Neuroblastoma.

Neuroblastoma is one of the most common solid tumors in children and has a diverse clinical behavior that largely depends on the tumor biology. Neuroblastoma exhibits unique features, such as early age of onset, high frequency of metastatic disease at diagnosis in patients over 1 year of age and the tendency for spontaneous regression of tumors in infants. The high-risk tumors frequently have amplification of the MYCN oncogene as well as segmental chromosome alterations with poor survival. Recent advanced genomic sequencing technology has revealed that mutation of ALK, which is present in ~10% of primary tumors, often causes familial neuroblastoma with germline mutation. However, the frequency of gene mutations is relatively small and other aberrations, such as epigenetic abnormalities, have also been proposed. The risk-stratified therapy was introduced by the Japan Neuroblastoma Study Group (JNBSG), which is now moving to the Neuroblastoma Committee of Japan Children's Cancer Group (JCCG). Several clinical studies have facilitated the reduction of therapy for children with low-risk neuroblastoma disease and the significant improvement of cure rates for patients with intermediate-risk as well as high-risk disease. Therapy for patients with high-risk disease includes intensive induction chemotherapy and myeloablative chemotherapy, followed by the treatment of minimal residual disease using differentiation therapy and immunotherapy. The JCCG aims for better cures and long-term quality of life for children with cancer by facilitating new approaches targeting novel driver proteins, genetic pathways and the tumor microenvironment.

Preoperative pain in patient with an inguinal hernia predicts long-term quality of life

Neuroblastoma (NB) is the most common extracranial solid tumor in infancy and originates in the peripheral sympathetic nervous system (PSNS). High-risk NB is fatal in the majority of patients, despite intensive myeloablative chemotherapy. The MYCN oncogene is amplified in over 20% of NB, particularly in those with highest risk treatment failure. We have developed a zebrafish NB model by overexpressing human MYCN under the control of the dopamine-beta-hydroxylase (D) promoter specific for noradrenergic cells in the PSNS. Fish from this stable transgenic line developed tumors as early as 4 months of age with approximately 20% penetrance at 8 months of age. The tumors resemble human NB histologically, immunohistochemically, and ultrastructurally. The expression of MYCN suppressed the normal development of PSNS neurons and chromaffin cells in the head kidney during embryogenesis and in young adult fish. In some fish, tumor cells began to repopulate the interrenal gland of the head kidney by 2 months of age. Germline and somatic activating mutations have been identified in the ALK gene, which encodes a receptor tyrosine kinase, in human NB, including those with MYCN amplification. To assess cooperativity between amplified MYCN and mutant ALK genes in transformation, we generated a zebrafish stable transgenic line in which the activated mutant form of ALK (F1174L) was expressed under the control of the DßH promoter. These transgenic animals did not display an abnormal phenotype nor did they develop tumors during the first 6 months of life. In contrast, mutant ALK expression accelerated the onset of MYCN-induced neuroblastoma when the 2 genes were co-expressed in double transgenic fish, indicating that MYCN over-expression and activating ALK mutations can cooperate in tumorigenesis. Although co-expression of mutant ALK accelerated the onset of tumors, it did not rescue the MYCN-induced suppression of PSNS development, suggesting that an as-yet-unidentified tumor suppressor gene, possibly located on distal 1p in the human genome, may be lost to fulfill this role in NB tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-162.

Catheter ablation (CA) is a recognized first-line treatment for atrial fibrillation (AF) in selected patients; however, the differences between CA and antiarrhythmic drugs (AADs) in terms of long-term outcomes and quality of life (QoL) have not often been compared. We performed a meta-analysis of randomized controlled trials (RCTs) to compare long-term outcomes and QoL with CA and AADs in the treatment of AF. We searched the MEDLINE database for English-language RCTs of CA or AADs in AF from 1 January 2005 to 30 October 2019 with no other restrictions. We included studies that reported sample sizes and the long-term outcomes of interest as well as sample size, mean ± standard deviation or 95% confidence intervals (CIs) for QoL outcomes with CA and AADs. We identified 20 RCTs involving 5425 participants. Compared with patients who received only AADs, patients receiving CA had a significantly decreased risk of all-cause death (relative risk [RR] 0.72; 95% CI 0.58-0.90) and cardiovascular hospitalization (RR 0.85; 95% CI 0.79-0.91). We found a significant increase in the risk of cardiac tamponade (RR 5.86; 95% CI 1.77-19.44) but no difference in the risk of heart failure, stroke or transient ischemic attack, atrial tachycardia, bleeding or hematoma, and pulmonary vein stenosis. For long-term QoL after treatment, both therapies resulted in improved scores on the Medical Outcomes Study 36-Item Short Form Survey (SF-36): weighted mean differences (WMDs) for the physical component score (PCS) were 5.89 for CA and 4.26 for AADs and for the mental component score (MCS) were 7.12 for CA and 5.06 for AADs. At the end of follow-up, groups receiving CA had significantly higher scores in both areas. The change in PCS and MCS between baseline and end of follow-up was also significantly higher in the CA groups: WMD 1.51 for change in PCS and 1.49 for change in MCS. All eight SF-36 subscale scores improved for patients receiving CA, whereas patients receiving AADs recorded no improvement in the general health and bodily pain subscales. At the end of follow-up, CA groups had significantly higher scores than AAD groups in the following subscales: physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, and role limitations due to emotional problems. In the treatment of AF, CA appeared to be superior to AADs, decreasing the risk of all-cause death and cardiovascular hospitalization and improving the long-term QoL of patients with AF. CA was better tolerated and more effective than pharmacological therapy and allowed for improved QoL.

Orthotopic liver transplantation can provide a large number of patients with end-stage liver disease an opportunity for significant improvement in long-term survival and quality of life. Transplantation should not be considered a last-ditch attempt to save a dying patient. Early referral of patients to transplant centers will allow for further improvement in survival of patients after transplantation. Ongoing communication between the referring physician and the transplant team is important in keeping abreast of changes in the patient's status so that optimal timing of the transplant may be achieved.

Insulin dependence and pancreatic enzyme replacement therapy are independent prognostic factors for long-term survival after operation for chronic pancreatitis

This secondary report from our 52-week, double-blind, relapse prevention trial tested whether stable patients with schizophrenia who were taken off active drug treatment would experience greater improvements in long-term quality of life than those who were continued on antipsychotic treatment. On average, Heinrichs-Carpenter Quality-of-Life Scale total scores improved by 4.3 +/- 10.6 points during treatment with olanzapine (10-20 mg/d; n = 212), but decreased by 7.1 +/- 14.6 points during treatment with placebo (n = 92; P < 0.001). Mean Quality-of-Life Scale total scores worsened in both treatment groups for the relapsing patient subgroup, whereas for nonrelapsing patients, those treated with olanzapine had significantly improved mean Quality-of-Life Scale total scores compared with those given placebo. For a subset of nonrelapsing patients who were considered "nonexacerbating" on the basis of minimal non-clinically relevant increases in psychopathology, Quality-of-Life Scale total mean change was no better (P = 0.066) for those given placebo (2.7 +/- 11.0; n = 40) than those treated with olanzapine (5.7 +/- 8.9; n = 174). Path analysis indicated a direct effect of treatment (approximately 29%) on quality of life that was not accounted for by differential changes in psychopathology. In conclusion, stable patients with schizophrenia who were taken off active drug treatment experienced no greater improvements in long-term quality of life than those who were continued on antipsychotic treatment, even in the absence of psychotic symptoms.

BACKGROUND: Lorlatinib, a 3rd generation ALK tyrosine kinase inhibitor, has shown overall and intracranial activity in ALK+ advanced NSCLC. In the randomized, multicenter, phase 3 study in pts with previously untreated ALK+ advanced NSCLC (CROWN; NCT03052608), lorlatinib resulted in a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs crizotinib.1 To identify molecular correlates of response, we performed molecular profiling of circulating free DNA (cfDNA) and tumor tissue. METHODS: Plasma and tumor tissue samples were available from 130 and 118 pts in the lorlatinib arm, and from 125 and 104 pts in the crizotinib arm, respectively. Plasma DNA was analyzed for ALK fusions and mutations by next-generation sequencing (NGS; Guardant360, Guardant Health, Inc., Redwood City, CA, USA); tumor tissue DNA was analyzed with an ALK-mutation focused NGS panel (MolecularMD, Portland, OR, USA). Objective response rate (ORR), duration of response (DOR), and PFS were evaluated by blinded independent central review according to EML4-ALK variant type and ALK resistance mutation status. RESULTS: At screening, 19 ALK missense mutations and 1 deletion were detected in plasma of 11 pts (5 and 6 in the lorlatinib and crizotinib arms, respectively). Most pts harbored 1 mutation, but 3 pts harbored ≥3 mutations. ALK fusions were detected in plasma of 48% of pts. EML4-ALK variants 1, 2, and 3 were detected in 14.6%, 5.4%, and 13.8% and in 20.0%, 1.6%, and 16.8% of pts, in the lorlatinib and crizotinib arms, respectively. Variants 4, 5, 7, and 8 were detected in 11.5% and 7.2% of pts, and less frequent fusion partners in 1.5% and 3.2% of pts, respectively. ORRs were generally higher in the lorlatinib arm vs the crizotinib arm, regardless of variant subtypes and/or mutational status, with no striking differences between EML4-ALK variants 1, 2, and 3 (range, 72% to 86% for lorlatinib and 50% to 76% for crizotinib). Median DOR and PFS were not reached for variants 1 and 3 in the lorlatinib arm, and ranged from 5.7 to 6.5 months, and from 7.4 to 7.6 months in the crizotinib arm, respectively. CONCLUSION: Pts with untreated ALK+ advanced NSCLC had higher ORRs and potentially longer DOR and PFS across predefined biomarker subgroups when treated with lorlatinib compared with crizotinib in a phase 3 CROWN study. Based on pretreatment cfDNA analysis, lorlatinib led to similar clinical benefit regardless of the type of EML4-ALK variant or presence of ALK kinase mutations. REFERENCE: 1. Shaw AT, et al. N Engl J Med. 2020;383:2018-2029. Citation Format: Alessandra Bearz, Jean-François Martini, Jacek Jassem, Sang-We Kim, Gee-Chen Chang, Alice Shaw, Deborah Shepard, Elisa Dall'O', Anna Polli, Holger Thurm, Gerard Zalcman, Maria Rosario Garcia Campelo, Konstantin Penkov, Hidetoshi Hayashi, Benjamin J. Solomon. Efficacy of Lorlatinib in Treatment-Naïve Patients (pts) With ALK-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) in Relation to EML4-ALK Variant Type and ALK Mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB043.

Hereditary angioedema (HAE) is a rare hereditary disorder characterized by episodic swelling and life-threatening airway obstruction caused by laryngeal angioedema. In most HAE patients, reduced level of serum C1-Inhibitor (type-I-HAE) or presence of aberrant C1-Inhibitor (type-II-HAE) result in the lost of regulation of the complementary system and contact activation system with downstream over-activation of bradykinin - the chief mediator leading to angioedema. Type-III HAE (HAE-nl-C1INH) is rare without deficient or dysfunction of C1-Inhibitor, often with genetic aberrant related to the contact activation system. The prevalence of HAE in the population is estimated at 1 in 50,000 individuals, often with early onset, but due to the heterogeneity of the disease, there is frequently a significant delay in diagnosis. Recently, better awareness by physicians, more access to diagnostic tools, better management and prophylaxis has decreased morbidity and mortality. A focus in HAE patient care shift from management of attacks with on-demand medication, to use of prophylaxis to reduce attacks has improved the overall quality of life of patients with HAE. One area in HAE research that has not been emphasized is the long-term consequence of C1-INH deficiency in HAE patients, other than the typical manifestations of HAE, as evidence have emerged linking this disorder with increased risk of cardiovascular diseases, auto-immune disorders, and malignancy. This review aims to gather the current knowledge and evidence of potential consequence of C1-Inhibitor deficiency in HAE aside from angioedema with emphasis in the improvement of long-term care and overall quality of life for HAE patients.

BackgroundStudies have previously shown laparoscopic antireflux surgery is a safe and effective treatment for GERD even in elderly patients. The aim of the current study was to evaluate patients receiving laparoscopic antireflux surgery before and after 65 years of age and to assess their surgical outcomes and improvements in long term quality of life.MethodsPatients were given a standardized symptoms questionnaire and the Short-Form 36 Health Survey for quality-of-life evaluation before and after laparoscopic total fundoplication.ResultsForty-nine patients older than 65 years of age were defined as the elderly group (EG) whereas the remaining 262 younger than 65 years of age were defined as the young group (YG).There were 114 (36.6%) patients who filled out the SF36 questionnaire (98 in the younger group, rate: 37.4%; 16 in the elderly group, rate: 32.6%) pre- and post-operatively. There was no significant difference between the two age groups regarding preoperative PCS ( 45.6 ± 7.8 in YG vs. 44.2 ± 8.2 in EG; P = 0.51) and MCS ( 48.1 ± 10.7 in YG vs. 46.9 ± 9.2 in EG; P = 0.67). There was no significant difference between the two age groups regarding postoperative PCS (49.8 ± 11.9 in YG and 48.2 ± 9.5 in EG ; P = 0.61 and MCS (48.4 ± 10.7 in YG vs. 50.1 ± 6.9 in EG; P = 0.54).ConclusionsIn conclusion, laparoscopic total fundoplication is a safe and effective surgical treatment for gastroesophageal reflux disease generally warranting low morbidity and mortality rates and a significant improvement of symptoms comparable. An improved long-term quality of life is warranted even in the elderly.

The authors report two siblings with familial neuroblastoma with a germline R1275Q mutation of the tyrosine kinase domain of ALK. Whole exome sequencing and copy number variation assay were performed to investigate genetic alterations in the two cases. No common somatic mutations or gene polymorphisms related to the tumorigenesis of neuroblastoma were detected. A distinct pattern involving both segmental chromosomal alteration and MYCN amplification was detected. The diversity of biological behavior of familial neuroblastoma harboring a germline ALK mutation may depend on conventional prognostic factors, such as segmental chromosomal alterations and MYCN amplification, rather than additional acquired mutations.

Pre-operative chemoradiotherapy followed by a total mesorectal excision (TME) is the standard of care for patients with locally advanced (stage II or III) rectal cancer. Approximately 20% of patients may achieve a pathologic complete response after chemoradiation therapy (CRT), which has been shown to be associated with better oncologic outcomes. Whether surgery can be avoided in this population is an area of active investigation. Recent studies demonstrated feasibility and safety of non-operative management in patients with clinical complete response (cCR) after chemoradiotherapy. In this article, we set out to review the current data on non-operative management and to identify areas requiring further investigation, including improvement in imaging for reassessment after CRT and identifying the optimal time frame for restaging. As the field moves forward with non-operative management in select patients with rectal cancer, there continues to be a need to better understand the prognostic factors and biomarkers that may more accurately characterize patients who are qualified for this "wait-and-see" approach and thereby avoid overtreatment, potentially leading to improvements in long-term quality of life.

The excellent results obtained today in solid-organ transplantation allow the envisaging of an improvement in long-term quality of life with a functioning graft. One way for this to be achieved is by the reduction, or even better, the avoidance, of steroid-based immunosuppression. Avoidance of steroids is indeed known to enhance the physical and psychological well being of the allograft recipient. This paper reviews the current status of steroid-free immunosuppression in renal, pancreatic, hepatic, intestinal, and cardiac transplantation.

Late-onset myasthenia gravis (LOMG) features prominent immunosenescence, high myasthenic crisis risk, and refractoriness due to comorbidities limiting conventional immunosuppressants, leading to poor prognosis. Eculizumab, which blocks complement C5 activation, may provide rapid symptom improvement and has shown an acceptable safety profile in previous studies, holding potential for LOMG management. Although the REGAIN trial and some real-world studies have demonstrated the efficacy of eculizumab, evidence for its use in patients with refractory LOMG is scarce. This study aimed to evaluate the clinical outcomes, safety profile, and impact on quality of life of eculizumab treatment in patients with refractory acetylcholine receptor antibody-positive [AChR-Ab(+)] generalized LOMG. This study retrospectively enrolled 31 patients with refractory AChR-Ab(+) generalized LOMG treated with eculizumab for ≥2 months. Primary outcome was change in myasthenia gravis activities of daily living (MG-ADL) score analyzed using mixed models for repeated measures. Secondary outcomes included 15-item Revised Myasthenia Gravis Quality of Life Questionnaire (MG-QOL 15r) score, Minimal Symptom Expression (MSE) response rate, clinically meaningful improvement (a decrease of ≥3 points in MG-ADL, CMI) in ADL, and concomitant immunosuppressant dosage reduction. Safety was assessed via drug-related adverse events. The mean age of onset in the 31 patients with refractory LOMG was 62.87±5.95 years, with a mean follow-up duration of 10±4.29 months after eculizumab treatment. Compared with baseline, the MG-ADL score was reduced by 2.976 points at Month 1 and 5.430 points at Month 12 (both P<0.001); MG-QOL 15r scores reduced by 7.724 and 15.343 points respectively (both P<0.001). Alluvial plots showed that MG-ADL and MG-QOL 15r scores continuously shifted to lower ranges with treatment. MSE cumulative rate was 22.58% at Month 1 and 72.24% at Month 12, with CMI rate rose from 51.61% to 96.41%. Mean prednisone daily dose decreased by 7.574 mg/day (P<0.001). Sensitivity analyses using multiple imputation and conservative baseline observation carried forward (BOCF) yielded consistent results, supporting the robustness of the findings. One patient reported headache (CTCAE 1 grade), no serious adverse events occurred. Eculizumab was associated with clinical improvement in patients with refractory AChR-Ab(+)-generalized LOMG. In this cohort, patients demonstrated rapid symptom reduction and improvements in long-term quality of life.

Background There is a lack of certain evidence for the therapeutic efficacy of probiotics for adult atopic dermatitis (AD). Methods PubMed, EMBASE, and the Cochrane Database were searched for relevant studies, and randomized controlled trials of AD describing treatment with single/mixed probiotic therapy were included. Changes in outcomes were calculated by standard mean difference (SMD) and 95% confidence interval (CI). Relative efficacies of the probiotics were ranked by the surface under the cumulative ranking (SUCRA). Results Nine studies with a total of 402 participants, including 208 AD patients who received probiotic treatments and 194 controls, were considered during the current analysis. A reduction in disease severity for probiotic supplementation compared to controls in both the short term (SMD: 0.63; 95% CI: 0.02–1.25) and the long term (SMD: 1.57; 95% CI: 0.66–2.49). There was a significant improvement in long-term quality of life after probiotic supplementation compared with controls (SMD: 0.74; 95% CI: 0.39–1.09). A mixture of L. salivarius (LS01) and Bifidobacterium (BR03) was found the highest probability of the best supplementation. Conclusions Probiotic supplementation decreases clinical severity and improves the quality of life among adult AD patients. The mixture of LS01 and BR03 appeared optimal.