Failure Of First-line Therapy Research Articles

Comparative Efficacy of First-Line Regimens in Relapsed/Refractory Mantle Cell Lymphoma (MCL): A Proportional Meta-Analysis

Introduction: Mantle cell lymphoma (MCL) is an incurable B-cell malignancy that disproportionately affects the elderly. After first-line therapy failure, relapsed/refractory MCL assumes a more aggressive and universally fatal course. Currently, several classes of chemo/biologic therapies are approved in the second line. However, these agents and their combinations have not been compared head-to-head. We conducted this proportional meta-analysis to evaluate their relative impact on selected clinical outcomes. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of relapsed/refractory MCL; trials that explored the efficacy of first-line approved antineoplastic agents and their combinations that comprised: BTK-inhibitors (Ibrutininb (IB), Acalabrutinib, Zanubrutinib), Bortezomib (Velcade, VEL), Venetoclax (VEN), Lenalidomide (LEN), and Bendamustine+Rituximab (B-R); and studies reporting types of responses and duration of response. Proportional meta-analysis was conducted using random-effects model. The respective 95% confidence intervals were calculated, and funnel plots were constructed. Results: Thirteen studies comprising a total of 1,264 participants were included. The pooled overall response rates, ORR (95%CI), of the regimens were: 74% (66,81) BTK-inhibitors, 39% (25,53) VEL, 34% (24,46) LEN, 85% (78,92) B-R, 75% (58,92) VEN-IB, and 88% (79,97) IB-R. The pooled complete responses, CR (95%CI), of the regimens were: 33% (20,47) BTK-inhibitors, 9% (5,13) VEL, 6% (4,9) LEN, 45% (36,54) B-R, 42% (22,63) VEN-IB, and 44% (30,58) IB-R. There were no significant differences in ORR and CR between BTK-inhibitors, B-R, VEN-IB, and IB-R. ORR of VEL and LEN also did not significantly differ. However, ORR and CR of the former group were significantly higher than those of the latter. The pooled partial responses, PR (95%CI), of the regimens were: 41% (32,50) BTK-inhibitors, 28% (20,38) VEL, 28% (15,43) LEN, 41% (35,47) B-R, 34% (15,53) VEN-IB, and 44% (30,58) IB-R. There were no significant differences between PR of the regimens. The weighted duration of responses in months, DOR (95%CI), of the regimens were: 20 BTK-inhibitors, 9 VEL, 16 LEN, and 20 B-R. Conclusions: This proportional meta-analysis is the first to compare the current regimens in first-line relapsed/refractory MCL. It indicates that BTK-inhibitors monotherapy, IB combinations with R or VEN, and B-R provide equivalent ORR and CR rates that are significantly better than VEL and LEN with notably longer duration of response. It also raises questions about whether there is an additional ORR and CR benefits when adding VEN or R to IB in this clinical setting. Disclosures No relevant conflicts of interest to declare.

Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma.

Despite the advances in screening protocols and treatment options, hepatocellular carcinoma (HCC) is still considered to be the most lethal malignancy in patients with liver cirrhosis. Moreover, the survival outcomes after failure of first-line therapy for unresectable HCC is still poor with limited therapeutic options. One of these options is immune checkpoint inhibitors. The aim of this study is to comprehensively review the efficacy and safety of immune checkpoint inhibitors for patients with HCC.

Bowel Ultrasound Scan Predicts Corticosteroid Failure in Children With Acute Severe Colitis.

Acute severe colitis (ASC) is a potentially life-threatening event. Optimal timing for second-line treatment in children is mainly based on the clinical score Pediatric Ulcerative Colitis Activity Index. The aim of our study was to evaluate the potential role of bowel ultrasound scan (BUS) in predicting the need of second-line therapy in ASC. Patients younger than 18 years admitted to a single tertiary referral center with ASC were included. We retrospectively reviewed medical records collecting clinical and BUS data. Colonic wall thickness (CWT), loss of colonic wall stratification (CWS), presence of hyperechoic lymph nodes, and colonic wall flow evaluated at power Doppler were assessed at BUS performed within the third day of hospitalization. Sixty-nine ASC episodes from 52 different patients were identified. CWT showed significantly higher values in patients who required second-line therapy (5.14 vs 3.69 mm; P < 0.001). Loss of CWS was present in 17 of 36 (47.2%) of steroid-resistant ASC versus only 1 of 33 of those responding to intravenous corticosteroids (P < 0.001, sensitivity = 47%, specificity = 97%). Using a receiver operating characteristic curve, a cut-off of 3.4 mm was individuated for CWT to predict steroid treatment failure, showing a sensitivity of 92% and a specificity of 52%. The multivariable binary logistic regression analysis identified thickened colonic wall (CWT >3.4 mm) and loss of CWS as independent predictors of steroid resistance. BUS is a noninvasive, easily accessible, and cost-effective resource that may identify at an early stage first-line therapy failure in pediatric ASC.

Efficacy and safety of single-agent pralatrexate for treatment of angioimmunoblastic T-cell lymphoma after failure of first line therapy: a pooled analysis

Angioimmunoblastic T-cell lymphoma (AITL) is a histological subtype of peripheral T-cell lymphoma associated with a poor prognosis. This post-hoc pooled analysis aims to provide insight about the efficacy of pralatrexate monotherapy in a subset of twenty-nine patients with relapsed or refractory (r/r) AITL drawn from two prospective registration trials completed in China and Japan. After a median of two prior lines of therapy, an overall response rate of 52% (15/29 patients; 95% CI 0.34, 0.70) was demonstrated. The estimated median duration of response, progression free survival (PFS) and overall survival (OS) were 6.4 months (196 days), 5.0 months (151 days), and 18.0 months (548 days), respectively. Grades 1–3 mucositis was observed in twenty-three patients (79.3%); and hemato-toxicity in twenty-six (89.7%) patients. Results of this analysis corroborate with data from two previously reported US retrospective cohorts, supporting the potential benefits of pralatrexate monotherapy in patients with r/r AITL.

Inhibition of Resistance-Refractory P. falciparum Kinase PKG Delivers Prophylactic, Blood Stage, and Transmission-Blocking Antiplasmodial Activity

SummaryThe search for antimalarial chemotypes with modes of action unrelated to existing drugs has intensified with the recent failure of first-line therapies across Southeast Asia. Here, we show that the trisubstituted imidazole MMV030084 potently inhibits hepatocyte invasion by Plasmodium sporozoites, merozoite egress from asexual blood stage schizonts, and male gamete exflagellation. Metabolomic, phosphoproteomic, and chemoproteomic studies, validated with conditional knockdown parasites, molecular docking, and recombinant kinase assays, identified cGMP-dependent protein kinase (PKG) as the primary target of MMV030084. PKG is known to play essential roles in Plasmodium invasion of and egress from host cells, matching MMV030084's activity profile. Resistance selections and gene editing identified tyrosine kinase-like protein 3 as a low-level resistance mediator for PKG inhibitors, while PKG itself never mutated under pressure. These studies highlight PKG as a resistance-refractory antimalarial target throughout the Plasmodium life cycle and promote MMV030084 as a promising Plasmodium PKG-targeting chemotype.

The cost-effectiveness of radiofrequency ablation for treating patients with gastric antral vascular ectasia refractory to first line endoscopic therapy

Objective: This economic evaluation aims to provide a preliminary assessment of the cost-effectiveness of radiofrequency ablation (RFA) compared with argon plasma coagulation (APC) when used to treat APC-refractory gastric antral vascular ectasia (GAVE) in symptomatic patients.Methods: A Markov model was constructed to undertake a cost-utility analysis for adults with persistent symptoms secondary to GAVE refractory to first line endoscopic therapy. The economic evaluation was conducted from a UK NHS and personal social services (PSS) perspective, with a 20-year time horizon, comparing RFA with APC. Patients transfer between health states defined by haemoglobin level. The clinical effectiveness data were sourced from expert opinion, resource use and costs were reflective of the UK NHS and benefits were quantified using Quality Adjusted Life Years (QALYs) with utility weights taken from the literature. The primary output was the Incremental Cost-Effectiveness Ratio (ICER), expressed as cost per QALY gained.Results: Over a lifetime time horizon, the base case ICER was £4840 per QALY gained with an 82.2% chance that RFA was cost-effective at a threshold of £20,000 per QALY gained. The model estimated that implementing RFA would result in reductions in the need for intravenous iron, endoscopic intervention and requirement for blood transfusions by 27.1%, 32.3% and 36.5% respectively. Compared to APC, RFA was associated with an estimated 36.7% fewer procedures.Conclusions: RFA treatment is likely to be cost-effective for patients with ongoing symptoms following failure of first line therapy with APC and could lead to substantive reductions in health care resource.

Management and treatment options when facing malignant ureteral obstruction.

Malignant ureteral obstruction is an unfortunate finding that can be caused by a wide-ranging number of malignancies with a prognosis of limited survival. Given its presentation and progression, it can be refractory to treatment by traditional single polymeric ureteral stents. With a higher failure rate than causes of benign ureteral obstruction, a number of other options are available for initial management, as well as in cases of first-line therapy failure, including tandem stents, metallic stents, percutaneous nephrostomies and extra-anatomic stents. We reviewed the literature and carried out a PubMed search including the following keywords and phrases: "malignant ureteral obstruction," "tandem ureteral stents," "metallic ureteral stents," "resonance stent," "metal mesh ureteral stents" and "extra-anatomic stents." The vast majority of studies were small and retrospective, with a large number of studies related to metallic stents. Given the heterogenous patient population and diversity of practice, it is difficult to truly assess the efficacy of each method. As there are no guidelines or major head-to-head prospective trials involving these techniques, it makes practicing up to the specific provider. However, this article attempts to provide a framework with which the urologist who is presented with malignant ureteral obstruction can plan in order to provide the individualized care on a case-by-case basis. What is clear is that prospective, randomized clinical trials are necessary to help bring evidence-based medicine and guidelines for patients with malignant ureteral obstruction.

Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial

Few options exist for treatment of patients with small-cell lung cancer (SCLC) after failure of first-line therapy. Lurbinectedin is a selective inhibitor of oncogenic transcription. In this phase 2 study, we evaluated the acti and safety of lurbinectedin in patients with SCLC after failure of platinum-based chemotherapy. In this single-arm, open-label, phase 2 basket trial, we recruited patients from 26 hospitals in six European countries and the USA. Adults (aged ≥18 years) with a pathologically proven diagnosis of SCLC, Eastern Cooperative Oncology Group performance status of 2 or lower, measurable disease as per Response Criteria in Solid Tumors (RECIST) version 1.1, absence of brain metastasis, adequate organ function, and pre-treated with only one previous chemotherapy-containing line of treatment (minimum 3 weeks before study initiation) were eligible. Treatment consisted of 3·2 mg/m2 lurbinectedin administered as a 1-h intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary outcome was the proportion of patients with an overall response (complete or partial response) as assessed by the investigators according to RECIST 1.1. All treated patients were analysed for activity and safety. This study is ongoing and is registered with ClinicalTrials.gov, NCT02454972. Between Oct 16, 2015, and Jan 15, 2019, 105 patients were enrolled and treated with lurbinectedin. Median follow-up was 17·1 months (IQR 6·5-25·3). Overall response by investigator assessment was seen in 37 patients (35·2%; 95% CI 26·2-45·2). The most common grade 3-4 adverse events (irrespective of causality) were haematological abnormalities-namely, anaemia (in nine [9%] patients), leucopenia (30 [29%]), neutropenia (48 [46%]), and thrombocytopenia (seven [7%]). Serious treatment-related adverse events occurred in 11 (10%) patients, of which neutropenia and febrile neutropenia were the most common (five [5%] patients for each). No treatment-related deaths were reported. Lurbinectedin was active as second-line therapy for SCLC in terms of overall response and had an acceptable and manageable safety profile. Lurbinectedin could represent a potential new treatment for patients with SCLC, who have few options especially in the event of a relapse, and is being investigated in combination with doxorubicin as second-line therapy in a randomised phase 3 trial. Pharma Mar.

Autoimmune hemolytic anemia in children, 20 years experience of single center

Aim: Autoimmune hemolytic anemia (AIHA) is a rare disease in pediatrics, whose mortality rate was reported to be as high as 10%. AIHA can be primary or secondary to other diseases, Availability of new immunsupressive drugs like mycofenolate mofetil (MMF), has provided the opportunity to reduce long term steroid administration and mortality. In this study we aimed to represent AIHA patients of 20 years, from single centre and focus on the causes, treatment and outcomes. The secondary object was to represent outcomes of patients who received MMF.Material and Methods: This study was designed as a retrospective study. Patients aged three months to 18 years old with hemoglobin level less than 10 g/dl and positive DAT with signs of hemolysis were included in the study.Results: Twenty five AIHA patients (F/ M: 14/ 11) aged 6.2± 4.6 years old were followed- up for a mean period of 5.3± 4.8 years. Primary AIHA was detected in 12 (48%) patients. Immune deficiency/ autoimmune lymphoproliferative syndrome was the prominent etiological factor in secondary AIHA. The other underlying diseases were systemic lupus erythematosus, malignancy, autoimmune hepatitis and infection.Eleven patients received MMF with a mean duration of 2.6± 1.6 years. Two of them had primary AIHA, the others had secondary disease. During the follow- up time, eight patients (75%) achieved remission with MMF. None of MMF users developed side effect. One but all patients with AIHA achieved remission. No death related to AIHA was recorde': recorded Conclusion: Understanding the biology of the disease and making accurate diagnosis is important to avoid harmful treatment and to consider targeted therapy. After the failure of first line therapy with steroids or as a steroid- sparing agent, MMF seems to be an effective second-line maintanance immunosuppressive drug without significant side effects.

A prospective, open-label, interventional study protocol to evaluate treatment efficacy of nivolumab based on serum-soluble PD-L1 concentration for patients with metastatic and unresectable renal cell carcinoma

IntroductionNivolumab has been proven to prolong overall survival as a second-line therapy for patients with advanced renal cell carcinoma (RCC) in a phase III clinical trial. However, versatile biomarkers have...

Clinical Features of Post-Transplant Lymphoproliferative Disease Are Different between Kidney-Transplant Recipients from a Cadaveric Donor and Those from a Living Donor

Background: The number of solid organ transplantation (SOT) is increasing. While the remarkable improvement in SOT procedures provides recipients with a good chance of long-term survival, the prolonged immunosuppression has led toa variety of malignancies in solid organ transplant (SOT) recipients; post-transplant lymphoproliferative disorder (PTLD) is a life-threating complication among them. However, there remain some controversies regarding its clinical features. Method: We retrospectively surveyed the patients who had visited both departments: hematology and urology, or renal surgery in kidney center at Tokyo Women's Medical University Hospital from 2003 to 2017. We identified 61 patients diagnosed with hematological disorder in kidney-transplant recipients. Among them, PTLD were analyzed. Continuous variables were compared using Student's t-tests. Overall survival rate (OS) was calculated using the Kaplan-Meier method. P values &lt; 0.05 were considered significant. Statistical analyses were performed using JMP Pro 14 (SAS Institute Inc., Cary, NC, USA) and GraphPadPrism version 7.0 (GraphPad Software, San Diego, USA). This study was conducted in accordance with the Declaration of Helsinki and approved by the institutional review boards. Results: During the survey period, 3,133 patients had visited both departments: hematology and urology, or surgery in Kidney Center. Among them, 61 kidney-transplant recipients were diagnosed with hematological disorder; they comprised 27 PTLD, 10 plasmacytic disorder, 6 idiopathic thrombocytopenic purpura, 5 myelodysplastic syndromes, 4 acute leukemia, 3 polycythemia, 6 other diseases. Among the patients with PTLD (n = 27), 18 patients (66.7%) were male.Median patient ages at the diagnosis of PTLD and kidney transplant were 54 (25-79) and 43 (16-75) years, respectively. Eighteen and nine patients had received kidney-transplant from a living donor (15 related and three unrelated donors) and a cadaveric donor, respectively. The median time from kidney transplant to diagnosis of PTLD was 7.8 years; there was a significant difference in the time between the kidney-transplant recipients from a cadaveric donor and those from a living donor (Figure 1A, 11.3 and 5.6 years, P = 0.02). With regard to the histological subtypes of PTLD, they comprised 17 diffuse large B-cell lymphoma (63.0%), 2 Burkitt lymphoma (7.4%), 4 unclassified B-cell lymphoma (14.8%), 2 T-cell lymphoma (7.4%), and 2 unknown cases (7.4%). 24 of 27 patients had extranodal involvement: 9 central nervous system (33.3%), 7 gastrointestinal tract (25.9%) and other sites. First-line treatment procedure which all patients received was the modification of immunosupressants; complete response (CR) rate was 37.0%. After the failure of first-line therapy, 15 of 27 patients received chemotherapy: 4 rituximab monotherapy (30.8%), 6 CHOP-like regimens (46.2%), and other regimens (33.3%). Among them, five patients experienced relapse. They received salvage chemotherapy, and 2 and one patients achieved CR and partial response, respectively. Rest of them died of lymphoma and infection. The estimated five-year OS from the diagnosis of PTLD and the initiation of chemotherapy was 88.7% and 86.7%, respectively. During the survey period, 5 patients died; their causes of death were 3 lymphomas, 1 infection, and 1 heart failure. There were no deaths in kidney-transplant recipients from a cadaveric donor (Figure 1B). Discussion: While our cohort had more extranodal PTLD recipients than those reported previously, the modification of immunosupressants improved them in more than one-third of cases, which showed the usefulness of it as first-line treatment procedure for PTLD. Nearly half of cases were identified in recipients from a cadaveric donor; the results suggest that the incidence o PTLD among them is higher than those from a living donor because the number of kidney-transplant from a living donor was 10 times higher than those from a cadaveric donor. This study has several limitations due to its retrospective nature and small sample size. In addition, the estimated five-year OS might be better than actual because some patients became lost to follow-up. Further large-scale studies are warranted to validate the findings of this study. Disclosures Hagiwara: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Tanaka:Bristol-Myers Squibb: Research Funding.

P1.01-100 Effect of Osimertinib in Non-Small Cell Lung Cancer Patients with Brain Metastases After Progression Following Front-Line EGFR-TKI Therapy

Osimertinib has been adopted as the standard of care for T790M-mediated acquired epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. In this study, we aim to investigate the effect of osimertinib in advanced NSCLC with brain metastases after the failure of first-line therapy. We retrospectively studied 43 NSCLC patients with BM received osimertinib after progression following front-line EGFR-TKI therapy from January 2013 to December 2016 at our institution. Overall survival (OS) was measured from the date of brain metastases. Among the 43 patients, 25(58.1%) received EGFR-TKIs as first-line therapy, 15(34.9%) were treated with EGFR-TKIs therapy after the progression of chemotherapy, and there’re also 3(7.0%) received the combination of EGFR-TKIs and chemotherapy as first-line therapy. 16(37.2%) were EGFR T790M positive, 4(9.3%) were EGFR T790M negative and 23(53.5%) were unknown T790M status. 34(79.1%) patients had received local radiation therapies (RT). The median overall survival (OS), and the median intracranial progression free survival (iPFS) was 32.0 months, 14 months, respectively. Patients with EGFR T790M mutation had the median OS of 24.7 months, these without T790M mutation had the median OS of 17.0 months, and the patients with unknown status of T790M showed the longest OS of 34.4months, although it did not reach statistical significance (P =0.727). There was also no difference in iPFS among the T790M-positive group, T790M-negetive group and the unknown status group (5.0 vs. 7.0 vs. 18.0 months, P=0.195). Similar results in OS were found among the first line TKIs group, chemotherapy followed by EGFR-TKI therapy group and the combination of TKIs and chemotherapy group (P=0.491). Three patients had leptomeningeal metastasis (LM), showed to have a worse iPFS of 12 months compared to 14 months of these without LM (P=0.991). Osimertinib had a good efficacy in patients with brain metastasis of advanced non–small-cell lung cancer in whom disease had progressed following front-line EGFR-TKIs.

The evaluation of efficacy and tolerability of gemcitabine vs. capecitabine therapy in the second-line setting for metastatic pancreatic cancer patients with poor performance status

Abstract Aim The aim of this study was to evaluate the efficacy and tolerability of single-agent gemcitabine vs. capecitabine therapy in the second-line setting for metastatic Pancreatic Cancer (mPC) patients with poor performance status. Material and methods A total of 48 patients with mPC, who were followed and treated in oncology center between 2012 and 2017, were included. After a failure of first-line therapy, patients with an ECOG-PS 2 treated with capecitabine or gemcitabine monotherapy in the secondline setting were retrospectively analyzed. Results Of the 48 patients, 26(54.2%) were males and 22(45.8%) were females. The median age of the patients was 62 years(range, 31-82). Treatment regimens in the first-line setting were as follows; gemcitabine+cisplatin in 24(50%) patients, gemcitabine+nub-paclitaxel in 4(8.3%) patients, FOLFIRINOX in 8(16.7%) patients, FOLFOX in 8(16.7%) patients, and gemcitabine+oxaliplatine in 4(8.3%) patients. After progression on first-line therapy, 29(60.5%) patients were treated with capecitabine in the second-line setting, while 19(39.5%) patients were given gemcitabine. Median progression-free survival was found to be 4 months(95% CI,1.9-6.0) in patients receiving capecitabine compared to 2 months(95% CI, 0.5-3.4) in those treated with gemcitabine (p=0.271). Median overall survival was 6.0 months(95% CI, 2.0-9.9) in patients receiving capecitabine therapy versus 5.0 months (95% CI, 1.0-8.9) in those treated with gemcitabine monotherapy (p=0.353). Conclusions Optimal second-line treatment for mPC has not yet been established. In the present study, capecitabine monotherapy was compared to gemcitabine and it was found that they both had similar efficacy in the second-line treatment for mPC patients who were not eligible for combination chemotherapy regimen.

Metastatic Renal Cell Cancer: An Analysis of Reimbursement Decisions.

Metastatic renal cell carcinoma is a complex cancer for which several drugs have been developed over the years. More recently, drugs that target the specific cancer cell mutations have been developed for metastatic cell carcinoma. However, even with the recent influx of targeted therapy options, significant unmet needs exist in around half of treated renal cell carcinoma patients following the failure of first-line therapy. The aim of this study was to review the health technology appraisals of renal cell carcinoma treatments in several countries to establish what factors might affect the reimbursement decisions. The reimbursement data for 10 drugs in several countries were collated from the health technology assessment bodies for each country. The data included information on clinical trials used in the submission documents for the health technology assessment, the reimbursement decisions and the reasons for those decisions, as well as any specific restrictions for use of any of the included drugs. Of the 10 drugs reviewed, only everolimus received a positive reimbursement decision by all the health technology assessment bodies included in the study. The most common reason for a negative reimbursement decision was lack of demonstration of cost-effectiveness of the drugs. Another frequently cited reason was unproven clinical efficacy and poor impact on overall survival. Despite the many treatment guidelines and current treatment options that are available for renal cell carcinoma, there remains an unmet need in patients with metastatic renal cell carcinoma. On the basis of this analysis, the key reason for a drug not obtaining a positive reimbursement decision is due to poor efficacy or uncertainty of the drug's efficacy. Eisai, Inc.

Clinical analysis of 71 cases of anti-N-methyl-D-aspartate receptor encephalitis in children

Objective: To investigate the clinical features, treatment strategies and long term outcomes of children with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Methods: The data of clinical features, auxiliary examinations, treatments and prognosis in children with anti-NMDAR encephalitis in Xiangya Hospital of Central South University from March 2014 to October 2017 were collected and retrospectively analyzed. A total of 71 patients were enrolled, including 33 males and 38 females. The youngest age of onset was 4 months old, and the age of onset was (9±4) years. The first-line immunotherapy treatment for anti-NMDAR encephalitis was short course corticosteroid (high-dose impulse therapy and oral maintenance therapy for 1 month in acute period) and (or) immunoglobulin. The clinical evaluation was performed 2 weeks after first-line immunotherapy treatment. The second-line immunotherapy treatment, including rituximab and (or) cyclophosphamide, would be started if the symptoms did not improve significantly and the modified Rankin scale (mRS) score ≥3. All patients were followed up and evaluated for prognosis. T-test, Mann-Whitney U, Chi square test and Fisher's exact probability method were used for comparison between good outcome group and poor outcome group, first-line immunotherapy group and first-line immunotherapy combined with second-line immunotherapy group. Results: The more common clinical manifestations were psychiatric symptoms (n=61, 86%), dyskinesia (n=55, 77%) and convulsions (n=51, 72%). Two cases (3%) had tumors. Electroencephalogram (EEG), cerebro-spinal fluid (CSF) and brain magnetic resonance imaging (MRI) studies were abnormal in 83% (59/71), 39% (27/69) and 38% (27/71) patients, respectively. For the treatment regimens, all the 71 patients underwent first-line immunotherapy, resulting in improvement within 14 days in 40 cases (56%), and 1 case (1%) died. The rest 30 cases (42%) received second-line immunotherapy. The patients were followed up for 5.0-41.8 months, with a median of 19.3 months. At the last follow-up, 49 cases (69%) recovered completely, 15 cases (21%) had mild disability, 6 cases (8%) had severe disability, 1 case (1%) died and 3 cases (4%) had relapse. There were significant differences between the groups with good prognosis and poor prognosis on admission to pediatric intensive care unit (PICU) and consciousness disorder (10/64 vs. 5/7, 39/64 vs. 7/7, P=0.047, 0.004). There were significant differences between first-line immunotherapy group and the first-line combined second-line immunotherapy group on admission to PICU, consciousness disorder, sleep disorder and first mRS score (12% (5/41) vs. 33% (10/30), 44% (18/41) vs. 93% (28/30), 56% (23/41) vs. 90% (27/30), 3 (1-5) vs. 4 (3-5), respectively; χ(2)=4.645, 18.555, 9.560, Z=5.184, P=0.031, <0.01, 0.002, <0.01, respectively). Conclusions: Anti-NMDAR encephalitis can occur in all ages of children. The most common clinical manifestations are psychotic symptoms, dyskinesia and convulsions. Paraneoplastic cases are less common in children. Immunotherapy is effective. The second-line immunotherapy should be given after the failure of first-line therapy (mRS score≥3).

Intravenous Corticosteroids as an Adjunctive Treatment for Refractory and Super-Refractory Status Epilepticus: An Observational Cohort Study

Status epilepticus (SE) represents a neurological emergency that leads to considerable morbidity and mortality. Following failure of first-line therapy, usually with benzodiazepines, there is no clear evidence to guide treatment of refractory SE, although a wide variety of approaches has been described anecdotally. The aim of this study was to assess the clinical response to corticosteroids in adults with refractory and super-refractory SE, describing, to the best of our knowledge, the first adult SE cohort treated with corticosteroids. We retrospectively analysed our adult SE registry (2006-2017), identifying 15 out of 987 episodes (1.5%) in which corticosteroids were prescribed de novo as adjuvant therapy to a variety of antiepileptic drug regimens. We analysed incident episodes and defined clinical response as SE ceasing within 1week of administration, without any other medical intervention. Out of 987 SE episodes, 15 (1.5%) were treated with de novo corticosteroids, corresponding to 12 patients, with increasing prevalence as the SE became refractory (10/411; 2.4% of episodes) and super-refractory (5/108; 4.6% of episodes). One patient (a woman with Rasmussen encephalitis) presented with four SE episodes over a period of 3years, so only her index SE episode was included in subsequent analyses. The episodes treated were predominantly of inflammatory origin (6/12), such as autoimmune or Rasmussen encephalitis. In five out of 12 (42%) of the considered incident episodes, SE resolved following corticosteroids (all within 3days). The outcome was better in this responders group (for 2/5 episodes, patients did not have a new handicap at discharge, versus 0/7 in non-responders). In patients with inflammatory and acute symptomatic causes, global prognosis was better than in those with progressive or neurodegenerative aetiologies (6/8 vs. 4/4 had a new handicap at discharge or died). Our observations seem to support the use of corticosteroids, especially for acute SE of putative inflammatory origin; these compounds, however, were prescribed infrequently.

HIV Drug Resistance Mutations in Patients with HIV and HIV-TB Coinfection After Failure of First-Line Therapy: A Prevalence Study in a Resource-Limited Setting

Introduction:The present study aimed to report the prevalent HIV-1 drug-resistant mutations in patients with HIV-1 alone and tuberculosis (TB) coinfection alone to improve our understanding of the mutation patterns and aid treatment decisions.Methods:Patients with HIV-1 and HIV-TB on treatment for more than 1 year with suspected failure were recruited. Sequencing of protease and two-thirds of the region of reverse transcriptase gene was done for drug-resistant mutations.Results:In the HIV-TB group (n = 25), 88%, 92%, and 12% had mutations to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs), respectively. In the HIV-alone group (n = 25), 84%, 100%, and 4% had mutations to NRTIs, NNRTIs, and PIs, respectively. M184V, M41L, D67N, G190A, A98G, and K103N were the most common mutations seen.Conclusion:There is a high prevalence of drug-resistant mutations in HIV and HIV-TB coinfected patients.

Clinical and Immunological Outcomes after Initiation of Second Line Antiretroviral Therapy in People Living with HIV

Introduction: Resistance to first-line Antiretroviral Therapy (ART) has been a major concern in People Living with HIV (PLHIV), which necessitates a switch to second-line therapy. Data regarding the outcomes of second-line ART, especially in patients receiving Lopinavir/Ritonavir and Atazanavir/Ritonavir based therapy in a resource-limited setting like India is limited. Aim: To determine the clinical and immunological response to second-line ART as measured by change in mean body weight, change in WHO staging and change in CD4 cell count respectively. Materials and Methods: This facility based cross-sectional was done on PLHIV who were initiated on second-line ART following first-line therapy failure between January 2010 and March 2015. The patients were followed up for a minimum duration of one year after initiating on second-line therapy. The data was collected using a semi-structured proforma. Data regarding the CD4 cell count, body weight and WHO clinical staging at second-line ART initiation, at six months and one year after second-line ART was collected. Statistical analysis was done using ANOVA with Bonferroni test and proportions were compared using chi-square test. Results: A total of 110 patients who received second-line ART following first-line therapy failure were analysed. Majority 75 (68.2%) were males. The mean baseline body weight at the start of the second-line therapy was 50.65±7.9 kg which increased to 53.02±7.93 kg and 54.69±8.16 kg at 6 and 12 months of therapy respectively. The number of patients categorised as WHO Stage 3/Stage 4 reduced to 25 and 6 at the end of 6 and 12 months of therapy respectively. The mean baseline CD4 count at the start of the therapy was 210.95±104.53 cells/mm3 which increased to 352.15±149.78 cells/mm3 and 417.01±147.80 cells/mm3 at 6 and 12 months respectively. There were a total of nine deathsin present study. Conclusion: Second-line ART has a satisfactory outcome in terms of clinical and immunological improvement following first-line failure in PLHIV

Molecular Patterns of Resistance Among Helicobacter pylori Strains in South-Western Poland.

Treatment failure of Helicobacter pylori infection is caused mainly by progressive antibiotic resistance among H. pylori strains. In Poland, the prevalence of H. pylori strains resistant to metronidazole is higher than in other developed countries, reaching almost 50%, and resistance to clarithromycin is as high as 30% and is still increasing, contributing to the failure of first-line therapy in approximately 70% of patients. Moreover, the introduction of levofloxacin to eradication therapy of H. pylori infection quickly led to the emergence of resistant strains. Therefore, a necessary approach in microbiological diagnostics of H. pylori infection should be determination of susceptibility of H. pylori strains before the eradication treatment.Aim: In this study was to evaluate the molecular mechanisms of resistance among 170 H. pylori strains to clarithromycin, involving mutations in the 23S rRNA gene (A2143G, A2142G, A2143G) and to levofloxacin, involving mutations of gyrA and gyrB. Analysis was performed by using polymerase chain reaction and classical sequencing of DNA fragments.Results: Among examined strains, 26% were fully sensitive and 74% were resistant to at least one of the tested antibiotics. The overall resistance rate to metronidazole was as high as 56%, whereas to clarithromycin 46%, respectively. Resistance to LEV occurred among 6% of strains. All tested strains were susceptible to AMC and TET. The A2143G point mutation was found in 72% of clarithromycin-resistant strains. The most common mutation, present in 40% of H. pylori strains resistant to levofloxacin, was a change at position 91 of gyrA.Conclusion: The increasing number of point mutations in the 23S rRNA gene leads to an increase in the rates of antimicrobial resistance. Presence of the GCG allele at position 122 of the gyrA gene may cause an eightfold increase in risk of development of resistance to levofloxacin.

Prevalence of Helicobacter pylori resistance after failure of first-line therapy. A systematic review

There are no systematic data on the rates of antibiotic resistance after the failure of a first eradication treatment. The objective of this study was to determine the prevalence of secondary resistance to antibiotics by conducting a systematic review of studies evaluating the secondary resistance of Helicobacter pylori. We identified 31 studies (2,787 patients). Resistance was determined in 1,764 patients. A percentage of 99.1 of patients received clarithromycin as first-line treatment and 58.7% developed resistance. A percentage of 24.3 received metronidazole and 89.7% developed resistance. Secondary resistance to amoxicillin was extremely rare. Secondary resistance after first-line treatment was very common. These findings support the recommendation not to repeat clarithromycin or metronidazole after the failure of a first eradication treatment.