Long-term Relapse Research Articles

Tocilizumab for Neuromyelitis Optica Spectrum Disorder


 Patients with neuromyelitis optica spectrum disorder treated with tocilizumab may experience decreased risks of relapse or disability progression compared to before treatment, but it is uncertain whether these changes can be entirely attributed to tocilizumab (TCZ) treatment.
 TCZ might be better than azathioprine for patients with neuromyelitis optica spectrum disorder in reducing relapse risk.
 TCZ might improve or have no impact on pain and fatigue measures for patients with neuromyelitis optica spectrum disorder.
 Adverse events were common during TCZ treatment, but patients treated with TCZ may experience adverse events at a similar or lower rate to those treated with azathioprine.
 One evidence-based guideline suggests that TCZ can be used as 1 of the second-line drugs to prevent long-term relapse for patients with neuromyelitis optica spectrum disorder who have no response to other immunosuppressants.
 We did not find any studies that compared TCZ to other immunosuppressants or any studies on the cost-effectiveness of TCZ for treating neuromyelitis optica spectrum disorder that met the inclusion criteria for this report.

The Initial Efficacy of Stand-Alone DBT Skills Training for Treating Impulsivity Among Individuals With Alcohol and Other Substance Use Disorders

Impulsivity is considered a core feature of substance use disorders (SUDs), including personological (i.e., negative urgency, positive urgency, lack of premeditation) and neuropsychological (i.e., cognitive and motor disinhibition, impulsive choice) dimensions. Dialectical Behavior Therapy Skills Training (DBT-ST) as a stand-alone treatment is an effective intervention for alcohol use disorder (AUD) and other SUDs. However, there are no studies that have investigated changes in impulsivity levels during a DBT-ST program, especially testing the therapeutic effects of DBT skills. Twenty-nine patients with AUD and other SUDs were admitted to a 3-month DBT-ST program. Self-report (i.e., UPPS-P) and computerized neuropsychological (i.e., Attentional Network test; Go/No-Go task; Iowa Gambling Task) measures of impulsivity were administered at the beginning and end of the DBT-ST. Distress tolerance (DTS), mindfulness (MAAS, FFMQ) and emotion regulation (DERS) were also assessed pre- and post-intervention. The study included two age- and gender-matched control groups: (a) untreated patients with SUDs (N = 29); (b) healthy controls (HCs) (N = 29). Twenty-four (82.7%) patients concluded the DBT-ST program. Emotion-based forms of impulsivity significantly improved during the program. At the end of treatment, impulsivity levels were significantly lower than those of untreated patients with SUDs and they were not significantly different from HCs. Cognitive disinhibition significantly decreased during the treatment. The improvement in impulsivity was explained by pre- posttreatment changes in distress tolerance, mindfulness and emotion regulation. Motor disinhibition did not improve during the treatment. These findings supported the initial efficacy of the DBT-ST program for addressing different features of impulsivity among individuals with AUD and other SUDs. Future follow-up studies should demonstrate the role of impulsivity domains in long-term relapse prevention.

Improved Vδ2+ T cells recovery correlates to reduced incidences of mortality and relapse in acute myeloid leukemia after hematopoietic transplantation.

Acute myeloid leukemia (AML) patients can benefit from allogeneic hematopoietic cell transplantation (alloHCT) and achieve long-term remission. Recovery of T cell quantity and quality is critical to reduce the incidences of life-threatening complications after alloHCT. Although the general recovery level of γδ T cells is recognized to be associated with outcomes of patients who suffered from various hematological diseases and received alloHCT, the correlation between γδ T cell subsets and the prognosis in AML patients following transplantation remains to be investigated. In the current study, the recoveries of T cell subpopulations in 103 AML patients were dissected at different time points after haploidentical HCT (haploHCT). Statistical analyses showed that the absolute number of Vδ2+ T cells on day 90 was an independent risk factor for predicting 2-year OS in AML patients following haploHCT. The survival advantage from the improved recovery of day-90 Vδ2+ T cells was attributed to reducing the infection-related mortality. Consistently, lower 2-year non-relapse mortality was found in recipients with higher day-90 levels of Vδ2+ T cells. Notably, day-270 Vδ2+ T cell numbers reversely correlated to both 2-year and 5-year probabilities of relapse in this scenario. These results highlighted the significant correlation of Vδ2+ T cells recovery with long-term survival and relapse after alloHCT, suggesting that Vδ2+ T cells-based immune strategies may help control infectious complications and leukemia recurrence in AML patients.

Abstract B027: PIK3CA hotspot mutations as biomarkers for prognosis and treatment prediction in low-risk postmenopausal breast cancer patients

Abstract The PIK3CA gene, encoding the p110α catalytic subunit of PI 3-kinase (PI3K), is mutated in more than 30% of breast cancers. Most mutations concentrate to the hotspots E542K and E545K and H1047R and are associated with hyperactivation of the phosphatidylinositol 3′-kinase/Akt pathway in vitro. The estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) (ER+/HER2-) breast cancers stand for more than 40% of the PIK3CA mutations where these constitute a new therapeutic target for endocrine-treatment resistant advanced breast cancers. Although PIK3CA is an oncogene, its mutations are associated with good prognosis. Here, we explored the prognostic and predictive role of PIK3CA hotspot mutations for low-risk postmenopausal breast cancer patients randomized to receive tamoxifen vs. no systemic treatment, followed for over 25 years and with extensive clinical records. Mutation analysis was performed using formalin-fixed paraffin-embedded tumors with digital droplet PCR (ddPCR). PIK3CA mutations were present in 35,6% of patients, predominantly within the ER+/HER2- subtype (49,8%) compared with the HER2+ and TNBC subtypes. The most frequent mutation found in all patients was H1047R (18%) followed by E545K (14%) and E542K (6%). Significant associations were found between all hotspot mutations and low grade, positive progesterone receptor (PR) expression, HER2 negative status, low Ki-67 (proliferation marker), and high expression score of a PIK3CA-mutation-associated gene module. Moreover, PIK3CA mutations were often found in patients with ultralow risk to develop distant recurrences according to the 70-gene signature. All PIK3CA mutations were coupled with longer distant recurrence-free interval (DRFI) in all patients in univariate and multivariable analysis after adjusting for tumor size, receptor status (ER, PR, HER2), tumor grade, Ki-67 and tamoxifen: HR multivariable (95% CI)=0.53 (0.28-0.98). In agreement with our previous results, PIK3CA mutations indicated good prognosis for patients with highly proliferative tumors (Ki-67>15%): H.R multivariable (95% CI)=0.15 (0.03-0.69) and high risk by the 70-gene signature: HR multivariable (95% CI)=0.14 (0.03-0.61) but not for low proliferative tumors (Ki-67<15%). In fact, PIK3CA mutations indicated adverse prognosis within those patients with ultralow risk where the registered survival was 100% in presence of the PIK3CA wild type genotype. PIK3CA mutations did not have predictive value for tamoxifen. In conclusion, PIK3CA mutations predominate within the ER+/HER2- subtype, are coupled with good clinical markers and longer DRFI in all patients and especially among aggressive tumors but not in ultralow risk patients. Further investigation will be needed to decipher the role of PIK3CA in patients with ultralow risk or indolent tumors who may present long-term relapses and specially benefit from PI3K inhibition. Citation Format: Carolin Jönsson, Zeinab Alkashaf, Josefine Sandström, Annelie Johansson, Tommy Fornander, Linda S. Lindström, Gizeh Perez Tenorio. PIK3CA hotspot mutations as biomarkers for prognosis and treatment prediction in low-risk postmenopausal breast cancer patients [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B027.

Hypertriglyceridemia Induced Acute Pancreatitis: A Learn from New Cases

An increased risk of morbidity and mortality is associated with acute pancreatitis (AP) brought on by hypertriglyceridemia (HTG). It is essential to locate the root cause as soon as possible and give those affected the attention they need. The treatment plan includes efforts to lower blood triglyceride levels and supportive care. HTG-induced AP has a similar clinical course to people with other types of acute pancreatitis. However, HTG-induced AP patients have significantly higher clinical severity and associated consequences. As a result, therapy and preventing sickness recurrence depend on a correct diagnosis. At the moment, there are no acknowledged standards for the treatment of HTG-induced AP. Some therapy approaches that effectively decrease serum triglycerides include fibric acids, apheresis/plasmapheresis, insulin, heparin, and omega-3 fatty acids. Following acute phase care, lifestyle modifications, including dietary and drug therapy, are essential for long-term HTG-induced AP control and relapse prevention. To create complete and efficient HTG-induced AP treatment guidelines, more study is required.

Impact of endoscopic metallic stent placement and emergency surgery on detection of viable circulating tumor cells for acute malignant left-sided colonic obstruction

BackgroundSelf-expanding metal stents (SEMS) served as a bridge to surgery (BTS). However, this method may be associated with worse long-term prognosis and relapse of CRC patients. Therefore, we attempted to clarify this in the angle of circulating tumor cells (CTCs).MethodsA multicenter study was performed from March 2018 to January 2021. Thirty-two colorectal cancer patients with obstruction were selected, of which 21 patients were performed SEMS as a BTS while 11 patients were performed emergency surgery. Bloods samples were collected in two groups of patients for further detecting CTCs. In the SEMS group, the samples were collected before and after stent insert and after radical surgery performed. In the ES group, the samples were collected before stent insert and after emergency surgery performed.ResultsThe number of CTCs did not show statistically significant differences before and after stent placement (34.90 vs 38.33, p=0.90), neither between the SEMS group and ES group in initial CTC levels (34.90 vs 58.09, p=0.394). No significant differences (38.33 vs 58.09, p=0.632) were observed after stent insert in the SMES group and the initial CTC levels in the ES group. Moreover, no major differences (24.17 vs 42.27, p=0.225) were observed after radical operation performed in both groups.ConclusionThe treatment of SEMS does not cause an increase in the number of CTC after stent insertion. Furthermore, there are may be other factors besides CTC to cause these poorer oncologic outcomes after SEMS placement.

Clinical Practice Guidelines for the Use of Transcranial Direct Current Stimulation in Psychiatry.

Clinical Practice Guidelines for the Use of Transcranial Direct Current Stimulation in Psychiatry.

Efficacy of sacral transcutaneous electrical nerve stimulation in patients with overactive bladder refractory to anticholinergic treatment: a prospective multi-center study.

To determine whether sacral transcutaneous electrical nerve stimulation (S-TENS) is an effective treatment in patients refractory to anticholinergic drugs (Achs). A prospective multi-center study of patients with overactive bladder (OB) refractory to Achs treated with S-TENS from 2018 to 2021 was carried out. S-TENS was applied over 3 months. Symptom progression was assessed using the voiding calendar and the Pediatric Lower Urinary Tract Symptoms Score (PLUTSS), excluding questions 3 and 4 -referring to enuresis- so that progression of daytime symptoms only (LUTS variable) was analyzed. 66 patients -50% of whom were female- were included, with a mean age of 9.5years (range: 5-15). S-TENS significantly lowered PLUTSS (19.1 baseline vs. 9.5 final, p< 0.001) and LUTS (13.1 baseline vs. 4.8 final, p< 0.001). It also reduced the number of mictions (8.5 baseline vs. 6.4 final, p< 0.001), while increasing urine volume in the voiding records (214 ml baseline vs. 258 ml final, p< 0.001). Enuresis was the only variable refractory to S-TENS. Complication rate was 3% (2 patients with dermatitis in the S-TENS application area). S-TENS is effective and safe in the short-term in patients with OB refractory to Achs. Further studies assessing long-term efficacy and potential relapses are required.

Evaluate the long-term hard tissue stability and relapse factors following surgical–orthodontic treatment

Background and aim: the present study was conducted with the aim of evaluating the long-term hard tissue stability and relapse factors following surgical-orthodontic treatment. Method: Databases of PubMed, Scopus, Web of Science, EBSCO, ISI Web of knowledge and Embase were searched for systematic literature until July 2022. 95% confidence interval for mean differences with fixed effect model and Inverse-variance method were calculated. To deal with potential heterogeneity, random effects were used and I2 showed heterogeneity. Meta-analysis was performed using Stata/MP v.17 software. Result: In the initial review, duplicate studies were eliminated and abstracts of 201 studies were reviewed, the full text of 38 studies was reviewed by two authors, finally, ten studies were selected. Overbite changes, Upper incisor changes and Lower incisor changes after combined orthodontic and orthognathic surgical treatment in class II and III patients during long-term follow-up was 1.80 (MD 95% CI; 1.43 and 2.17), -0.51 (MD 95% CI; -1.08 and 0.05) and 0.27 (MD 95% CI; 1.03 and 1.58), respectively. Conclusion: Based on the findings of the present study, in patients with skeletal class II and III, the results of long-term dental changes after combined orthodontic and orthognathic surgery are very diverse.

Comparison of recurrence rate and risk factors in patients with focal adenomyosis with and without medical treatment after conservative surgery.

To compare the recurrence rate and risk factors between conservative surgery followed by medical treatments and conservative surgery-only in patients with focal adenomyosis. This retrospective study was conducted in a single teaching hospital from May 2011 to October 2016. All eligible patients were identified into three groups: surgery-only group, surgery combined with gonadotropin-releasing hormone agonist (GnRHa), and a levonorgestrel-releasing intrauterine system (LNG-IUS) group. The recurrence rate and risk factors were compared among groups using Kaplan-Meier and Cox proportional hazards analyses. Receiver operating characteristic (ROC) curve analysis was applied to determine a cut-off value for identifying recurrence-related risk factors. A total of 249 postoperative patients with adenomyosis were included in the final analysis with a mean of 41 months of follow up. The recurrence rate at the long-term follow up was significantly lower in intervention groups than in the surgery-only group (P= 0.011). The Cox proportional hazards and ROC analyses showed that a menstrual cycle longer than 26 days (P= 0.026), diameter of lesions <6cm (P= 0.030), and combination treatment using GnRHa (P= 0.039) or LNG-IUS (P= 0.007) were protective against relapse. The risk of recurrence was lower in patients with anterior (P= 0.034) or fundus (P= 0.038) adenomyosis. Postoperative therapy using GnRHa or LNG-IUS decreases the long-term relapse rate in women undergoing conservative surgery.

One-piece fronto-orbital distraction osteogenesis without bandeau in patients with coronal craniosynostosis: A five-year follow-up retrospective study of 45 consecutive patients

This study aimed to review the surgical outcomes, complications, and long-term relapses in patients with unilateral or bilateral coronal craniosynostosis, who underwent one-piece fronto-orbital distraction osteogenesis (FODO) without bandeau.The cephalic index, frontal angle, and supraorbital symmetry ratio were measured on the initial and follow-up computed tomography images. Esthetic outcomes were evaluated using the Whitaker classification.45 patients were included in this study. The average follow-up interval was 5.4 ± 1.1 years (range 2.5–8.5 years). In patients with bilateral coronal craniosynostosis, the frontal angle decreased with a relapse ratio of −2.8 ± 4.3% during long-term follow-up compared with that during short-term follow-up (p = 0.028). In patients with unilateral coronal craniosynostosis, the supraorbital symmetry ratio decreased slightly, with a relapse ratio of −3.8 ± 2.6% during long-term follow-up (p = 0.017). Complications included dural tears during osteotomy (n = 2), early distractor removal (n = 2), and wound problems (n = 3).Within the limitations of the study it seems that one-piece fronto-orbital distraction osteogenesis (FODO) generates successful and sustainable results even in the long term. Therefore, this treatment option should be considered for patients with unilateral and bilateral coronal craniosynostoses whenever appropriate.

The many NOs to the use of Class IC antiarrhythmics: weren't the guidelines too strict?

Class IC antiarrhythmic drugs (AADs) currently represent a cornerstone in the therapy of atrial fibrillation, both for the restoration of sinus rhythm and for the prophylaxis of long-term relapses. They also play an important role in the treatment of idiopathic ventricular arrhythmias. Following the results of the Cardiac Arrhythmia Suppression Trial study, flecainide and by extension the other Class IC AADs were contraindicated in patients with ischaemic and structural heart disease, due to their pro-arrhythmic effect and the consequent increase in mortality observed in the study. Recent studies carried out on patients with chronic coronary heart disease without previous heart attacks and/or residual ischaemia have shown a good safety profile for this class of drugs. In addition, other studies have shown excellent efficacy in the absence of pro-arrhythmic effects of Class IC AADs in patients with structural heart disease such as arrhythmogenic right ventricular cardiomyopathy (ARVC) and tachy-cardiomyopathy. The purpose of this review is to evaluate the appropriate use of Class IC AADs in the different patient subgroups, in the light of the evidence and new diagnostic and therapeutic tools available.

Description and outcome of dogs with primary immune-mediated polyarthritis: 73 cases (2012-2017).

To provide a description of primary idiopathic immune-mediated polyarthritis, including long-term outcome and relapse rates, for dogs starting treatment with corticosteroids alone or corticosteroids with a second immunosuppressant. Medical records were reviewed between January 2012 and December 2017 to identify dogs diagnosed with primary immune-mediated polyarthritis. Data including signalment, clinicopathological findings, type and duration of treatment, relapse and outcome were recorded. Seventy-three dogs were included. Fifty-four dogs were started on corticosteroid monotherapy (an additional immunosuppressant was introduced later in 27/54 dogs) and 19 dogs were treated with multi-modal immunosuppression from the outset. Ninety-five percent (69/73) of dogs responded favourably to therapy although death was attributed to immune-mediated polyarthritis in 19% (14/73) of dogs. Relapse of clinical signs was reported in 53% (39/73) dogs (31/39 while on treatment), with multiple relapses observed in 17 dogs. Complete cure (permanent withdrawal of immunosuppressive medication) was achieved in 46 dogs (63%). Overall, 81% of dogs had a well-managed disease for an extended timeframe (≥1131 days). Fourteen of 19 (74%) dogs that started treatment with multi-modal immunosuppression and 32 of 54 (59%) started on corticosteroids alone achieved a complete cure. This study provides extended follow-up information for a large cohort of dogs with primary immune-mediated polyarthritis. Immunosuppressive therapy was discontinued in the majority of dogs but disease-associated mortality remains high.

Comparative analysis of anti-relapse treatment regimens in 110 patients with hepatic and pulmonary hydatid echinococcosis.

Hydatid echinococcosis is worm disease caused by Echinococcus granulosus, that is primarily detected in the liver and lungs. This study aimed at determining the clinical tolerance and efficacy of albendazole in patients with cystic echinococcosis, depending on the volume of the previous one. We retrospectively (from 2016 to 2020 years) analyzed patients who have been treated with two treatment regimens (28-day courses with a 14-day break and continuous drug intake for 60 days), which are used in the Russian Federation. There were 110 patients (after surgery) who had hydatid echinococcosis of the liver and lungs; the diagnosis of these patients was confirmed morphologically (intra-vitam). A retrospective analysis was carried out on the following matters: (1) the duration of anti-relapse chemotherapy depending on the localization of the parasitic cyst; (2) chemotherapy's side effects and long-term relapses after treatment. We evaluated patients' tolerability of albendazole according to the level of blood cells count and hepatic enzymes. The effectiveness of anti-parasitic treatment was evaluated by imaging studies that did not reveal the growth of new parasitic cysts even in the presence of serum antibodies to echinococcal antigens. A correlation was found between the choice of antiparasitic treatment regimen and the frequency of adverse reactions in lab tests: more often adverse reactions (drug-induced hepatitis, anemia, granulocytopenia) occurred in patients who received a continuous treatment regimen for 60 days (p < 0.05). The frequency of relapses reached 4.5% and was more often observed in patients who received treatment for 28 days with a 14-day break. Continuous drug intake for 60 days is the most effective.

Characteristics and outcomes in patients with infective endocarditis caused by Enterococcus faecium and Enterococcus faecalis

Abstract Background Enterococcus faecalis is the third most common cause of infective endocarditis (IE) and has been associated with a higher risk of relapse and death. Within the enterococcus species, E. faecium is the second most frequent cause of IE. As IE from E. faecalis or E. faecium most likely have different presentations and outcomes, research is needed for individualised and optimised clinical management. Purpose This study aims to characterise baseline characteristics and clinical outcomes for patients with IE caused by E. faecalis or E. faecium, including short- and long-term mortality and relapse. Additionally, we aim to determine risk factors associated with IE caused by the two bacterial species. Methods This is a retrospective study of patients hospitalised with at least one positive blood culture with E. faecalis or E. faecium between January 1, 2016 and December 31, 2018 at two large hospitals in Denmark. IE was diagnosed according to the modified Duke criteria. Index and follow-up data were collected from medical records. Categorical values were compared using chi-square test and categorial data using students t-test. Results 614 patients had a positive blood culture with either E. faecalis (n=279) or E. faecium (n=335). Of these, 64 (10.4%) patients developed IE; E. faecalis in 56 patients (87.5%, male 83.3%, mean age 70 years (SD 14)) and E. faecium in 8 patients (12.5%, male 75.0%, mean age 65 years (SD 13)). The prevalence of IE was 20.1% for E. faecalis bacteraemia and 2.4% for E. faecium bacteraemia (p&amp;lt;0.001). Embolic events during primary admission were seen more often in the E. faecium group (62.5%) compared to the E. faecalis group (10.7%) (p=0.002). Both groups had multiple co-morbidities without significant differences between groups (Table 1). Nineteen (40.4%) of the patients with E. faecalis IE had a minimum of one previous admission with E. faecalis bacteraemia within the last year before the IE diagnosis, whereas this was not seen for any patients with E. faecium IE. The 30-days all-cause mortality was 5.4% for patients with E. faecalis IE and 25% for patients with E. faecium IE (p=0.22). After a median follow up of 3.1 years (IQR=0.46–3.94) all-cause mortality was 55.4% for patients with E. faecalis IE and 62.5% for patients with E. faecium IE (p=1.00) (Table 1). Conclusion The prevalence of IE was significantly higher in patients with E. faecalis bacteraemia than with E. faecium bacteraemia. While the prevalence of complications was higher in patients with E. faecium IE, the difference was only significant for embolic events. This indicates that E. faecium IE is associated with a worse outcome compared to the outcome in patients with E. faecalis IE. All-cause mortality was above 50% for both groups, i.e. considerably higher than generally seen in patients with IE. These findings may be of importance of management of patients with E. faecalis or with E. faecium bacteraemia – and endocarditis. Funding Acknowledgement Type of funding sources: None.

Vincristine, Doxorubicin, and Dexamethasone Induction before Autologous Stem Cell Transplantation in Patients with AL Amyloidosis: A Retrospective Comparison with Frontline Stem Cell Transplantation.

Objective High-dose melphalan and autologous stem cell transplantation (ASCT) therapy for AL amyloidosis are now associated with reduced mortality based on the application of strict criteria. However, there is no long-term evidence concerning the performance of induction therapy with newer agents, such as bortezomib or daratumumab. Concerns regarding long-term relapse despite treatment with ASCT exist, and missing the opportunity to perform ASCT might occur if induction proves to not be efficacious and cardiac amyloidosis progression deprives the patients of a chance to receive ASCT. We herein report good amyloid control by vincristine, doxorubicin, and dexamethasone (VAD) induction therapy and argue the importance of induction therapy before ASCT. Methods We compared patients who underwent VAD induction and ASCT (VAD+ASCT) with patients who underwent frontline ASCT in our hospital. Patients A total of 26 patients with histologically proven AL amyloidosis were included (18 in the VAD+ASCT group and 8 in the frontline ASCT). Results In the VAD+ASCT group, the 10-year overall survival and renal response rates were 82% and 43%, respectively. The renal response rate at two years in the VAD+ASCT group was significantly better than that in the frontline ASCT group. Although there was no significant difference in the survival rates between the two groups, the time to next treatment or death was significantly better in the VAD+ASCT group than in the the frontline ASCT group. Acute kidney injury was the most frequent reason for failure to receive two courses of VAD, and early mortality was mainly due to gastrointestinal complications. Conclusion Considering that only those who underwent 2 courses of VAD experienced a 10-year renal response, induction therapy was deemed to be directly related to the long-term control of AL amyloidosis.

RANKL inhibition for giant cell lesions of the jaw: A retrospective cohort analysis

BackgroundIn all giant-cell-rich lesions (GCRL) occurring in bone, a common underlying excessive RANKL expression is held responsible for the osteolytic activity. Apart from giant cell tumour of bone (GCTB), systematic outcome analysis of RANKL inhibition in other GCRL is unavailable. The aim of this study is to assess the efficacy and safety of a 1-year denosumab protocol in giant cell lesions of the jaw (GCLJ). MethodsA retrospective cohort study was conducted compromising patients treated with a 1-year protocol of monthly subcutaneously administered 120 mg denosumab. Objective tumour response based on histology and imaging was used to calculate objective tumour response rate, progression-free survival (PFS) and time to progression. Type, severity and frequency of adverse events were recorded in a standardised way to assess safety. ResultsTwenty patients, predominantly female (90%), were included. Fifty-five per cent of lesions were located in the mandible; most classified as aggressive lesions (90%). Thirty-five per cent (7/20) of cases were either recurrent after prior treatment or progressive, while on other drug treatment. Objective tumour response rate was 100% after 12 months of treatment. Median PFS was 50.4 months (95% CI 38.0–62.8) with a cumulative PFS rate of 22.6% (95% CI 1.8–43.4) at 5 years follow-up. Median time to progression was 38.4 months (95% CI 26.0–50.8). Treatment was well tolerated, and none of the patients had to interrupt therapy for toxicity. ConclusionHigh-dose denosumab is effective and safe in achieving a complete response in GCLJ within 12 months. The high long-term relapse rate after treatment cessation is the main obstacle for denosumab to become standard treatment for GCLJ.

Integrated longitudinal analysis of adult grade 4 diffuse gliomas with long-term relapse interval revealed upregulation of TGF-β signaling in recurrent tumors.

Adult-type diffuse gliomas, CNS WHO grade 4 are the most aggressive primary brain tumors and represent a particular challenge for therapeutic intervention. In a single-center retrospective study of matched pairs of initial and post-therapeutic glioma cases with a recurrence period greater than 1 year, we performed whole exome sequencing combined with mRNA and microRNA expression profiling to identify processes that are altered in recurrent gliomas. Mutational analysis of recurrent gliomas revealed early branching evolution in 75% of the patients. High plasticity was confirmed at the mRNA and miRNA levels. SBS1 signature was reduced and SBS11 was elevated, demonstrating the effect of alkylating agent therapy on the mutational landscape. There was no evidence for secondary genomic alterations driving therapy resistance. ALK7/ACVR1C and LTBP1 were upregulated, whereas LEFTY2 was downregulated, pointing towards enhanced Tumor Growth Factor β (TGF-β) signaling in recurrent gliomas. Consistently, altered microRNA expression profiles pointed towards enhanced Nuclear Factor Kappa B and Wnt signaling that, cooperatively with TGF-β, induces epithelial to mesenchymal transition (EMT), migration, and stemness. TGF-β-induced expression of pro-apoptotic proteins and repression of antiapoptotic proteins were uncoupled in the recurrent tumor. Our results suggest an important role of TGF-β signaling in recurrent gliomas. This may have clinical implications since TGF-β inhibitors have entered clinical phase studies and may potentially be used in combination therapy to interfere with chemoradiation resistance. Recurrent gliomas show high incidence of early branching evolution. High tumor plasticity is confirmed at the level of microRNA and mRNA expression profiles.

Prophylactic central neck dissection in differentiated thyroid cancer: risks and benefits in a population with a high rate of tumour recurrence.

The role of prophylactic central neck dissection (pCND) in differentiated thyroid cancer (DTC) is still controversial. In a cohort of 274 DTC cN0 patients with a high rate of tumour recurrence, who underwent total thyroidectomy with or without pCND, clinical and histopathological features were retrospectively analysed. In our cohort, no clinical or histopathological features are able to predict the presence of central lymph node metastases (CLNM) at diagnosis, which instead represents the only variable significantly associated with a higher risk of long-term tumour relapse, independently from age, sex, BMI and radioiodine treatment (OR=1.03, CI95% 1.002-1.074, p<0.05). Moreover, our study demonstrates that pCND does not significantly increase the risk of post-surgical complications. In our setting, pCND could have a key role in the management of DTC. The risks and benefits of pCND should be evaluated for each population to make the most appropriate therapeutic choice.

Long-term seizure, psychiatric and socioeconomic outcomes after frontal lobe epilepsy surgery

ObjectiveResective surgery for selected individuals with frontal lobe epilepsy can be effective, although multimodal outcomes are less established than in temporal lobe epilepsy. We describe long-term seizure remission and relapse patterns, psychiatric comorbidity, and socioeconomic outcomes following frontal lobe epilepsy surgery. MethodsWe reviewed individual data on frontal lobe epilepsy procedures at our center between 1990 and 2020. This included the presurgical evaluation, operative details and annual postoperative seizure and psychiatric outcomes, prospectively recorded in an epilepsy surgery database. Outcome predictors were subjected to multivariable analysis, and rates of seizure freedom were analyzed using Kaplan-Meier methods. We used longitudinal assessment of the Index of Multiple Deprivation to assess change in socioeconomic status over time. ResultsA total of 122 individuals with a median follow-up of seven years were included. Of these, 33 (27 %) had complete seizure freedom following surgery, with a further 13 (11 %) having only auras. Focal MRI abnormality, histopathology (focal cortical dysplasia, cavernoma or dysembryoplastic neuronal epithelial tumor) and fewer anti-seizure medications at the time of surgery were predictive of a favorable outcome; 67 % of those seizure-free for the first 12 months after surgery never experienced a seizure relapse. Thirty-one of 50 who had preoperative psychiatric pathology noticed improved psychiatric symptomatology by two years postoperatively. New psychiatric comorbidity was diagnosed in 15 (13 %). Persistent motor complications occurred in 5 % and dysphasia in 2 %. No significant change in socioeconomic deciles of deprivation was observed after surgery. SignificanceFavorable long-term seizure, psychiatric and socioeconomic outcomes can be seen following frontal lobe epilepsy surgery. This is a safe and effective treatment that should be offered to suitable individuals early.