Citations

Abstract Mannose phosphate isomerase‐congenital disorder of glycosylation (MPI‐CDG) deficiency is a rare subtype of congenital disorders of protein N ‐glycosylation. It is characterised by deficiency of MPI caused by pathogenic variants in MPI gene. The manifestation of MPI‐CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI‐CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence‐based data and experts' opinions. Those guidelines also reveal more questions about MPI‐CDG which need to be further studied.

The World Health Organization (WHO) has declared coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a pandemic. Global health care now faces unprecedented challenges with widespread and rapid human-to-human transmission of SARS-CoV-2 and high morbidity and mortality with COVID-19 worldwide. Across the world, medical care is hampered by a critical shortage of not only hand sanitizers, personal protective equipment, ventilators, and hospital beds, but also impediments to the blood supply. Blood donation centers in many areas around the globe have mostly closed. Donors, practicing social distancing, some either with illness or undergoing self-quarantine, are quickly diminishing. Drastic public health initiatives have focused on containment and “flattening the curve” while invaluable resources are being depleted. In some countries, the point has been reached at which the demand for such resources, including donor blood, outstrips the supply. Questions as to the safety of blood persist. Although it does not appear very likely that the virus can be transmitted through allogeneic blood transfusion, this still remains to be fully determined. As options dwindle, we must enact regional and national shortage plans worldwide and more vitally disseminate the knowledge of and immediately implement patient blood management (PBM). PBM is an evidence-based bundle of care to optimize medical and surgical patient outcomes by clinically managing and preserving a patient’s own blood. This multinational and diverse group of authors issue this “Call to Action” underscoring “The Essential Role of Patient Blood Management in the Management of Pandemics” and urging all stakeholders and providers to implement the practical and commonsense principles of PBM and its multiprofessional and multimodality approaches.

COPA syndrome is a newly discovered, rare genetic autoimmune disorder, which can affect the lungs, joints, and kidneys. It is difficult to recognize, and the survival benefit of lung transplantation for these patients is not yet known. We present a case of a 24-year-old woman who received bilateral lung transplant for COPA syndrome. At 15 months posttransplant, her pulmonary function is stable with no episodes of acute cellular- or antibody-mediated rejection and no evidence of disease recurrence.

Abstract Great heterogeneity in survival exists for patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL). Three scoring systems incorporating simple clinical parameters (age, lactate dehydrogenase, number/sites of involvement, stage, performance status) are widely used: the International Prognostic Index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI). We evaluated 2124 DLBCL patients treated from 1998 to 2009 with frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; or variant) across 7 multicenter randomized clinical trials to determine which scoring system best discriminates overall survival (OS). Median age was 63 years, and 56% of patients were male. Five-year OS estimates ranged from 54% to 88%, from 61% to 93%, and from 49% to 92% using the IPI, R-IPI, and NCCN-IPI, respectively. The NCCN-IPI had the greatest absolute difference in OS estimates between the highest- and lowest-risk groups and best discriminated OS (concordance index = 0.632 vs 0.626 [IPI] vs 0.590 [R-IPI]). For each given IPI risk category, NCCN-IPI risk categories were significantly associated with OS (P ≤ .01); the reverse was not true, and the IPI did not provide additional significant prognostic information within all NCCN-IPI risk categories. Collectively, the NCCN-IPI outperformed the IPI and R-IPI. Patients with low-risk NCCN-IPI had favorable survival outcomes with little room for further improvement. In the rituximab era, none of the clinical risk scores identified a patient subgroup with long-term survival clearly <50%. Integrating molecular features of the tumor and microenvironment into the NCCN-IPI or IPI might better characterize a high-risk group for which novel treatment approaches are most needed.

AbstractBackground: Abnormal aggregates of α‐synuclein are pathologic hallmarks of multiple system atrophy (MSA) and Lewy body disease (LBD). LBD sometimes coexists with MSA, but the impact of co‐pathology, particularly diffuse LBD, on presentation of MSA has not been studied. We aimed to determine the frequency and clinicopathologic features of MSA with LBD (MSA+LBD). Methods: Using hematoxylin & eosin and α‐synuclein‐immunostained slides, we assessed the distribution and severity of LBD in 230 autopsy‐confirmed MSA patients collected from 1998 to 2018. Alzheimer‐type pathology was assessed to assign the likelihood of clinical presentations of dementia with Lewy body (DLB) using the consensus criteria for DLB. We reviewed medical records to characterize clinicopathologic features of MSA+LBD. Genetic risk factors for LBD, including APOE ε4 allele and mutations in GBA, SNCA, LRRK2, and VPS35, were analyzed. Results: LBD was observed in 11 MSA patients (5%); seven were brainstem type, three were transitional type, and one was diffuse type. The latter four had an intermediate or high likelihood of DLB. Three of the four had an antemortem diagnosis of Parkinson’s disease with dementia (PDD) or clinically probable DLB. Two patients had neuronal loss in the substantia nigra, but not in striatal or olivocerebellar systems with widespread glial cytoplasmic inclusions, consistent with minimal change MSA. In these cases, LBD was considered the primary pathology, and MSA was considered coincidental. APOE ε4 allele frequency was not different between MSA+LBD and MSA without LBD. Two of nine MSA+LBD patients had a risk variant of GBA (p.T408M and p.E365K). Conclusions: Although rare, MSA with transitional or diffuse LBD can develop clinical features of PDD or DLB. Minimal change MSA can be interpreted as a coincidental, but distinct, α‐synucleinopathy in a subset of patients with diffuse LBD.

Abstract Aims Lung congestion in patients with heart failure (HF) has traditionally been treated using interventions that reduce pulmonary capillary hydrostatic pressure. The transient receptor potential vanilloid 4 (TRPV4) channel regulates fluid transit across the pulmonary capillary-interface, and represents a novel target to reduce lung water, independent of pulmonary capillary hypertension. This pilot study examined the safety and potential efficacy of TRPV4 blockade as a novel treatment for HF. Methods and results In this randomized, double-blind, placebo-controlled crossover pilot trial, 11 subjects with chronic, compensated HF were treated with a novel TRPV4 antagonist (GSK2798745) or placebo. The primary endpoint was lung diffusing capacity for carbon monoxide (DLCO) after 7 days of treatment with GSK2798745 as compared to placebo. Secondary endpoints included additional diffusion parameters, spirometry and safety assessments. Compared to placebo, treatment with GSK2798745 resulted in a trend to improvement in DLCO (placebo: −0.336 mL/mmHg/min; GSK2798745: +0.458 mL/mmHg/min; treatment difference: +0.793 mL/mmHg/min; 95% confidence interval: −0.925 to 2.512) that was not statistically significant. GSK2798745 was well-tolerated with no serious adverse events. Conclusion In this pilot trial, GSK2798745 was found to be safe and well-tolerated, with a trend toward improved gas transfer. Further investigation is warranted in larger studies to determine whether treatment with TRPV4 antagonists or alternative treatments targeting capillary permeability might be effective to improve lung congestion, pulmonary gas transfer and clinical status in patients with acute or chronic HF.

Abstract Background: Endx is a Tam metabolite with promising antitumor activity in Tam and aromatase inhibitor (AI) resistant estrogen receptor (ER) positive (+) metastatic breast cancer (MBC). Methods: This randomized phase II study compared progression-free survival (PFS) and toxicity of Endx 80 mg/day to Tam 20 mg/day in patients (pts) with ER+ MBC. Eligibility included postmenopausal women, ECOG PS 0-2, prior progression on AI but not Tam (unlimited endocrine therapy [ET] lines allowed), and a preregistration biopsy confirming ER+ (>10% nuclear staining) and HER2-negative MBC. Stratified randomization was used balancing prior CDK 4/6 inhibitor (CDK 4/6i) use and/or everolimus (yes/no), measurable disease (yes/no) and endocrine resistance (primary/secondary) between arms. Pts randomized to Tam were allowed to cross over to Endx at progression. Due to short expected median PFS, differences in PFS were assessed using approaches for interval-censored data (ICD). 40 eligible pts were to be randomized to each arm so a one-sided alpha=0.10 generalized log-rank test (GLRT) would have a 90% chance of detecting a 50% decrease in hazard of disease progression with Endx (median: 6 months) relative to Tam (median: 3 months). Secondary endpoints include clinical benefit rate (stable or partial response > 6 cycles) (CBR) for measurable and non-measurable disease. Pharmacokinetic (PK) data were obtained Day (d) 1 (4 hour), end of cycle 2, and at time of progression. Results: From March 2015 to March 2017, 108 women with endocrine refractory recurrent or MBC were preregistered. 27 pts did not register due to: biopsy demonstrating ER-/HER2- (3 pts), ER+/HER2+ (5 pts), cancer other than breast (3 pts), no cancer in specimen (6 pts), brain metastases (2 pts), acute infection (1 pt), progression on or recent use of Tam (2 pts), or pt refusal (5 pts). 4/81 pts who registered were excluded due to ineligibility (3 pts) or refusal to start protocol treatment (1 pt). The study cohort consisted of 40 pts randomized to Endx and 37 pts to Tam. The median (m) number of ETs in the metastatic setting was 2 (range 1-4) for each arm including prior CDK 4/6i (Endx: 42.5%, Tam: 29.7%) and everolimus (Endx: 35.0%, Tam: 40.5%). The m cycle number was 6 for Endx (range: 1-35) and 3 for Tam (range: 1-42). PFS for Endx was not significantly different compared to Tam (HR= 0.77; 95% CI: 0.49-1.22, GLRT p=0.309; mPFS: Endx 130 days [95% CI: 76-138 days] and Tam 42 days [95%CI: 24-129 days]). However, PFS was significantly longer in pts with no prior CDK 4/6i in the Endx arm (GLRT p=0.002; HR(no/yes)=0.31; 95%CI: 0.15-0.65) but not in the Tam arm (GLRT p=0.708) (unplanned analysis). Severe (grade (G) 3+) toxicities included: Endx G3 hypertriglyceridemia (3 pts); Tam: G3 hypertension with G2 stroke (1 pt), G3 thromboembolic event (1 pt), and G3 abdominal, bone and liver pain (1 pt). In Endx arm, d1 m Endx plasma concentration (conc) was 216 ng/ml (n=17; range: 144-400). For Tam arm, d1 m Tam conc was 17 ng/ml (n=17; range:11-23) (Endx not detectable). For the 25 pts that crossed over to Endx, CBR was 28.0% (90% CI: 14.0-46.2%) and 14 pts had pk data at progression. A lower median Endx conc (6 ng/ml range: 3.3-16.3) was observed in Tam patients at progression who then had Endx clinical benefit compared to Tam pts without clinical benefit after Endx crossover (median Endx 12 ng/ml; range 4.4-36.6).Conclusions: In endocrine-resistant breast cancer, Z-Endx was not significantly superior to Tam, but clinical benefit was observed in 28% that crossed over to Endx after Tam progression. In pts with no prior CDK 4/6i, the observation of significantly longer PFS in the Endx arm is hypothesis generating. Support: U10CA180821, U10CA180882, U24CA196171, U10CA180820 (ECOG-ACRIN), https://acknowledgments.alliancefound.org; Clinical Trials.gov Identifier:NCT02311933 Citation Format: Matthew P. Goetz, Vera J Suman, Joel M Reid, Mary Kuffel, Sarah A Buhrow, Renee M McGovern, John Black, Travis Dockter, William F Symmans, Minetta C Liu, John R Hawse, James Doroshow, Anna M Storniolo, Jerry M Collins, Howard Streicher, Matthew M Ames, James N Ingle, Ann Partridge, Lisa Carey. A randomized phase II trial of tamoxifen versus Z-endoxifen HCL in postmenopausal women with metastatic estrogen receptor positive, HER2 negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD7-06.