evaluate the motor cortical excitability through measurements of the muscle potentials (MEPs) evoked in the left abductor pollicis brevis by transcranial magnetic stimulation (TMS) of the right motor cortex in 10 Highs, 10 medium (Mediums) and 10 low hypnotizable individuals (Lows) classified according to the Stanford Hypnotic Susceptibility Scale, form A (SHSS). They were studied in basal conditions (B) and during motor imagery (MI). Results showed significant, negative correlations (i) between hypnotizability and MEPs Resting Motor Threshold (RMT) in basal conditions, and (ii) between hypnotizability and both MEPs RMT and suprathreshold (I 1mv ) stimulation intensities during MI. ANOVA revealed significantly lower stimulation intensities in Highs than in Lows, with Mediums exhibiting intermediate values. Thus, the Highs' greater cortical excitability could sustain their greater FE and proneness to ideomotor behavior. In cognitive neuroscience these findings are relevant to the physiological interpretation of the response to sensorimotor suggestions by participants in the ordinary state of consciousness. In the clinical field they can predict the efficacy of mental training based on motor imagery and, possibly, the degree of imagery-induced cortical plasticity., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in BIRC3 -mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3 -mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, P <0.001) similar to cases harboring TP53 mutations (median progression-free survival: 2.6 years, P <0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, P =0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches., (Copyright© 2020 Ferrata Storti Foundation.)

Magnetic resonance imaging (MRI) is a pivotal radiological examination in clinical practice, being widely applied for musculoskeletal examinations. In this setting, strict adherence to standardized protocol is crucial to increase diagnostic performance and minimize variability among different diagnostic centres and readers. The aim of this paper is to provide standardized technical recommendations for musculoskeletal MRI scans proposed by the Italian College of Musculoskeletal Radiology. These recommendations are designed to give a uniform application of MRI protocols over the national territory, to increase reproducibility and improve diagnostic performance.

In the era of personalised medicine, genetic information is critical to directing therapeutic options, aiding risk stratification and disease monitoring of lymphomas. Liquid biopsy is a novel noninvasive, real-time and tumour-specific technique, reliably reflecting the comprehensive tumour genetic profile, and thus holds great promise for the genetic assessment, response monitoring and relapse detection of lymphomas. Standard methods for disease response assessment in patients with lymphoma, including positron emission tomography, are imperfect. In other haematological malignancies, particularly leukaemias, the ability to detect minimal residual disease (MRD) is increasingly influencing treatment paradigms. However, in some subtypes of lymphoma, such as diffuse large B-cell lymphoma and classic Hodgkin&rsquo;s lymphoma, the application of MRD assessment techniques such as flow cytometry or polymerase chain reaction-based methods has been challenged by the absence of circulating disease. The review summarises the applications of liquid biopsy in the assessment of tumour burden and response to therapy, noninvasive genomic profiling, and monitoring of clonal dynamics in patients with diffuse large B-cell lymphoma and classic Hodgkin&rsquo;s lymphoma.

Chronic lymphocytic leukemia (CLL) is the most frequent leukemia type in which the genetic alterations influencing the clinico-biological course are not entirely understood. CLL has a heterogeneous course, with some patients showing an indolent course and others experiencing an aggressive course. Whole-genome sequencing and whole-exome sequencing studies identified recurrently mutated genes in CLL and profiled its clonal evolution patterns. However, more recent whole-genome sequencing studies also identified variants in non-coding sequences of the CLL genome, revealing important lesions outside the protein-coding regions. Here we describe the most representative non-coding lesion of the CLL genome, including lesions in the 3'-UTR region of NOTCH1 which result in the truncation of the NOTCH1 protein PEST domain, and non-coding mutations in an enhancer region on chromosome 9p13 which result in reduced expression of the PAX5 transcription factor. In addition, we describe the role of microRNA in CLL, in particular the miR15a/miR16-1 microRNA recurrently affected by deletions of chromosome 13q14. Together, new findings in non-coding genome genetic lesions provide a more complete portrait of the genomic landscape of CLL with clinical implications., (© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Plasma cell-free DNA (cfDNA) is an easily accessible source of tumor DNA that allows accurate profiling of lymphoma patients, representing a complementary source of tumor DNA to tissue biopsy for genotyping. Applications of cfDNA analysis in lymphomas include: (1) identification of tumor mutations in a biopsy-free manner; (2) tracking tumor clonal evolution and identification of mutations causing resistance to treatment; and (3) monitoring of residual disease after therapy.

This article discusses the role of imaging modalities including radiography, multi-detector computed tomography, magnetic resonance imaging, and ultrasound in diagnosing and monitoring skeletal abnormalities in mucopolysaccharidoses (MPS). The advantages and disadvantages of these different imaging tools will be discussed, along with their feasibility in this class of patients. As the musculoskeletal involvement is common to all MPS and is one of the main reasons for seeking medical attention, an increased awareness among paediatricians, rheumatologists, orthopaedists, radiologists, and other musculoskeletal specialists on the possible spectrum of abnormalities observed could facilitate a timely diagnosis, an appropriate severity evaluation, and better management.

Background & Aims: Long-term liver-related complications of Gaucher disease (GD) include cirrhosis, portal hypertension and hepatocellular carcinoma. Although liver fibrosis is the main determinant of adverse liver-related clinical outcomes, it has rarely been evaluated in previously published cohorts of GD patients. We aimed at: assessing the prevalence of significant liver fibrosis in a cohort of patients with type 1 GD; identifying its predictors among GD-related variables, enzyme replacement therapy (ERT) and metabolic features., Methods: 37 adult type 1 GD patients from two Italian academic referral centers were prospectively submitted to vibration controlled transient elastography (Fibroscan®); significant fibrosis was defined as liver stiffness ≥7 kPa., Results: Median liver stiffness was 4.6 [3-15.1] kPa and 7 patients (19%) had significant fibrosis. Significant fibrosis was associated with splenectomy (p = .046) and with scores (DS3: p = .002; SSI: p = .026) and biomarkers (ACE: p = .016; HDL cholesterol: p = .004) of GD severity. Length of ERT was significantly lower in GD patients with significant fibrosis. In the subgroup of 29 patients who were on stable ERT for at least 24 months, further to splenectomy, GD severity and non-N370S GBA1 genotypes, also diastolic blood pressure, BMI and the number of metabolic syndrome (MetS) components emerged as factors significantly associated with significant fibrosis., Conclusions: Significant fibrosis is present in a remarkable proportion of adult type 1 GD patients. Splenectomy, GD severity and GBA1 genotypes are major GD-related predictors of liver fibrosis. Length of ERT is inversely correlated with liver disease in GD patients, suggesting a beneficial effect of ERT on liver fibrosis. However, GD patients on stable ERT should be monitored for metabolic complications, since MetS features may enhance liver disease progression despite optimal GD control., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Richter syndrome (RS) is the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL). Two pathologic variants of RS are recognized: namely, the diffuse large B-cell lymphoma (DLBCL) variant and the rare Hodgkin lymphoma (HL) variant. Histologic documentation is mandatory to diagnose RS. The clinical suspicion of RS should be based on clinical signs and symptoms. Differential diagnosis between CLL progression and RS and choice of the biopsy site may take advantage of positron emission tomography/computed tomography. Molecular lesions of regulators of proliferation ( CDKN2A , NOTCH1 , MYC ) and apoptosis ( TP53 ) overall associate with ∼90% of DLBCL-type RS, whereas the biology of the HL-type RS is largely unknown. The prognosis of the DLBCL-type RS is unfavorable; the outcome of HL-type RS appears to be better. The most important RS prognostic factor is the clonal relationship between the CLL and the aggressive lymphoma clones, with clonally unrelated RS having a better prognosis. Rituximab-containing combination chemotherapy for DLBCL is the most widely used treatment in DLBCL-type RS. Fit patients who respond to induction therapy should be offered stem cell transplantation (SCT) to prolong survival. Adriamycin, bleomycin, vinblastine, and dacarbazine is the preferred regimen for the HL-type RS, and SCT consolidation is less used in this condition., (© 2018 by The American Society of Hematology.)

Objective: To evaluate the accuracy of pelvic MRI in the diagnosis of unusual ectopic pregnancy (EP), when ultrasound (US) examination is inconclusive., Methods: We retrospectively reviewed the medical records of 150 patients with suspected EP. Clinical, US and MRI features of 15 unusual EPs were analysed. Two radiologists independently reviewed each case resolving by consensus any diagnostic discrepancy. Interobserver agreement was assessed using the Cohen κ test., Results: MRI displayed a gestational sac-like structure surrounded by a thick wall in all cases. The thick wall displayed hyperintensity in 41 %, isointensity in 35 % and hypointensity in 24 % of cases on T1-weighted images. Diffusion- and fat saturation T1-weighted images were the most accurate sequences, as they enabled identification of 15/15 and 14/15 patients, respectively. Although US was false negative in detecting cervical and uterine infiltration underlying the caesarean scar, MRI was able to identify the invasion. Interobserver agreement was very good for all sequences (κ=0.892-1.0)., Conclusions: MRI plays an important role in the early diagnosis of unusual EP. It should be considered after negative US findings, providing accurate evaluation of the site and the possible infiltration of these lesions, which help in the management of these patients., Key Points: • MRI is being increasingly used as a problem-solving modality in ectopic pregnancy. • MRI plays an important role in early diagnosis of unusual ectopic pregnancy. • Knowledge of MRI features in EP is essential to determinate appropriate management.

The rarity of neoplastic cells in the biopsy imposes major technical hurdles that have so far limited genomic studies in classical Hodgkin lymphoma (cHL). By using a highly sensitive and robust deep next-generation sequencing approach for circulating tumor DNA (ctDNA), we aimed to identify the genetics of cHL in different clinical phases, as well as its modifications on treatment. The analysis was based on specimens collected from 80 newly diagnosed and 32 refractory patients with cHL, including longitudinal samples collected under ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) chemotherapy and longitudinal samples from relapsing patients treated with chemotherapy and immunotherapy. ctDNA mirrored Hodgkin and Reed-Sternberg cell genetics, thus establishing ctDNA as an easily accessible source of tumor DNA for cHL genotyping. By identifying STAT6 as the most frequently mutated gene in ∼40% of cases, we refined the current knowledge of cHL genetics. Longitudinal ctDNA profiling identified treatment-dependent patterns of clonal evolution in patients relapsing after chemotherapy and patients maintained in partial remission under immunotherapy. By measuring ctDNA changes during therapy, we propose ctDNA as a radiation-free tool to track residual disease that may integrate positron emission tomography imaging for the early identification of chemorefractory patients with cHL. Collectively, our results provide the proof of concept that ctDNA may serve as a novel precision medicine biomarker in cHL., (© 2018 by The American Society of Hematology.)

Accessible and real-time genotyping for diagnostic, prognostic, or treatment purposes is increasingly impelling in diffuse large B-cell lymphoma (DLBCL). Cell-free DNA (cfDNA) is shed into the blood by tumor cells undergoing apoptosis and can be used as source of tumor DNA for the identification of DLBCL mutations, clonal evolution, and genetic mechanisms of resistance. In this study, we aimed at tracking the basal DLBCL genetic profile and its modification upon treatment using plasma cfDNA. Ultra-deep targeted next generation sequencing of pretreatment plasma cfDNA from DLBCL patients correctly discovered DLBCL-associated mutations that were represented in >20% of the alleles of the tumor biopsy with >90% sensitivity and ∼100% specificity. Plasma cfDNA genotyping also allowed for the recovery of mutations that were undetectable in the tissue biopsy, conceivably because, due to spatial tumor heterogeneity, they were restricted to clones that were anatomically distant from the biopsy site. Longitudinal analysis of plasma samples collected under rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) chemotherapy showed a rapid clearance of DLBCL mutations from cfDNA among responding patients. Conversely, among patients who were resistant to R-CHOP, basal DLBCL mutations did not disappear from cfDNA. In addition, among treatment-resistant patients, new mutations were acquired in cfDNA that marked resistant clones selected during the clonal evolution. These results demonstrate that cfDNA genotyping of DLBCL is as accurate as genotyping of the diagnostic biopsy to detect clonally represented somatic tumor mutations and is a real-time and noninvasive approach to tracking clonal evolution and the emergence of treatment-resistant clones., (© 2017 by The American Society of Hematology.)

Genomic studies have improved our understanding of the biological basis of splenic (SMZL) and nodal (NMZL) marginal zone lymphoma by providing a comprehensive and unbiased view of the genes/pathways that are deregulated in these diseases. Consistent with the physiological involvement of NOTCH, NF-κB, B-cell receptor and toll-like receptor signaling in mature B-cells differentiation into the marginal zone B-cells, many oncogenic mutations of genes involved in these pathways have been identified in SMZL and NMZL. Beside genetic lesions, also epigenetic and post-transcriptional modifications contribute to the deregulation of marginal zone B-cell differentiation pathways in SMZL and NMZL. This review describes the progress in understanding the molecular mechanism underlying SMZL and NMZL, including molecular and post-transcriptional modifications, and discusses how information gained from these efforts has provided new insights on potential targets of diagnostic, prognostic and therapeutic relevance in SMZL and NMZL., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Nodal marginal zone lymphoma (NMZL) is a rare, indolent B-cell tumor that is distinguished from splenic marginal zone lymphoma (SMZL) by the different pattern of dissemination. NMZL still lacks distinct markers and remains orphan of specific cancer gene lesions. By combining whole-exome sequencing, targeted sequencing of tumor-related genes, whole-transcriptome sequencing, and high-resolution single nucleotide polymorphism array analysis, we aimed at disclosing the pathways that are molecularly deregulated in NMZL and we compare the molecular profile of NMZL with that of SMZL. These analyses identified a distinctive pattern of nonsilent somatic lesions in NMZL. In 35 NMZL patients, 41 genes were found recurrently affected in ≥3 (9%) cases, including highly prevalent molecular lesions of MLL2 (also known as KMT2D; 34%), PTPRD (20%), NOTCH2 (20%), and KLF2 (17%). Mutations of PTPRD, a receptor-type protein tyrosine phosphatase regulating cell growth, were enriched in NMZL across mature B-cell tumors, functionally caused the loss of the phosphatase activity of PTPRD, and were associated with cell-cycle transcriptional program deregulation and increased proliferation index in NMZL. Although NMZL shared with SMZL a common mutation profile, NMZL harbored PTPRD lesions that were otherwise absent in SMZL. Collectively, these findings provide new insights into the genetics of NMZL, identify PTPRD lesions as a novel marker for this lymphoma across mature B-cell tumors, and support the distinction of NMZL as an independent clinicopathologic entity within the current lymphoma classification., (© 2016 by The American Society of Hematology.)

Splenic marginal zone lymphoma is a rare mature B-cell malignancy involving the spleen, bone marrow and blood. Over the past years, the rapid expansion of sequencing technologies allowing the genome-wide assessment of genomic, epigenetic and transcriptional changes has revolutionized our understanding of the biological basis of splenic marginal zone lymphoma by providing a comprehensive and unbiased view of the genes/pathways that are deregulated in this disease. NF-κB is a family of transcription factors that plays critical roles in development, survival, and activation of B lymphocytes. Consistent with the physiological involvement of NF-κB signalling in proliferation and commitment of mature B-cells to the marginal zone of the spleen, many oncogenic mutations involved in constitutive activation of the NF-κB pathway were recently identified in splenic marginal zone lymphoma. This review describes the progress in understanding the mechanism of NF-κB activation in splenic marginal zone lymphoma, including molecular, epigenetic and post-transcriptional modifications of NF-κB genes and of upstream pathways, and discusses how information gained from these efforts has provided new insights on potential targets of diagnostic, prognostic and therapeutic relevance for splenic marginal zone lymphoma., (Copyright © 2016. Published by Elsevier Ltd.)

Genomic studies have led to a significant impact both on the pace and the nature of understanding the molecular and biological bases of a variety of lymphoid tumors. An increasingly emerging aspect from genomic studies is that malignant lymphoid cells manipulate signaling pathways that are central to the homeostasis of their normal counterpart, including B- and T-cell receptor signaling, NF-κB signaling, Toll-like receptor signaling, cytokine signaling, MAP kinase signaling, and NOTCH signaling. This review aims at covering the signaling pathways that are affected by mutations in lymphoid tumors, and how genetic alteration of these pathways may contribute to disease pathogenesis and management., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)