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This study investigated the effect of the timing of primary endodontic treatment and dosage of radiotherapy on the remaining filling material (RFM) during endodontic reintervention. 60 single-rooted human mandibular premolars were distributed into five groups (n = 12), according to the timing and dosage of radiation (55Gy or 70Gy): NegativeCG-non-irradiated teeth; Endo-pre-RT 55/70 -obturation before irradiation (55Gy or 70Gy); Endo-post-RT 55/70 -obturation and reintervention after irradiation (55Gy or 70Gy). Roots were cleaved and analysed under stereomicroscope and Scanning Electron Microscope to quantify (%) the RFM. Experimental groups had a significantly greater amount (p < 0.05) of RFM in the middle and apical thirds than the control group, except for Endo-pre-RT 55 in the middle third (p < 0.0001). The apical third had greater amount of RFM (p < 0.05). Radiation therapy, before and after primary endodontic treatment, increased the amount of RFM, regardless of the dose delivered. When necessary, reintervention preferably must be performed before radiation therapy., (© 2024 Australian Society of Endodontology Inc.)

Both root canal sealer-based and supplementary protocols may influence removal of filling material during endodontic retreatment. Mesial root canals of extracted mandibular molars were prepared using HyFlex EDM 25/.08, and filled with a calcium silicate sealer (Bio-C Sealer), or an epoxy resin (AH Plus), using the single cone technique (n = 12). Retreatment was performed using ProDesign Logic (PDL) RT and PDL 35/.05. The specimens were randomly divided into two experimental groups (n = 12), and the sealers were distributed similarly. A supplementary protocol was performed with PDL 50/.01 or XP-endo Finisher. Root canal transportation and volume, in addition to the remaining filling material percentage were evaluated using high-resolution (5 µm voxel size) micro-CT. Statistical analysis was performed using t-tests (α = 0.05). Root canals filled with AH Plus presented high residual filling material (p < 0.05). Both protocols decreased residual volume of filling material in the apical third (p < 0.05). PDL 50/.01 increased the apical root canal volume (p < 0.05). No difference was observed between the systems regarding canal transportation (p > 0.05). In conclusion, AH Plus is more difficult to remove from the apical third than Bio-C Sealer. PDL 50/.01 and XP-endo Finisher enabled greater removal of filling materials in the apical third, in the retreatment of curved root canals, without promoting apical transport.

Objective: A systematic review and meta-analysis of the literature was carried out assessing the success rate of root canal retreatment using gutta percha., Data Sources: Four of the largest databases were used to identify existing literature with no date or language restrictions. PubMed, Cochrane, ScienceDirect, Scopus and other additional sources were searched. Grey literature was also reviewed., Study Selection: Two authors, with Master's degrees in endodontics and with extensive university teaching experience, were selected to screen the databases to identify suitable studies. In case the authors were not able to agree during the study selection process, a third investigator was consulted. Specific inclusion and exclusion criteria were outlined and adhered to in the study selection. Two randomised controlled trials, seven single arm prospective studies and one single arm ambispective study published before the 10th of December 2022 were included. These studies evaluated the success of root canal re-treatment, obturated with gutta percha with at least a 1-year follow-up. Nine of the studies were published between 1998 and 2022. Seven studies were conducted in Europe, one in North America and one in Asia., Data Extraction and Synthesis: Standard Cochrane methods to assess interval validity were used. Risk of bias in individual studies was assessed using The Newcastle-Ottawa quality assessment scale (NOS) for single-arm studies, and the Cochrane risk of bias tool (RoB2) was used for randomised controlled trials. Outcome measures were standardised as either success or failure of root canal retreatment. Success was classified into 2 different criteria: Strict criteria = absence of clinical signs and symptoms and radiographically normal periodontal ligament space; and Loose criteria = absence of clinical signs and symptoms and absence or reduction of apical radiolucency in the control radiograph. Statistical analysis was undertaken using R software and the Freeman-Turkey transformation was performed. Results were visualised using forest plots. Heterogeneity between studies was measured using the Cochrane Q test and I 2 values., Results: Whilst following strict criteria, the success rate of non-surgical root canal retreatment obturated with gutta percha was 71% for 1-3 years follow-up (95% CI, 0.66-0.77) and 77% for 4-5 years follow-up (95% CI, 0.67-0.86). Heterogeneity was moderate (I 2  = 61.4) and low (I 2  = 0.0), respectively. Factors reducing the success rate of root canal re-retreatment under the strict criteria were older patients, mandibular teeth, molar teeth, the presence of a peri-apical radiolucency, teeth with a previous radiolucency, large peri-apical radiolucency's, higher initial periapical index scores and multiple visit-retreatments. Following the loose criteria, the success rate of non-surgical root canal re-treatment obturated with gutta percha was 87% for 1-3 years follow-up (95% CI, 0.79-0.93) with significant heterogeneity across the studies (I 2  = 88.5%). Factors influencing the success rate under the loose criteria were large periapical lesions >5 mm and higher initial periapical index (PAI) scores., Conclusions: Non-surgical root canal retreatment results in favourable outcomes. However, there are several factors which can result in a lower success rate: the presence and size of a periapical radiolucency, a higher initial PAI score, multiple-visit retreatments, and the size and position of the tooth., (© 2024. The Author(s).)

Importance: Multiple myeloma is a hematologic malignancy characterized by presence of abnormal clonal plasma cells in the bone marrow, with potential for uncontrolled growth causing destructive bone lesions, kidney injury, anemia, and hypercalcemia. Multiple myeloma is diagnosed in an estimated 34 920 people in the US and in approximately 588 161 people worldwide each year., Observations: Among patients with multiple myeloma, approximately 73% have anemia, 79% have osteolytic bone disease, and 19% have acute kidney injury at the time of presentation. Evaluation of patients with possible multiple myeloma includes measurement of hemoglobin, serum creatinine, serum calcium, and serum free light chain levels; serum protein electrophoresis with immunofixation; 24-hour urine protein electrophoresis; and full-body skeletal imaging with computed tomography, positron emission tomography, or magnetic resonance imaging. The Revised International Staging System combines data from the serum biomarkers β2 microglobulin, albumin, and lactate dehydrogenase in conjunction with malignant plasma cell genomic features found on fluorescence in situ hybridization-t(4;14), del(17p), and t(14;16)-to assess estimated progression-free survival and overall survival. At diagnosis, 28% of patients are classified as having Revised International Staging stage I multiple myeloma, and these patients have a median 5-year survival of 82%. Among all patients with multiple myeloma, standard first-line (induction) therapy consists of a combination of an injectable proteasome inhibitor (ie, bortezomib), an oral immunomodulatory agent (ie, lenalidomide), and dexamethasone and is associated with median progression-free survival of 41 months, compared with historical reports of 8.5 months without therapy. This induction therapy combined with autologous hematopoietic stem cell transplantation followed by maintenance lenalidomide is standard of care for eligible patients., Conclusions and Relevance: Approximately 34 920 people in the US and 155 688 people worldwide are diagnosed with multiple myeloma each year. Induction therapy with an injectable proteasome inhibitor, an oral immunomodulatory agent and dexamethasone followed by treatment with autologous hematopoietic stem cell transplantation, and maintenance therapy with lenalidomide are among the treatments considered standard care for eligible patients.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors are effectively being used in the treatment of non-small cell lung cancer. Although most of their adverse effects are mild to moderate, they occasionally can cause life-threatening interstitial lung disease. We aimed to present a case of lung adenocarcinoma successfully re-treated with erlotinib after recovery with effective treatment of erlotinib-induced interstitial lung disease., Case Description: A 54-year-old nonsmoking woman was diagnosed with metastatic adenocarcinoma of the lung. After progression with first-line chemotherapy, erlotinib 150 mg daily was initiated. On the 45th day of erlotinib treatment, interstitial lung disease occurred and erlotinib was discontinued. Clinical improvement was achieved with dexamethasone treatment and erlotinib was re-initiated. Ten weeks after re-initiation of erlotinib, 100 mg daily partial response was observed., Conclusions: Incidence of interstitial lung disease is higher in men, smokers, and patients with pulmonary fibrosis. Interstitial lung disease radiologically causes ground-glass opacity and consolidation. The physician should quickly evaluate new respiratory symptoms in patients treated with epidermal growth factor receptor tyrosine kinase inhibitors, discontinue the epidermal growth factor receptor tyrosine kinase inhibitor treatment, and initiate corticosteroids if clinical diagnosis is interstitial lung disease.

Purpose: Previously published studies have shown small prostate size, capsular perforation and intraoperative bladder distension are associated with failed trial without a catheter (TWOC) after HoLEP. The study objective was to determine the relationship between MOSES pulse modulation versus standard laser technology and short-term catheter reinsertion following failed TWOC., Materials and Methods: The study included 487 patients who underwent HoLEP, using standard holmium laser settings (180 patients) or MOSES pulse modulation (255 patients), between August 2018 and February 2021. Catheter reinsertion defined as reinsertion following failed TWOC within 30 days of surgery. Association of pulse modulation with catheter reinsertion was examined using single and multivariable logistic regression models. Comparisons of pre and intraoperative characteristics between patients treated without and with pulse modulation were made using a Wilcoxon rank sum test for numeric characteristics or Fisher's exact test for categorical characteristics., Results: Short-term catheter reinsertion occurred in 14% (26/180) of the standard laser setting group as compared with 10% (24/252) of the pulse modulation group. There was no statistically significant association with short-term catheter reinsertion in single (unadjusted OR [standard settings vs. pulse modulation], 1.60; 95% CI, 0.80-2.91; p=0.12) or multivariable analysis adjusting for specimen weight and operative time (adjusted OR [standard settings vs. pulse modulation], 1.44; 95% CI, 0.77-2.68; p=0.25)., Conclusions: In this study, we found no association between post-HoLEP short-term catheter reinsertion following failed TWOC and MOSES pulse modulation. Although MOSES pulse modulation offers several well-documented advantages, catheter reinsertion events appear to be attributable to other factors., Competing Interests: Chandler D. Dora, MD has received payment from Lumenis, LTD for speaking engagements, panel participation and case observation. The other authors have no conflicts of interest to declare., (© The Korean Urological Association, 2021.)

Rationale: Primary signet ring cell carcinoma of the uterine cervix is extremely rare and the clinical characteristics and prognosis are not well known and there are no specific guidelines for treatment., Patient Concerns: A 43-year-old woman was referred to our hospital for abnormal uterine bleeding lasting 1 month., Diagnoses: Histological examination revealed a signet ring cell carcinoma of the uterine cervix. After evaluation of extragenital origin, the patient was diagnosed International Federation of Gynecology and Obstetrics stage IIIC1 primary signet ring cell carcinoma or the uterine cervix., Intervention: The patient was prescribed concomitant chemo-radiation followed by intracavitary brachytherapy., Outcomes: She showed no evidence of disease after treatment but, it recurred after 7 months of last treatment., Lessons: Different approaches to diagnosis and treatment of this rare disease are needed and molecular pathological studies related to the onset of the disease are required., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The safety and efficacy of early second session shock wave lithotripsy (SWL) compared with laser ureteroscopy (URS) for the treatment of upper ureteric stones were evaluated., Methods: From January to October 2019, 108 patients with upper ureteric stones (< 1.5 cm and ≤ 1000 Hounsfield unit (HU)) were randomized into SWL and laser URS groups. The second SWL session was performed within 48-72 h of the first session. Using plain abdominal X-ray and ultrasonography, patients were evaluated 48-72 h after the first SWL session and one week after the second and third SWL sessions or one week after URS. The procedure was considered a success when no additional procedures were needed to clear the stone. To determine the stone-free rate (SFR), noncontrast computed tomography of the urinary tract was performed three months postoperatively., Results: In the SWL group, the success rates were 92.6% and 94.4% after the second and third sessions. The SFR was 96.2% in the laser URS group. The success rates were not significantly different between the second and third SWL sessions versus the laser URS (p = 0.418 and 0.660, respectively). Operative and fluoroscopy times were significantly longer in the SWL group (p = 0.001), and JJ stent insertions were needed after laser URS., Conclusion: Ultraslow full-power SWL treatment of patients with upper ureteric stones (< 1.5 cm and ≤ 1000 HU) with an early second session is safe and effective compared to laser URS. Patients who do not respond to early second SWL session should be shifted to another treatment modality., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Background: In subfertile couples, couples who have tried to conceive for at least one year, intrauterine insemination (IUI) with ovarian hyperstimulation (OH) is one of the treatment modalities that can be offered. When IUI is performed a second IUI in the same cycle might add to the chances of conceiving. In a previous update of this review in 2010 it was shown that double IUI increases pregnancy rates when compared to single IUI. Since 2010, different clinical trials have been published with differing conclusions about whether double IUI increases pregnancy rates compared to single IUI., Objectives: To determine the effectiveness and safety of double intrauterine insemination (IUI) compared to single IUI in stimulated cycles for subfertile couples., Search Methods: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase and CINAHL in July 2020 and LILACS, Google scholar and Epistemonikos in February 2021, together with reference checking and contact with study authors and experts in the field to identify additional studies., Selection Criteria: We included randomised controlled, parallel trials of double versus single IUIs in stimulated cycles in subfertile couples., Data Collection and Analysis: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information., Main Results: We identified in nine studies involving subfertile women. The evidence was of low quality; the main limitations were unclear risk of bias, inconsistent results for some outcomes and imprecision, due to small trials with imprecise results. We are uncertain whether double IUI improves live birth rate compared to single IUI (odds ratio (OR) 1.15, 95% confidence interval (CI) 0.71 to 1.88; I 2 = 29%; studies = 3, participants = 468; low quality evidence). The evidence suggests that if the chance of live birth following single IUI is 16%, the chance of live birth following double IUI would be between 12% and 27%. Performing a sensitivity analysis restricted to only randomised controlled trials (RCTs) with low risk of selection bias showed similar results. We are uncertain whether double IUI reduces miscarriage rate compared to single IUI (OR 1.78, 95% CI 0.98 to 3.24; I 2 = 0%; studies = 6, participants = 2363; low quality evidence). The evidence suggests that chance of miscarriage following single IUI is 1.5% and the chance following double IUI would be between 1.5% and 5%. The reported clinical pregnancy rate per woman randomised may increase with double IUI group (OR 1.51, 95% CI 1.23 to 1.86; I 2 = 34%; studies = 9, participants = 2716; low quality evidence). This result should be interpreted with caution due to the low quality of the evidence and the moderate inconsistency. The evidence suggests that the chance of a pregnancy following single IUI is 14% and the chance following double IUI would be between 16% and 23%. We are uncertain whether double IUI affects multiple pregnancy rate compared to single IUI (OR 2.04, 95% CI 0.91 to 4.56; I 2 = 8%; studies = 5; participants = 2203; low quality evidence). The evidence suggests that chance of multiple pregnancy following single IUI is 0.7% and the chance following double IUI would be between 0.85% and 3.7%. We are uncertain whether double IUI has an effect on ectopic pregnancy rate compared to single IUI (OR 1.22, 95% CI 0.35 to 4.28; I 2 = 0%; studies = 4, participants = 1048; low quality evidence). The evidence suggests that the chance of an ectopic pregnancy following single IUI is 0.8% and the chance following double IUI would be between 0.3% and 3.2%., Authors' Conclusions: Our main analysis, of which the evidence is low quality, shows that we are uncertain if double IUI improves live birth and reduces miscarriage compared to single IUI. Our sensitivity analysis restricted to studies of low risk of selection bias for both outcomes is consistent with the main analysis. Clinical pregnancy rate may increase in the double IUI group, but this should be interpreted with caution due to the low quality evidence. We are uncertain whether double IUI has an effect on multiple pregnancy rate and ectopic pregnancy rate compared to single IUI., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

The removal of direct composite veneers, when the retreatment is necessary, represents a challenge to the clinician, since the healthy dental structure must be preserved. Thus, the aim of this study was to compare the accuracy provided by different auxiliary devices during retreatment of direct composite veneers. Seventy-five bovine teeth were prepared for direct composite veneers, scanned (T1), and restored. Specimens were divided into 5 groups for retreatment: conventional high-speed handpiece without auxiliary device (WD); high-speed handpiece with a white LED (WL); high-speed handpiece with an UV light (UL); electric motor and multiplier 1/5 handpiece (EM); and conventional high-speed handpiece using magnifying loupe (ML). After retreatments, other scanning was performed (T2). Changes on dental wear or composite residues areas, as well as, the average between wear and presence of residues were measured. Data were submitted to Kruskal-Wallis and Dunn's post-test (p≤ 0.05). There were greater areas of wear for ML, being statistically superior to WD and EM groups. The ML presented smaller residues areas, being statistically lower than the WD and EM groups. Regarding the average between wear and the presence of resin residues, additional wear occurred after re-preparation, regardless of the group. Magnifying loupe promoted greater areas of wear and smaller areas of resin residues than conventional high-speed handpiece and electric motor. Both techniques using light accessories did not differ from other ones., Competing Interests: The authors have declared that no competing interests exist.

Background: Idiopathic intracranial hypertension is a disease of raised intra-cranial pressure of unknown etiology. Lateral cerebral venous sinus stenosis (VSS) has been increasingly reported in these patients, and stenting has emerged as an alternative treatment for medically refractory symptoms. Treatment efficacy on meta-analysis appears promising, but identifying which patients are likely to benefit most, and which are likely to require repeat procedures, is currently unclear., Methods: We retrospectively reviewed a prospectively collected database of 79 patients treated with venous sinus stenting at a single academic center with minimum follow-up of 18 months. We extracted baseline clinical data, as well as manometry at lumbar puncture and during angiography, and used logistic regression to identify parameters that could predict stent failure., Results: Retreatment rate after successful VSS was 13.9%. Lumbar puncture opening pressure (OP) was shown to significantly predict treatment failure (ß=0.06; OR=1.064 (1.003-1.135); P=0.039). This effect remained significant when age, sex and body mass index were added to the model (ß=0.06; OR=1.066 (1.002-1.140); P=0.043). OP was correlated with venous sinus manometry readings in the superior sagittal and transverse sinus pre-stent placement, as well trans-stenotic gradient (P<0.001)., Conclusions: Higher lumbar puncture OP was associated with an increased risk of stent failure in transverse sinus stenting for idiopathic intracranial hypertension, although the performance of this model as a linear discriminator was poor. Further studies are required to better assess which patients are at greatest risk of treatment failure., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

The continuous advances in the treatment landscape of multiple myeloma has led to the approval of several novel agents and their combinations that significantly improved patient outcomes. Despite their undoubtful effectiveness in the context of clinical trials, their impact on real-world (RW) clinical practice remains debatable. RW data on the role of novel agents and their combinations among patients with relapsed/refractory multiple myeloma have confirmed the efficacy of proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. However, the magnitude of the benefit and the safety profile may differ among RW studies and between RW and pivotal clinical trials. Several variables may pertain to these observations and include patient selection, ethnicity, age, comorbidities, disease stage at diagnosis and at relapse, number of prior lines of therapy, disease subtype, presence of renal impairment, extramedullary disease, and cytogenetic abnormalities. All these contribute to a varying degree of disease and patient heterogeneity among the studies that may result in a differential treatment effect. The expertise of each medical center and the treatment setting in terms of availability and drug access are particularly important as well. Interestingly, RW observations may serve as proof of concept for designing novel clinical trials, as is the case with retreatment studies. In conclusion, clinical trial and RW data are complementary, and they should be considered to improve both clinical trial design and clinical practice., (Copyright © 2021. Published by Elsevier Inc.)

Background: Patients with COVID-19 and ARDS on prolonged mechanical ventilation are at risk for developing endotracheal tube (ETT) obstruction that has not been previously described in patients with ARDS due to other causes. The purpose of this report is to describe a case series of patients with COVID-19 and ARDS in which ETT occlusion resulted in significant clinical consequences and to define the pathology of the obstructing material., Methods: Incidents of ETT occlusion during mechanical ventilation of COVID-19 patients were reported by clinicians and retrospective chart review was conducted. Statistical analysis was performed comparing event rates between COVID-19 and non-COVID 19 patients on mechanical ventilation over the predefined period. Specimens were collected and submitted for pathological examination., Findings: Eleven COVID-19 patients experienced endotracheal tube occlusion over a period of 2 months. Average age was 69 (14.3, range 33-85) years. Mean APACHE III score was 73.6 (17.3). All patients had AKI and cytokine storm. Nine exhibited biomarkers for hypercoagulability. Average days on mechanical ventilation before intervention for ETT occlusion was 14 (5.18) days (range of 9 to 23 days). Five patients were discharged from the ICU, and 4 expired. Average documented airway resistance on admission was 14.2 (3.0) cm H 2 O/L/sec. Airway resistance before tube exchange was 28.1 (8.0) cm H 2 O /L/sec. No similar events of endotracheal tube occlusion were identified in non-COVID patients on mechanical ventilation during the same time period. Microscopically, the material consisted of mucin admixed with necrotic cell debris, variable numbers of degenerated inflammatory cells, oral contaminants and red blood cells., Interpretation: Patients with COVID-19 and ARDS on prolonged mechanical ventilation are at risk for developing ETT obstruction due to deposition of a thick, tenacious material within the tube that consists primarily of mucin and cellular debris. Clinicians should be aware of this dangerous but treatable complication.

Recent advances in molecular profiling, have reclassified medulloblastoma, an undifferentiated tumor of the posterior fossa, in at least four diseases, each one with differences in prognosis, epidemiology and sensibility to different treatments. The recommended management of a lesion with radiological characteristics suggestive of MB includes maximum safe resection followed by a post-surgical MR < 48 h, LCR cytology and MR of the neuroaxis. Prognostic factors, such as presence of a residual tumor volume > 1.5 cm 2 , presence of micro- or macroscopic dissemination, and age > 3 years as well as pathological (presence of anaplastic or large cell features) and molecular findings (group, 4, 3 or p53 SHH mutated subgroup) determine the risk of relapse and should guide adjuvant management. Although there is evidence that both high-risk patients and to a lesser degree, standard-risk patients benefit from adjuvant craneoespinal radiation followed by consolidation chemotherapy, tolerability is a concern in adult patients, leading invariably to dose reductions. Treatment after relapse is to be considered palliative and inclusion on clinical trials, focusing on the molecular alterations that define each subgroup, should be encouraged. Selected patients can benefit from surgical rescue or targeted radiation or high-dose chemotherapy followed by autologous self-transplant. Even in patients that are cured by chemorradiation presence of significant sequelae is common and patients must undergo lifelong follow-up.

Introduction: Rates of aneurysm occlusion with the pipeline embolization device (PED) has varied widely in the literature from 55.7% to 93.3% at 6 months, which may reflect a difference in technique including sizing and number of devices used., Methods: 140 cases at our institution were retrospectively reviewed, and aneurysms treated with a single PED vs. multiple were compared., Results: Complete aneurysm occlusion was achieved in 86.9% at 6 months, 91.8% at 1 year, and 97.6% at longest follow-up. Retreatment with an additional device was required in 7 (5.1%). Major and minor complication rate within 30 days was 1.4% and 5.0%, and at greater than 30 days was 0.8% and 3.1%. Patients treated with multiple PEDs had significantly higher rates of aneurysm occlusion at 6 months (92.9% vs. 75.6%, p = 0.017) and 12 months (98.4% vs. 81.1%, p = 0.014), with no difference in complications. The two groups were similar aside from a higher number of ophthalmic and paraophthalmic aneurysms treated with multiple PEDs (23.4% vs. 6.5%, p = 0.004; and 35.1% vs. 17.4%, p = 0.020), and more posterior communicating artery and recurrent aneurysms treated with a single PED (28.3% vs. 3.2%, p = 0.001; 23.9% vs. 8.5%, p = 0.031). The use of multiple PEDs was found to be an independent predictor of aneurysm occlusion in a multivariate analysis (p = 0.015)., Conclusions: The use of multiple PEDs for intracranial aneurysms leads to significantly higher occlusion rates without added morbidity. This benefit is particularly appropriate for ophthalmic segment aneurysms, while more distal segments with eloquent perforating branches should be managed with caution., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background & Aims: There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients., Methods: Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients., Results: Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12., Conclusions: VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients., Lay Summary: The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%)., Competing Interests: Conflict of interest Julia Dietz: Research support from Gilead. Dolores Merino: Speaking and/or consulting fees from Gilead, ViiV Health Care, Merck/MSD, Janssen. Johannes Vermehren: Speaking and/or consulting fees from Abbott, AbbVie, Gilead, Bristol-Myers Squibb, Medtronic, Merck/MSD, and Roche. Andreas E. Kremer: Speaking and/or consulting fees: AbbVie, Beiersdorf, Bristol-Myers Squibb, CymaBay, Eisai, Falk, Gilead, GSK, Intercept, Lilly, MSD, and Zambon. Heinz Zoller: Speaking and/or consulting fees: Abbott, AbbVie, Bristol-Myers Squibb, Gilead, Merck/MSD, Pharmacosmos, Roche, Vifor. Grant support from Abbvie, Gilead, Pharmacosmos, and Vifor. Elisabetta Degasperi: Speaking and/or consulting fees: AbbVie, Gilead, MSD. Laura Sighinolfi: Speaking and/or consulting fees: Merck/MSD, ViiV Healthcare. Elisa Fernández-Fuertes: Speaking and/or consulting fees: Abbvie, Gilead, Merck/MSD, Janssen, ViiV. Leopoldo Muñoz-Medina: Speaking and/or consulting fees: AbbVie, Gilead, Janssen, ViiV. Rudolf Stauber: Speaking and/or consulting fees: AbbVie, Bayer, BMS, Eisai, Ipsen Gilead, Roche. Pietro Lampertico: Speaking and/or consulting fees: AbbVie, Alnylam, Arrowhead, BMS, Eiger, Gilead, GSK, Janssen, MSD, MYR, Roche, Spring Bank. Stefan Zeuzem: Speaking and/or consulting fees: Abbvie, BMS, Gilead, Janssen, Merck/MSD. Francesca Ceccherini-Silberstein: Speaking and/or consulting fees: Abbvie, Gilead, Janssen, Merck/MSD, ViiV Healthcare. Federico García: Speaking and/or consulting fees: Abbvie, Gilead, Hologic, Merck/MSD, Roche, Qiagen. Christoph Sarrazin: Speaking and/or consulting fees: Abbvie, Gilead, Merck/MSD, Research support: Abbvie, Gilead. All other authors report no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Rationale: Antibiotic resistance poses a challenge for Helicobacter pylori eradication treatment. Current guidelines strongly recommend avoiding repeated treatments with the same antibiotic to prevent the emergence of drug resistance. However, for penicillin-allergic patients with recurrent H. pylori eradication failures, avoiding repeated treatments with the same antibiotic severely limits the choice of treatment., Patient Concerns: A 47-year-old woman with a penicillin allergy for whom 2 previous levofloxacin and bismuth-based therapies had failed., Diagnosis: H. pylori infection., Interventions: Agar dilution susceptibility testing and gene sequence analysis was performed to confirm levofloxacin susceptibility again. Therefore, we treated her with a 14-day regimen consisting of levofloxacin (500 mg once daily), furazolidone (100 mg twice daily), colloidal bismuth pectin (220 mg twice daily), and esomeprazole (20 mg twice daily)., Outcomes: The patient was successfully treated with a third levofloxacin and bismuth-based regimen., Lessons: Antibiotics included in previous failed therapies need not be eliminated if no antibiotic resistance is found on antimicrobial susceptibility testing., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The main goal of management in patients with non-small cell lung cancer (NSCLC) and malignant pleural effusion (MPE) is palliation. Patients with MPE and actionable mutations, because their disease is expected to respond quickly and markedly to targeted therapy, are less likely than those without actionable mutations to receive definitive MPE management. Whether such management is indicated in these patients is unclear., Research Questions: What is the time to ipsilateral MPE recurrence requiring intervention in patients with metastatic NSCLC by mutation status? What are the risk factors for MPE recurrence?, Study Design and Methods: Retrospective cohort study of consecutive patients who underwent initial thoracentesis for MPE. We used a Fine-Gray subdistribution hazard model to calculate the time to ipsilateral MPE recurrence requiring intervention within 100 days of initial thoracentesis and to identify variables associated with time to pleural fluid recurrence., Results: A total of 396 patients, comprising 295 (74.5%) without and 101 (25.5%) with actionable mutations, were included. Most patients with actionable mutations (90%) were receiving targeted treatment within 30 days of initial thoracentesis. On univariate analysis, patients with actionable mutations showed a significantly higher hazard of MPE recurrence. On multivariate analysis, this difference was not significant. Larger pleural effusion size on chest radiography (P < .001), higher pleural fluid lactate dehydrogenase (P < .001), and positive cytologic examination results (P = .008) were associated with an increased hazard of recurrence., Interpretation: Our findings indicate that patients with actionable mutations have a similar risk of MPE recurrence when compared with patients without mutations and would benefit from a similar definitive management approach to MPE., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Purpose: The present study aimed to investigate the efficacy and severity of adverse effects of HCAG and CAG re-induction chemotherapy in elderly low- and intermediate-risk group patients diagnosed with acute myeloid leukemia (AML) following induction failure., Methods: A total of 94 AML patients were enrolled in the study, of whom 46 were treated with HCAG chemotherapy, while 48 were treated with CAG chemotherapy., Result: The complete remission (CR) was 39.6% in the patients with HCAG, while the CR was 33.3% in the CAG group. The overall remission (ORR) was 63.0% and 43.5% in patients of the HCAG and CAG groups, respectively (P = 0.038). The median survival time of progression free survival (PFS) was 8.0 (95% CI 3.843-10.157) months in the HCAG group and 7.0 (95% CI 2.682-13.318) months in the CAG group (P = 0.032). A total of 31 patients in the HCAG group suffered from grade 4 hematological toxicity, whereas 29 patients were treated with CAG (P = 0.622). A total of 27 (58.7%) cases indicated apparent pulmonary infection in the HCAG group, while 25 (52.1%) were noted with this complication in the CAG group (P = 0.519). Oral cavity toxicity was evident for 13 (28.3%) and 11 (23.0%) cases in the HCAG and CAG groups, respectively (P = 0.216)., Conclusion: The HCAG regimen was more effective than the CAG regimen in elderly low- and intermediate-risk group patients diagnosed with acute myeloid leukemia although the HCAG regimen exhibited similar toxicity with that of the CAG group.

Background: The antibiotic resistance profile of Helicobacter pylori (H. pylori) is constantly changing. Up-to-date and reliable data for the effectiveness of first-line H. pylori treatment protocols are necessary to provide evidence-based best-practice guidelines., Objectives: To determine the effectiveness, compliance and safety of first-line treatment for H. pylori in Israel., Methods: An observational, prospective, multicenter study was conducted in tertiary referral centers in Israel, as part of the European registry on H. pylori management (Hp-EuReg). H. pylori-infected patients were included from 2013 to March 2020. Data collected included demographics, clinical data, diagnostic tests, previous eradication attempts, current treatment, compliance, adverse events, and treatment outcome result., Results: In total, 242 patients were registered, including 121 (50%) who received first-line therapy, 41% of these individuals received clarithromycin based triple therapy and 58.9% received a four-drug regimen. The overall effectiveness of first-line therapy was 85% and 86% by modified intention-to-treat and per protocol analyses, respectively. The effectiveness of both sequential and concomitant therapies was 100% while clarithromycin-based triple therapy achieved an eradication rate of 79%. Treatment eradication was higher among patients who received high dose proton pump inhibitor (PPI) compared to those treated with low dose PPI (100% vs. 81.5% respectively, P < 0.01). No difference in treatment effectiveness was found between 7-, 10-, and 14-day treatment., Conclusions: The effectiveness of clarithromycin-based triple therapy is suboptimal. First-line treatment of H. pylori infection should consist of four drugs, including high dose PPI, according to international guidelines.

Background: Immune checkpoint inhibitors (ICI) have transformed the standard care of cancer treatment. Recent case reports describe ICI-mediated myocarditis with an atypical presentation and fatal potential which lead to permanent interruption of immunotherapy., Objectives: To characterize ICI-mediated myocarditis and re-introduction to immunotherapy., Methods: During 2019, 849 patients were treated with ICI at Tel Aviv Sourasky Medical Center for the diagnosis of lung adenocarcinoma, gastric adenocarcinoma, urothelial carcinoma, and hepatocellular carcinoma. Overall, seven (0.8%) patients were diagnosed with ICI-mediated myocarditis, according to the European Society of Cardiology guidelines of myocarditis 2013. We retrospectively evaluated their presentation, severity, and clinical outcomes., Results: Among the seven patients, only one had a history of cardiac disease. The majority were diagnosed with lung adenocarcinoma and treated with anti-programmed death-1 antibody. All patients were treated with single-agent ICI. Most patients presented with cardiac symptoms, elevated troponin and typical cardiac magnetic resonance; however, only three had reduced ejection fraction. Overall, three patients were chosen for re-introduction with concomitant low dose steroids and weekly troponin follow-up. Two patients diagnosed with grade I and II renewed therapy successfully with no recurrence of symptoms and improvement in disease burden. The one patient diagnosed with grade III developed worsening of cardiac symptoms after the 1st cycle and, therefore, therapy was interrupted permanently., Conclusions: ICI-mediated myocarditis is potentially fatal and leads to permanent interruption of life-saving cancer therapy. The current data suggest that re-introduction may be considered in low-grade patients; however, a better definition of the diagnosis and grading is needed.

Objectives: Identifying and understanding the main risk factors associated with extubation failure of very low birthweight (VLBW) infants in different populations can subsequently help in establishing better criteria while taking decision of extubation. The aim of the study was to identify factors associated with extubation failure in VLBW infants., Methods: A cohort study of VLBW infants who underwent their first extubation between April 2018 and December 2019 in a Neonatal Intensive Care Unit, Alagoas, Brazil, were included in this study. Extubation failure was defined as reintubation within seven days of extubation. Relative risks of predictive variables different between the extubation success group (ES) and extubation failure group (EF) were estimated with a robust Poisson regression model., Results: Out of the 112 infants included, 26 (23%) cases exhibited extubation failure. Extremely low birth weight (RR 2.55, 95% CI 1.07, 6.06), mechanical ventilation duration for first extubation greater than seven days (RR 2.66, 95% CI 1.10, 6.45), vaginal delivery (RR 2.07, 95% CI 1.03, 4.18) and maternal chorioamnionitis (RR 4.89, 95% CI 1.26-18.98) remained independently associated with extubation failure. EF had a significant greater need for respiratory support, longer oxygen therapy duration, more bronchopulmonary dysplasia (BPD) and longer length of hospital stay, even when adjusted for confounding variables., Conclusions: Extremely low birth weight infants needing mechanical ventilation, wherein the duration for first extubation was longer than seven days, with vaginal delivery and maternal chorioamnionitis failed more frequently at the first attempt of extubation. And this failure increased the risk of BPD and the length of hospital stay., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Purpose: Treatment of multi-resistant epithelial ovarian cancer represents a clinical challenge with limited choices. Anti-angiogenic therapy has shown great potential in combination with frontline-therapy. Studies investigating heavily pre-treated patients are few. This study investigated the effect of re-treating patients with carboplatin combined with bevacizumab and cell-free DNA (cfDNA) as a potential predictor of outcome., Methods: This single-center study enrolled 73 multi-resistant ovarian cancer patients from 2008 to 2015. Patients were treated with a combination of bevacizumab (10 mg/kg) and carboplatin (AUC5) every 3 weeks. Baseline plasma samples were analyzed for cfDNA levels. Treatment response was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria and CA125 blood values., Results: The response rate according to RECIST and/or CA125 was 57%. Median number of cycles was 6. The median progression-free survival and overall survival was 5.0 and 11.2 months, respectively. Eighteen patients developed allergic reactions to carboplatin. Patients were grouped into two cfDNA-groups according to median value. The cfDNA value was correlated to progression-free survival (PFS, p = 0.015), but not to overall survival (OS, p = 0.067) in the univariate analysis. In the multivariate analysis both PFS and OS were highly correlated to the levels of cfDNA (PFS, hazard ratio = 1.87, p = 0.012; OS, hazard ratio = 1.67, p = 0.037) with patients with high levels of cfDNA having poorest outcome., Conclusion: Our results might provide guidance in cases with heavily pre-treated patients, where alternatives are limited. Carboplatin and bevacizumab treatment should be weighed against best supportive care, current non-platinum therapies and experimental treatment. cfDNA seems to offer prognostic insight.

Introduction: Immune checkpoint inhibitor (ICPis) re-challenge could be an attractive therapeutic option considering its good safety profile. However, little data is available regarding anti-PD-1/anti-PD-L1 retreatment. We conducted a meta-analysis focusing on outcomes of solid cancer patients performing this strategy., Methods: Fourteen full papers involving 74 patients were included. Individual data about best response or progression-free survival (PFS) upon the first and second course of anti-PD-1/anti-PD-L1 were collected., Results: Non-small-cell lung cancer (53%) and melanoma (34%) were the most represented cancers. Higher objective response (46% versus 24%, P=4.10 -4 ) and disease control rates (73% versus 52%, P=7.10 -3 ) were obtained upon the first ICPi course compared to re-challenge. No association between responses obtained with the two ICPis courses was found (P=3.10 -1 ). The PFS upon the first ICPi (PFS1) was longer than after re-challenge (PFSR) (6.6 versus 2.8 months, hazard ratio (HR) 0.57, P=2.10 -3 ). A longer PFSR was obtained in patients with a longer PFS1 (P=6.10 -3 ), in those who discontinued the first ICPi due to toxicity or per protocol (8.8 versus 2.1 months if disease progression occurs, P=2.10 -3 ), and in those not receiving intercalated treatment between the two ICPis (6.6 versus 2.1 months for the treated ones, P=1.10 -3 )., Discussion: Anti-PD-1/anti-PD-L1 re-challenge showed interesting clinical activity in selected patients, mainly in those achieving a long-term response upon the first ICPi course, that do not discontinue therapy because of disease progression, or that are able to keep a treatment-free period., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: In patients with atrial fibrillation (AF) who survive an anticoagulant-related intracranial hemorrhage (ICH), the benefits of restarting oral anticoagulation (OAC) remain unclear., Objective: In this study, we sought to determine the effectiveness and safety associated with resumption of OAC in atrial fibrillation patients who survive an ICH., Methods: Using 2010-2016 Medicare claims data, we identified patients with non-valvular AF who experienced an OAC-related ICH and survived at least 6 weeks after the ICH (n = 1502). The primary outcomes included the composite of ischemic stroke and transient ischemic attack (TIA), thromboembolism (TE), a composite of ischemic stroke/TIA and TE, recurrent ICH, and all-cause mortality. We constructed Cox proportional hazard models to evaluate the association between post-ICH OAC resumption, which was measured in a time-dependent manner, and the risk of primary outcomes, while controlling for a comprehensive list of covariates., Results: Among patients who survived an ICH, 69% reinitiated OAC within 6 weeks of the event, and among those who resumed OAC, 83% restarted warfarin. There was no significant difference in the risk of ischemic stroke/TIA (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.62-1.21), TE (HR 0.85, 95% CI 0.55-1.32), and ischemic stroke/TIA/TE (HR 0.81, 95% CI 0.61-1.07) between post-ICH OAC use and non-use. Post-ICH OAC use was associated with a lower risk of recurrent ICH (HR 0.62, 95% CI 0.41-0.95) and all-cause mortality (HR 0.48, 95% CI 0.37-0.62) compared with non-OAC use., Conclusions: In AF patients who survived an ICH, restarting OAC was not associated with a greater risk of recurrent ICH. Evidence from randomized controlled studies is needed to further clarify the clinical benefit of restarting OAC in this high-risk population. Further evaluation of which individuals benefit from restarting OAC is also needed to provide more clinical guidance.

Background: Residual or recurrent equinus deformity is a common problem in surgically treated clubfeet. This deformity may occur due to soft tissue-related reasons or due to bony deformity. An increased anterior distal tibial angle (ADTA) was previously found in 48% of the operated clubfeet. This study aimed to determine the efficacy and safety of anterior distal tibial hemiepiphysiodesis (ADTE) in the treatment of recurrent equinus deformity in patients with an increased ADTA., Methods: Eighteen children (23 feet) treated by ADTE to correct recurrent equinus deformity in surgically treated clubfeet were included in this retrospective, single-center study. ADTE using 8 plates was performed in children with an increased ADTA (>82 degrees) and inability to dorsiflex the ankle (≤0 degree of dorsiflexion). The mean patient age was 11.3 years (range: 10.2 to 12.9 y). All patients had completed treatment with implant removal after an average of 20.3 months (range: 9 to 37 mo)., Results: The mean preoperative ankle dorsiflexion significantly improved from -3.3 degrees (range: -20 to -0 degrees) to 6.1 degrees (range: -15 to 10 degrees) at the time of 8-plate removal (correction rate: 9.4 degrees; P<0.0001). The ADTA was a mean of 87.5 degrees (range: 83 to 110 degrees) before surgery and significantly improved to 75.8 degrees (range: 63 to 106 degrees) at the time of implant removal (correction rate: 11.7 degrees; P<0.0001). Average follow-up was 43.9 months (range: 10 to 76 mo). Follow-up examinations were continued in 11 patients (13 feet) after implant removal. Changes of ankle dorsiflexion (mean: -2.5 degrees) and ADTA (mean: 3.6 degrees) occurred in this group., Conclusions: ADTE was safe and effective in the treatment of recurrent equinus deformity in surgically treated clubfeet with increased ADTA. Deterioration of ankle dorsiflexion and ADTA occurred after implant removal in some cases. The results of this study have to be analyzed with caution due to the limited number of included patients and its retrospective nature., Level of Evidence: Level IV-retrospective case series.

This study aimed to analyze the potential occurrence of dentinal defects after the removal of a root canal filling with two different sealers using Reciproc (RC) or Reciproc Blue (RB). The mesial roots of 60 mandibular molars with a Vertucci type IV configuration were selected. The samples were initially instrumented with Reciproc (R25) and then divided into the following four experimental groups according to the endodontic sealer and retreatment instrument (n = 15): BC Sealer/Reciproc (BCRC); BC Sealer/Reciproc Blue (BCRB); AH Plus/Reciproc (AHRC); and AH Plus/Reciproc Blue (AHRB). Then, the samples were scanned under micro-CT after obturation and removal of the filling material. Two analyses were conducted. First, an evaluation was performed on all the axial images, and another analysis evaluated each millimeter of the 10 mm from the apex. Dentinal defects were observed in all the samples. All of the identified defects in the images after filling material removal were present in the corresponding images after obturation. The use of AH Plus and EndoSequence BC Sealer, and filling material removal using RC and RB instruments did not induce dentinal defects.

Purpose: To assess the impact of delaying anti-vascular endothelial growth factor (VEGF) treatment of active disease at any point during a patient's treatment journey on clinical outcomes in a real-world cohort of patients with neovascular age-related macular degeneration (nAMD)., Design: Longitudinal cohort study., Participants: Consecutive treatment-naive nAMD eyes commencing anti-VEGF monotherapy (bevacizumab, ranibizumab, or aflibercept) from January 2014 from a tertiary eye center in Singapore., Methods: We conducted a real-world study using registry data comparing delayed re-treatment (defined as not receiving treatment at 2 or more monitoring visits when disease was graded as active) versus timely re-treatment (defined as receiving treatment when disease was active)., Main Outcome Measures: The primary outcome was the change in visual acuity (VA) in the timely and delayed re-treatment groups at 12 months., Results: Data from 286 eyes were included and categorized into the timely (188 [66%]) or the delayed (98 ([34%]) group. The mean numbers of anti-VEGF injections over 12 months were similar: 5.6 (standard deviation [SD], 2.9) versus 4.9 (SD, 3.2; P = 0.11) for the timely and delayed groups, respectively. Timely treated patients showed larger gains in VA (6.4 letters [SD, 8.1 letters] vs. 1.2 letters [SD, 5.3 letters; P = 0.04), a higher proportion with VA of 6/12 or better (30% vs. 8%; P = 0.01), and greater reduction in OCT-measured central subfield thickness (135 μm [SD, 154 μm] vs. 87.8 μm [SD, 129 μm]; P = 0.04) at 12 months. A longer delay between detection of active disease and re-treatment was associated with poorer vision outcomes (0.02-letter decrease/day; P = 0.03; R 2  = 0.29)., Conclusions: Although it has been established that adequate numbers of injections are required for favorable outcomes, timely re-treatment of active disease also is important. This should be emphasized to patients to ensure optimal outcomes in real-world clinical settings., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: On the basis of retrospective analyses and phase 2 studies, metastatic colorectal cancer patients whose disease responded to a first-line regimen containing an anti-epidermal growth factor receptor (EGFR) agent may experience benefit from anti-EGFR readministration in later therapy lines. While the analysis of circulating tumor DNA seems a promising tool to select the best candidates for this strategy, identifying clinical predictors of anti-EGFR sensitivity would be useful to drive treatment choices in daily practice., Patients and Methods: A real-life database of 5530 patients treated at 6 institutions was queried. Included were patients who were retreated with anti-EGFRs, who had RAS/BRAF wild-type-status tissue samples, who had received a first-line anti-EGFR-based regimen with at least stable disease as best response, and who had received at least one further line of therapy before anti-EGFR retreatment. The association with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of variables potentially related to anti-EGFR sensitivity was investigated., Results: A total of 86 patients were identified. The ORR during anti-EGFR retreatment was 19.8%; median PFS and OS were 3.8 and 10.2 months, respectively. No significant association of clinical features of anti-EGFR sensitivity with ORR, PFS, and OS was observed. Among the 56 patients with a time from the last anti-EGFR administration to first-line progressive disease of < 3 months (rechallenge group), > 2 prior therapy lines and a longer anti-EGFR-free interval were associated with higher ORR, but not with longer PFS or OS., Conclusion: Clinical features we deemed surrogates of anti-EGFR sensitivity were not reliable predictors of benefit from anti-EGFR retreatment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Post transplant lymphoproliferative disorder (PTLD) is a rare complication after kidney transplantation. Graft dysfunction is often encountered during the course of the treatment of PTLD, at times leading to need for retransplantation. We describe here the case of a young boy who underwent retransplantation after treatment of early Epstein Barr virus (EBV) related post transplant lymphoproliferative disorder. Our case highlights the various factors needing deliberation before retransplantation including time from remission of PTLD, EBV serostatus and choice of induction and maintenance immunosuppression agents.

Introduction: The previous researches aimed to evaluate the efficacy and safety of fecal microbiota transplantation (FMT) for ulcerative colitis (UC) in a short-term observation. The present study aimed to explore the optimum timing of FMT for maintaining the long-term clinical benefits and to target the gut microbiota that may help to predict the long-term success or failure of FMT in UC., Methods: Two hundred two patients with UC were recruited from November 2012 to September 2018. The primary endpoint of this study was the maintaining time of the first and second courses of FMT. Relapse was defined as partial Mayo score ≥2 after achieving clinical remission and an increase of partial Mayo score ≥1 after achieving clinical response. The stool samples were analyzed by 16S rRNA gene sequencing., Results: The median maintaining time of the efficacy was 120 days (IQR, 45-180) and 182.5 days (IQR, 105-311.25) from the first course and second course of FMT, respectively. No FMT-related serious adverse events were observed. The differences of the relative abundance in Eggerthella, Lactobacillus, and Ruminococcus between pre-FMT and 5 days post-FMT were remarkably correlated with the long-term clinical remission (P < 0.05)., Discussion: This study demonstrated that patients with UC should undergo the second course of FMT within 4 months after the first course of FMT for maintaining the long-term clinical benefits. The short-term alterations of microbiota after FMT may be conducive to predicting the long-term efficacy of FMT in UC (see Visual Abstract, Supplementary Digital Content, http://links.lww.com/CTG/A363).

Purposes: To evaluate the outcome of different types of ulna osteotomy in missed Monteggia fracture with a particular interest in anatomical correction and overcorrection techniques. The outcome between the two groups were compared on aspects of (1) clinical outcome (2) radiologic outcome., Methods: Twenty-one patients with type 1 missed Monteggia fracture who underwent surgery between January 2005-2018 were retrospectively reviewed. The patients were divided into two groups according to the degrees of correction: group 1 anatomical correction (no ulnar dorsal angulation) and group 2 overcorrection (degrees of ulnar dorsal angulation ≥ 10°). Clinical outcomes were assessed using the Kim elbow performance score. Radiologic outcomes were categorized into four groups with regard to the radial head: excellent (complete reduction), good (slight subluxation), fair (moderate subluxation), and poor (dislocation)., Results: Eleven patients with anatomical ulna osteotomy and ten patients with overcorrection ulnar osteotomy were enrolled with a mean age of 7.95 (5-12) years at the time of operation. The mean duration from injury to surgery was 27.05 (3-120) months, and the mean period of follow-up was 29.90 ± 22.37 (12-84) months. The average angle of total correction measured in group 1 was 6.09° (3°-9°) and 28.37° (12°-40°), in group 2. Fair-to-poor radiological outcomes at the last follow-up were more frequently observed in overcorrection group (40% vs. 0%) (p = 0.035) as well as clinical outcome (20% vs. 0%) (p = 0.214). Among the patients in group 2, posterior dislocation was diagnosed in two patients at 18 months and 2 months after surgery., Conclusion: The postoperative result of overcorrection ulna osteotomy showed significant inferiority in radiologic outcome compared to anatomical correction. Overcorrection of ulna osteotomy could be associated with posterior dislocation of radial head.

Noninvasive positive pressure ventilation (NPPV) has been widely applied in patients with high-risk extubation failure, including heart failure. High-flow nasal cannula (HFNC) has been demonstrated to benefit patients with heart failure by reducing cardiac preload. This study aimed to compare the effectiveness of HFNC to NPPV for preventing extubation failure in patients with heart failure. This 3-year retrospective and single-center cohort study included patients with heart failure with left ventricular ejection fraction <50% who received prophylactic HFNC or NPPV after scheduled extubation from January 2015 to January 2018 from a medical center with four adult intensive care units. Demographics, comorbidities, diagnosis, and weaning status were collected. The primary outcome was treatment failure within 72 hours after extubation, which was defined as escalation to NPPV or reintubation in the HFNC group and was defined as requiring reintubation in the NPPV group. Secondary outcomes were reintubation within 72 hours, reintubation, duration of stay, and mortality during the intensive care unit and hospital stay. Of the 104 patients analyzed, characteristics of 58 patients in the HFNC group and 46 patients in the NPPV group were compared. The treatment failure within 72 hours in the two groups was not significantly different (25.9% vs 13%, p =0.106). Hypoxemic respiratory failure related treatment failure was significantly higher in the HFNC group. Prophylactic HFNC as first-line therapy had a comparable rate of reintubation within 72 hours to the prophylactic NPPV alone (17.2% vs 13%, p =0.556). Other secondary outcomes were similar between the two groups. Among patients with heart failure, HFNC was not inferior to NPPV for preventing extubation failure and reintubation. However, in case of an impending respiratory failure, selective patients may benefit from rescue NPPV., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2020 Che-Jung Chang et al.)

Second allogeneic hematopoietic stem cell transplantation (allo-HSCT) has a low survival outcome and a high non-relapse mortality (NRM) rate which is a major obstacle to this treatment. We hypothesized that the status of malnourishment after first allo-HSCT as represented by the geriatric nutritional risk index (GNRI) could be used as a prognostic factor to determine the outcomes of second allo-HSCT. A total of 108 patients with a median age of 42 (range, 17-69) years, who received second allo-HSCT for disease recurrence after first allo-HSCT from our institution, were included in this study. Low GNRI had a significant impact on NRM at 2 years after second allo-HSCT: 56.9% in patients with GNRI ≤ 92 compared with 27.5% in patients with GNRI > 92 (P = 0.002). In multivariate analysis, GNRI of ≤ 92 was the only significant factor for NRM (hazard ratio [HR] 2.29, 95% confidence interval [CI] 1.15-4.56, P = 0.018). High-risk disease status at second allo-HSCT (HR 2.74, 95% CI 1.46-5.14, P = 0.002) and GNRI of ≤ 92 (HR 1.70, 95% CI 1.02-2.82, P = 0.042) were identified as significant factors for overall survival (OS). A score of 1 was assigned to each factor, and the OS rate at 2 years after second allo-HSCT decreased according to the score: 53.0% in patients with score 0, 32.3% with score 1, and 2.5% with score 2 (P < 0.001). In conclusion, GNRI could be a useful predictor for the outcomes of second allo-HSCT. A prospective study in other cohorts is warranted to validate the findings of our study.

In 2009 a new type of endodontic sealers was introduced to the market. The so called "bioceramic" sealers are a promising alternative to the present golden standard of root canal fillings. Now a decade later, still very little is known about the ability to remove these sealers in cases of non-surgical endodontic retreatment (NSER). There are only a limited number of articles that provide such information. The commonly used hand files are not efficient in removing thoroughly the sealer from the main canal walls. Machine driven files are much easier and faster alternative to the hand ones, but are still not able to ensure complete removal. Although ultrasonics can be applied only in the straight portion of the main canal, they raise the efficacy of sealer removal. Photon-initiated photoacoustic streaming (PIPS) is another way to enhance the removal of bioceramics. Solvents like chloroform and orange oil are effective in softening gutta-percha, but not the bioceramics. This article reviews the available scientific data concerning removal of bioceramic materials in the context of a NSER., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Here we describe a case of a premature neonate who showed initial improvement after being on invasive ventilation. She was gradually weaned to room air and was started on a feeding protocol for preterm infants together with total parenteral nutrition through a peripherally inserted central catheter (PICC) when she suddenly deteriorated and developed respiratory distress associated with signs of shock, requiring support from a high-setting mechanical ventilation as well as an inotropic support. A full sepsis work-up was ordered and she was started on antibiotics. The diagnosis was confirmed on chest X-ray and ultrasound, which showed automigration and displacement of the PICC line from its initial site on the left side to the right lung base, causing significant right-side pleural effusion which affected her haemodynamics. The PICC line was removed, and 30 hours later the pleural effusion completely resolved and the patient improved. She was discharged from hospital without any concerns with regard to growth and development during her regular follow-up., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with cancer who developed severe, grade 3 or 4 immune-related adverse events (irAEs) during therapy with immune checkpoint inhibitors are at risk for developing severe toxicities again on rechallenge with checkpoint inhibitors. Consequently, medical oncologists and multidisciplinary teams are hesitant to retreat in this scenario, despite the fact that a number of patients may derive clinical benefit from this approach. Balancing such clinical benefit and treatment-related toxicities for each patient is becoming increasingly challenging as more and more patients with cancer are being treated with checkpoint inhibitors. In this manuscript, we provide an extensive overview of the relevant literature on retreatment after toxicity, and suggest prophylactic approaches to minimize the risk of severe irAE following rechallenge with immune checkpoint blockade, since treatment may be lifesaving in a number of occasions., Competing Interests: Competing interests: MO received education grants from Leenaards Foundation. ME and JT declare no conflicts of interest. SP received education grants, provided consultation, attended advisory boards and/or provided lectures for the following organizations: Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Eli Lilly, F. Hoffmann-La Roche, Janssen, Merck Sharp and Dohme, Novartis, Merck Serono, Pfizer, Regeneron and Takeda. JH received research grants from Novartis, MSD, BMS and Neon Therapeutics, and provided consultation, lectures or attended advisory boards for Amgen, AstraZeneca, Bayer, BMS, Celsius Therapeutics, Gadeta, GSK, Immunocore, MSD, Merck Serono, Neon Therapeutics, Pfizer, Roche/Genentech, Sanofi and Seattle Genetics. YW serves as consultant for Tillotts Pharma. JL received institutional research support for: BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, Aveo, NIHR RM/ICR Biomedical Research Center for cancer and consultancy from: Achilles, AZ, Boston Biomedical, BMS, Eisai, EUSA Pharma, GSK, Ipsen, Imugene, Incyte, iOnctura, Kymab, Merck Serono, MSD, Nektar, Novartis, Pierre Fabre, Pfizer, Roche / Genentech, Secarna, Vitaccess. PG provided unrelated consultation and advisory board (within 2 years) for Merck, Bristol-Myers Squibb, AstraZeneca, Clovis Oncology, EMD Serono, Seattle Genetics, Foundation Medicine, Driver, Pfizer, QED Therapeutics, HERON Therapeutics, Janssen, Bayer, Genzyme, Mirati Therapeutics, Exelixis, Roche, Glaxo Smith Kline. AM advisory board member for BMS, MSD, Novartis, Roche, Pierre-Fabre., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose/Aim of the study : The main purpose of the colonoscopy is screening for colorectal cancers and diagnosis of colorectal disease The cost-effectiveness of colonoscopy directly depend on the adequate bowel preparation. Inadequate colonoscopy is recommended to be re-scheduled within 1 year. Re-scheduling is an economic and patient burden. Thus instead of re-scheduling, another strategy may be attempted. The purpose of this study was to examine the usefulness and effect of the same day repeat colonoscopy after administration of an additional laxative dose. Materials and Methods: Patients with inadequate colonoscopy were enrolled in the study. The patients eligible for the enrollment were instructed to consume an additional laxative and scheduled in afternoon. The demographic data of the patient, the details of the index and repeat procedures were obtained by a questionnaire. Results: A total of 60 patients were enrolled in the study. The rate of adequate colonoscopy was 80%. Cecum intubation rate was 83.3%. There were no complications due to colonoscopy itself and additional laxatives. The polyp detection rate was 26.6%. The withdrawal time was 6.7 ± 1.34 min. Conclusion: The results of the present study showed that same day repeat colonoscopy with additional laxative dose can be a safe and effective method for repeat procedure of an inadequate colonoscopy. The patients tolerated and were satisfied with the same day protocol. Quality indicators of colonoscopy such as adenoma detection rate and cecum intubation rate were achieved. Same day bowel cleansing method may be considered as an alternative way rather than re-scheduling inadequate colonoscopy for a later time.

Objective: To evaluate the efficacy and safety of multiple- versus single-dose gonadotropin-releasing hormone agonist (GnRH-a) addition to luteal phase support (LPS), in patients with a first in vitro fertilization (IVF) failure associated with luteal phase deficiency (LPD)., Methods: Eighty patients with a first IVF failure associated with LPD were randomly assigned into single-dose and multiple-dose GnRH-a groups. In the second IVF attempt, patients in the single-dose group were given standard LPS plus a single dose of GnRH-a 6 days after oocyte retrieval. Patients in the multiple-dose group received standard LPS plus 14 daily injections of GnRH-a. Children conceived were followed up for 2 years., Results: Pregnancy (67.5% vs. 42.5%), clinical pregnancy (50.0% vs. 22.5%), and live birth rates (42.5% vs. 20.0%) were significantly higher in the multiple-dose versus single-dose GnRH-a group. Patients in the multiple-dose GnRH-a group had significantly higher progesterone levels 14 days after oocyte recovery (35.9 vs. 21.4 ng/mL). No significant difference existed in the status at birth or developmental and behavior assessments of 2-year-old children conceived in both groups., Conclusions: Daily addition of GnRH-a to standard LPS can achieve better pregnancy outcomes with a sustained safety profile in patients with a first IVF failure associated with LPD.

Background: Repeat transarterial chemoembolisation (rTACE) is often required for hepatocellular carcinoma (HCC) to achieve disease control, however, current practice guidelines regarding treatment allocation vary significantly. This study aims to identify key factors associated with patient survival following rTACE to facilitate treatment allocation and prognostic discussion., Method: Patients with HCC undergoing rTACE at six Australian tertiary centers from 2009 to 2014 were included. Variables encompassing clinical, tumour, treatment type and response factors were analysed against the primary outcome of overall survival. Univariate analysis and multivariate Cox regression modelling were used to identify factors pre- and post-TACE therapy significantly associated with survival., Results: Total of 292 consecutive patients underwent rTACE with mainly Child Pugh A cirrhosis (61%) and BCLC stage A (57%) disease. Median overall survival (OS) was 30 months (IQR 15.2-50.2) from initial TACE. On multivariate analysis greater tumour number (p = 0.02), higher serum bilirubin (p = 0.007) post initial TACE, and hepatic decompensation (p = 0.001) post second TACE were associated with reduced survival. Patients with serum AFP ≥ 200 ng/ml following initial TACE had lower survival (p = 0.001), compared to patients with serum AFP level that remained < 200 ng/ml post-initial TACE, with an overall survival of 19.4 months versus 34.7 months (p = 0.0001) respectively., Conclusion: Serum AFP level following initial treatment in patients undergoing repeat TACE for HCC is a simple and useful clinical prognostic marker. Moreover, it has the potential to facilitate appropriate patient selection for rTACE particularly when used in conjunction with baseline tumour burden and severity of hepatic dysfunction post-initial TACE.

Purpose: To analyze long-term outcomes after treatment discontinuation of anti-programmed death-1 (anti-PD-1) therapy in a cohort of patients with melanoma with the longest follow-up yet available to our knowledge, including a majority of patients treated outside of a clinical trial. We also assessed efficacy of retreatment with anti-PD-1 therapy with or without ipilimumab in relapsing patients., Methods: We retrospectively analyzed all patients with nonuveal, unresectable stage III/IV melanoma treated with single-agent anti-PD-1 therapy at Memorial Sloan Kettering from 2009-2018 who had discontinued treatment and had at least 3 months of follow-up after discontinuation (n = 396). Overall survival for patients with complete response (CR) was calculated from time of CR. Time to treatment failure for patients with CR was time from CR to the next melanoma treatment or death., Results: CRs were seen in 102 of 396 patients (25.8%). The median number of months of treatment after CR was zero (range, stopped before CR to 26 months after CR). With a median follow-up of 21.1 months from time of CR in patients who did not relapse, the probability of being alive and not needing additional melanoma therapy at 3 years was 72.1%. There was no significant association between treatment duration and relapse risk. In multivariable analysis, CR was associated with M1b disease and cutaneous versus mucosal or acral primaries. Among the 78 patients (of 396) retreated after disease progression, response was seen in 5 of 34 retreated patients with single-agent anti-PD-1 therapy and 11 of 44 patients escalated to anti-PD-1 plus ipilimumab., Conclusion: In our cohort, most patients discontinued treatment at the time of CR. Most CRs were durable but the probability of treatment failure was 27% at 3 years. Responses to retreatment were infrequent. The optimal duration of treatment after CR is not yet established.

Background/purpose: The study compared the hepatitis B surface antigen (HBsAg) changes between hepatitis B e antigen (HBeAg)-negative non-cirrhotic chronic hepatitis B patients who discontinued or maintained entecavir therapy., Methods: A total of 250 HBeAg-negative, non-cirrhotic patients who were treated with entecavir previously and had stopped treatment for at least 12 months (discontinued group) and 231 HBeAg-negative, non-cirrhotic patients who had received entecavir treatment for at least 4 years (maintained group) were recruited., Results: In the discontinued group, 71 had a persistent virological suppression (Group I), 35 experienced virological relapse but no clinical relapse or retreatment (Group II), 26 experienced clinical relapse without retreatment (Group III), and 118 experienced HBV relapse and retreatment (Group IV). Patients in Groups I, II, and III, but not in Group IV, experienced a significantly larger drop in HBsAg levels' post-treatment than during entecavir treatment. Patients in Groups I and III exhibited a greater post-treatment HBsAg decline than patients in Groups II and IV (p < 0.001). Discontinued group experienced a significantly larger drop in HBsAg levels (p < 0.001) and higher HBsAg loss rate (p = 0.001) than maintained group after adjusting for clinical features and HBsAg levels in propensity score matched patients. Patients in maintained group exhibited a smaller drop in HBsAg and lower HBsAg loss rate than patients in groups I, II, and III, but not in Group IV., Conclusions: Patients who discontinued entecavir therapy and achieved persistent virological suppression exhibited a greater HBsAg decline and higher HBsAg loss rate compared with patients who maintained entecavir therapy.

Background: Full-face aesthetic treatment involving several treatment modalities may improve facial aesthetic outcome., Objective: To evaluate clinical outcomes and patient perceptions of monotherapy with either abobotulinumtoxinA (ABO) or hyaluronic acid (HA) filler followed by full-face combination treatments of ABO, HA filler, and skin-boosting HA (RSB)., Materials and Methods: Subjects aged 35 to 50 years were randomized to monotherapy with 50 s.U ABO in the glabella or ≤1 mL HA filler in the nasolabial folds (NLFs)/cheeks. At Month 6 and Month 12, all subjects received combination treatment with ≤50 s.U ABO in the glabella, ≤2 mL HA filler in the NLFs/cheeks (and other facial areas as applicable), and ≤1 mL RSB (additional RSB treatment at Month 7). Assessments included global facial aesthetic appearance and improvement, first impression, perceived age, wrinkle severity, satisfaction questionnaires, and adverse events., Results: Repeated full-face combination treatment with ABO, HA filler, and RSB was associated with considerably higher levels of aesthetic improvement and subject satisfaction than monotherapy with ABO or HA filler. Improvement rate of glabellar lines was increasing with each treatment., Conclusion: Repeated combination treatment achieved greater change in global facial aesthetic appearance than monotherapy. Aesthetic improvement and subject satisfaction was high and increased with each treatment. All treatments were well tolerated.

Background: This case represents an exceptional response to pembrolizumab in a patient with epithelioid mesothelioma with a further response on rechallenge., Case Presentation: A 77-year-old woman with advanced epithelioid mesothelioma extensively pretreated with chemotherapy demonstrated a prolonged response of 45 months to 52 cycles of pembrolizumab. On rechallenge with pembrolizumab, further disease stability was achieved. Serial biopsies and analysis by immunohistochemistry and immunofluorescence demonstrated marked immune infiltration and documented the emergency of markers of immune exhaustion. Whole exome sequencing demonstrated a reduction in tumor mutational burden consistent with subclone elimination by immune checkpoint inhibitor (CPI) therapy. The relapse biopsy had missense mutation in BTN2A1., Conclusion: This case supports rechallenge of programme death receptor 1 inhibitor in cases of previous CPI sensitivity and gives molecular insights., Competing Interests: Competing interests: AM: honoraria from FARON and Bayer. AW: advisory boards for Bayer, Bristol-Myers Sqibb and Celgene. SP: honoraria from Boehringer Ingelheim, AstraZeneca, Roche, Takeda and Chugai Pharma; advisory boards from Boehringer Ingelheim, AstraZeneca, Roche, Novartis, Pfizer, Bristol-Myer Squibb, MSD, Guardant Health, Abbvie, EMD Serono and Takeda; expenses from Boehringer Ingelheim, Bristol-Myer Squibb and Merck Sharp & Dohme. MO: advisory boards for MSD, Abbvie, BMS, BI, Pierre Fabre. UB: honoraria from Astellas, Novartis, Karus Therapeutics, Phoenix Solutions, Eli Lilly, Astex and Vernalis; funding for phase I investigator-initiated trials from Onyx Pharmaceuticals, BTG International, Chugai, Astrazeneca and Verastem. JdB: personal fees and non-financial support from Astellas Pharma, Genentech/Roche, Pfizer, Sanofi, Bayer, Boehringer Ingelheim, Merck Serono and Merck Sharp & Dohme; grants, personal fees and non-financial support from AstraZeneca; non-financial support from Genmab, GlaxoSmithKline, Orion Pharma GmbH, Qiagen, Taiho Pharmaceutical and Vertex. In addition, JdB has a patent Abiraterone Rewards to Inventors with royalties paid to institution, no personal income and a patent PARP inhibitors and DNA repair defects with royalties paid to institution, no personal income. JL: research funding from Roche Genentech, Genmab and Basilea Travel from Basilea., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The aim of the study was to determine the best practice guidelines regarding the use of indwelling catheters after minimally invasive sacrocolpopexy., Methods: Multicenter (3 sites) randomized control trial comparing the standard overnight indwelling urethral catheterization (group 2) with removal of catheter immediately after surgery (group 1). Our primary outcome is the need for recatheterization. Secondary outcomes include the number of patients discharged with a catheter, length of hospital stay, number of urinary tract infections, patient satisfaction/pain scores, and whether patients would use the same treatment again., Results: There were 32 patients (43.8%) in group 1 and 41 patients (56.2%) in group 2. On average, patients in group 1 required straight catheterization 0.8 (SD = 0.9) times versus 0.6 (SD = 0.9) times for group 2 (P = 0.239). The number of days with a catheter between the 2 groups was not statistically significant. There was no statistical significance between group 1 and group 2 in terms of operative time, times to leave the operating room, and hospital. Zero patients in group 1 and 2 patients in group 2 had a urinary tract infection. After dividing the groups based on whether or not they underwent a transvaginal tape procedure, the final results were similar., Conclusions: We did not observe a difference in the risk of recatheterization or discharge home with a urinary catheter between the 2 groups. Addition of transvaginal tape to sacrocolpopexy did not show a difference in the risk of recatheterization. One reason for the lack of difference between the 2 groups could be due to a lack of power in our study.