Beyond Rings: Gathering in 1-Interval Connected Graphs

We examine the problem of gathering [Formula: see text] agents (or multi-agent rendezvous) in dynamic graphs which may change in every round. We consider a variant of the [Formula: see text]-interval connectivity model [9] in which all instances (snapshots) are always connected spanning subgraphs of an underlying graph, not necessarily a clique. The agents are identical and not equipped with explicit communication capabilities, and are initially arbitrarily positioned on the graph. The problem is for the agents to gather at the same node, not fixed in advance. We first show that the problem becomes impossible to solve if the underlying graph has a cycle. In light of this, we study a relaxed version of this problem, called weak gathering, where the agents are allowed to gather either at the same node, or at two adjacent nodes. Our goal is to characterize the class of 1-interval connected graphs and initial configurations in which the problem is solvable, both with and without homebases. On the negative side we show that when the underlying graph contains a spanning bicyclic subgraph and satisfies an additional connectivity property, weak gathering is unsolvable, thus we concentrate mainly on unicyclic graphs. As we show, in most instances of initial agent configurations, the agents must meet on the cycle. This adds an additional difficulty to the problem, as they need to explore the graph and recognize the nodes that form the cycle. We provide a deterministic algorithm for the solvable cases of this problem that runs in [Formula: see text] number of rounds.

Real World Experience of Etanercept in Steroid Refractory Acute Graft Versus Host Disease from a Tertiary Cancer Centre in India

Introduction Acute graft versus host disease (aGVHD) is an important complication of allogeneic hematopoietic stem cell transplant (AHSCT). Steroid refractory (SR) aGVHD is seen in about 40- 50% of patients with no recommended standard of care. We report our experience with etanercept (ETA) as the initial agent in SR aGVHD. Materials and Methods We retrospectively analysed 43 AHSCT patients from 2010 to 2019 who received ETA as initial agent for SR aGVHD amongst 311 patients who underwent AHSCT in the same period. Patients received myeloablative (MAC) or reduced intensity conditioning (RIC). The transplants were from matched sibling donor (MSD), matched unrelated donor (MUD) and haploidentical donor (Haplo). GVHD prophylaxis was calcineurin inhibitor (CNI) plus methotrexate (MTX)/ mycophenolate mofetil (MMF) in MSD/MUD. Rabbit ATG (2.5-5 mg/kg) was used for MUD. Haplo transplant patients received post-transplant cyclophosphamide (PTCy) with CNI and MMF. aGVHD was graded as per the modified Glucksberg criteria. Additionally, all aGVHD episodes were also classified as per the Minnesota Scoring into High Risk (HR) and Standard Risk (sr) GVHD. First line treatment of aGVHD Grade II-IV was systemic steroids with methylprednisolone 1-2 mg/kg/day. SR aGVHD was defined as per standard criteria. ETA was started as 25 mg (0.4 mg/kg in children) subcutaneously every 72 hours initially and was tapered gradually depending on response. Response of SR aGVHD to ETA was defined as follows:Complete response (CR) was the complete resolution of aGVHD manifestations in all organs. Partial response (PR) was improvement in GVHD stage in at least 1 of the initially involved organs without CR and worsening in any other organs. Very good partial response (VGPR) was improvement in GVHD in all initial organs, with maximum stage I involvement in 1 or more organs (except upper gut). No response (NR)/Progression/Failure of therapy was defined as same grade or progression of GVHD in any organ or the addition of further GVHD therapy beyond ETA. Death prior to 1st response assessment was taken as NR. Response assessment was done at 3 time points - Day 14, Day 28 and Day 56 after initiation of ETA. Reduction of initial systemic steroid dose by ≥30% from baseline on day 28 after start of ETA was analysed as a subgroup to assess outcomes of patients. Results The characteristics of all 43 patients are shown in Table 1. ETA was required in a total of 45 episodes in 43 patients. The overall grade of GVHD and organs involved at the start of first line treatment are as in Table 2. The median day of onset of acute GVHD was 58 days (range 8-738 days). The median day of start of ETA was 86 days (range 16-74 days). The median number of days steroid was given prior to start of ETA was 7 days. The median number of ETA doses given were 11 (range 2-25). Response assessment on the predetermined time points are as in Table 2. The response rates (CR+VGPR+PR) at Day 14, Day 28 and Day 56 were 62%, 69% and 64% respectively. The organ specific response rates (CR+VGPR+PR) were 70% for lower gut, 67% for skin and 50% for liver. A third line agent for aGVHD was added in 10 patients, which included ruxolitinib, cyclosporine, mycophenolate mofetil, basiliximab or low dose weekly cyclophosphamide. The median OS of the whole cohort of SR aGVHD was 5.2 months. The median OS of the responders (CR+PR+VGPR) at Day 28 from ETA start was 6.8 months versus 2.8 months (p=0.0003) in non-responders (Fig 1). The median OS of sr group of Minnesota Grading was 24 months versus 10 months in HR group (p=0.085) (Fig 2). Patients, in whom reduction in the systemic steroid dose ≥ 30% at Day 28 from start of ETA was possible, had a significantly better median OS (9.5 months versus 3.5 months; p=0.000021) (Fig 3). In multivariate analysis, steroid dose reduction on day 28 of start of ETA was the most significant factor (p=0.008; hazard ratio 3.33; CI 1.3-8.1) CMV reactivation was seen in 64% of the patients. Fungal infections in 51% and bacterial infections in 78% patients after start of ETA. The causes of death were infection in 25 (58%) patients, refractory GVHD in 8 (18%), combination of GVHD and infection in 2 (5%) and relapse in 4 (9%) patients. Conclusion ETA used as initial agent has shown acceptable response rates for SR aGVHD in our cohort, especially for lower gut and skin. However, infections were the major cause for mortality for this cohort and early tapering of systemic steroids may be the key to improving outcomes. Disclosures No relevant conflicts of interest to declare.

Clinical Outcomes in Patients with Immune Thrombocytopenia Treated with All 3 Approved Thrombopoietin Receptor Agonists

Introduction: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by a platelet count < 100 x 109 / L due to accelerated platelet destruction and impaired platelet production (McMillan 1981). At present, there are 3 available thrombopoietin receptor agonists (TPO-RAs) approved for treatment of chronic ITP in adults. All three agents have high response rates, 40-90%, depending on the criteria used to define response (Ghanima et al 2019). Previous studies illustrate efficacy of Romiplostim and Eltrombopag having surprisingly high response rates when switching from one to the other, particularly if there was a response to the first TPO-RA (Gonzalez-Porras et al 2015; Lakhwani et al 2017; Cantoni et al 2018) but no studies have compared all 3 approved TPO-RA. Herein we describe 7 patients with difficult to treat chronic ITP who received all 3 TPO-RA and assess responses of the 7 to each of Eltrombopag, Romiplostim and Avatrombopag. Methods This was a retrospective review of all patients with chronic ITP seen at the Platelet Disorders Program at Weill Cornell Medicine-NY Presbyterian Hospital between July 2019 (following FDA approval of Avatrombopag) and June 2020 who had been treated with Eltrombopag, Romiplostim and Avatrombopag. Seven patients were identified (most had been followed for many years) and information collected on demographics, laboratory results, and clinical data including response and tolerance to ITP treatments, in particular the 3 TPO-RA. Results There were 4 females and 3 males with median age of 64 years (range 33-77). All had primary ITP with median 3 (range 2-13) separate ITP treatments, including investigational therapies, preceding treatment with their first TPO-RA (Table 1). All 7 patients had difficult to treat ITP with episodes of severe thrombocytopenia despite chronic treatments, requiring periodic rescue with IVIg and/or steroids. Three patients received Eltrombopag as their first TPO-RA and 4 patients Romiplostim. All 7 patients received Avatrombopag as their third TPO-RA and all also received other therapies either in conjunction with or in between TPO-RAs (Figure 1). No patient went directly from one TPO-RA to another without intervening treatment. All 7 patients (100%) responded to their first TPO-RA. For the 3 initially on Eltrombopag, duration of treatment ranged from 1 week to 8 years. When these 3 were switched to Romiplostim as a second TPO-RA, they responded with median time on treatment 27 months (range 21-48 months). Reasons prompting the switch from Eltrombopag to Romiplostim included: lost response (1), allergic reaction (1), insurance/financial issues (1). The 4 patients who started with Romiplostim had a median duration on treatment of 18 months (range 4-96 months). Two of these 4 who switched to Eltrombopag as their second TPO-RA responded to Eltrombopag with median time on treatment 5.5 months. Reasons for switching from Romiplostim to Eltrombopag included: unstable platelet response (2), patient preference for an oral agent (2). Prior to taking Avatrombopag, 5 patients returned to a TPO-RA they had previously responded to with 3 requiring higher doses on re-exposure. These patients (4, 6, 7) had switched from that initial agent due to patient preference (1), financial issues (1) and unstable platelet response (1). Five/7 patients (71%) responded to the third TPO-RA, Avatrombopag. Reasons prompting the switch to Avatrombopag from the previous TPO-RA included: patient preference (4), lost response (2), unclear/suboptimal response (1). The 5 responders remain on only Avatrombopag with durations of 3 months to 11 months. Conclusions: All 7 patients responded initially to TPO-RA whereas response rates of around 70% were seen when patients are switched to a second and subsequent third TPO-RA; response was very good to all 3 agents without clear preference of one over the others. Responders to distinct second and third TPO-RAs included patients who switched due to lack of response to a preceding TPO-RA as well as those who switched due to preference (for an oral agent without dietary restrictions) or intolerance/side effects. Loss of response to one TPO-RA should not preclude trying another. Patients may not respond as well on re-exposure to a previously seen TPO-RA; hence, ideally treatment would be maintained if possible with the initial agent. Disclosures Bussel: RallyBio: Consultancy; Momenta: Consultancy; Dova: Consultancy; 3SBios: Consultancy; Regeneron: Consultancy; Principia: Consultancy; Rigel: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Argenx: Consultancy; UCB: Consultancy; CSL Behring: Consultancy; Shionogi: Consultancy.

Treatment of metastatic castration sensitive prostate cancer (mCSPC) by disease volume: A systematic review and a meta-analysis.

e17539 Background: Chemotherapy with Docetaxel (D) or androgen pathway inhibition (API) with Abiraterone Acetate plus prednisone (AAP), Aplautamide(APA) and Enzalutamide(E) are acceptable, FDA approved treatment options for mCSPC. It is not clear whether the magnitude of benefit varies by the choice of initial agent [chemotherapy vs API] or by volume of disease [High vs Low]. Data is now available from all registration trials by volume status and motivated this analysis to inform initial treatment choice in mCSPC. Methods: We systematically searched MEDLINE(Ovid), Embase, and Scopus for randomized controlled trials of chemotherapy(D) or APIs (AAP, APA, ENZ) that had available hazard ratios (HRs) for overall survival (OS) and Progression Free Survival (PFS) according to patient’s volume of disease. We also reviewed abstracts and presentations from all major conference proceedings. We calculated the pooled overall survival HR and 95% CI by chemotherapy and APIs and by high volume(HVD) and low volume(LVD) using a random effect model, and tested for heterogeneity to assess the null hypothesis that no difference in the survival advantage exists by choice of initial agent and volume of disease. Results: Of 4456 studies identified in our search, there were 8 eligible randomized controlled trials that were included in the analysis. Both D and APIs significantly improved PFS [HR 0.48; 0.45-0.51] and OS [0.72; 0.64-0.81] when added to ADT, however the latter was associated with significantly higher improvement in PFS( P < 0.01) and OS (P = 0.03). In patients treated with D, patients with HVD derive significantly more benefit as compared to LVD( P = 0.046) and patients treated with APIs both HVD and LVD patients derive similar benefit( P = 0.80) (Table). Conclusions: mCSPC patients derive higher magnitude of survival benefit when treated with APIs as compared to D; however, D may be preferred in HVD patients. [Table: see text]

Peripapillary Choroidal Neovascularization Associated with Optic Nerve Head Drusen Treated with Anti-VEGF Agents

Optic nerve head drusen can be associated with peripapillary choroidal neovascularization, in both the pediatric and adult population. These membranes can involve the macula, causing significant visual loss. Herein, we present a case that required treatment with an anti-VEGF agent. The patient failed to respond to the initial agent, but subsequently responded to a change of agent. Adult patients with macular degeneration involving peripapillary choroidal neovascularization associated with optic nerve head drusen may require individualized treatment plans.

Switching cholinesterase inhibitors in older adults with dementia

ABSTRACTBackground: Cholinesterase inhibitors (ChEIs) represent the mainstay of symptomatic treatment in Alzheimer's disease. Three medications belonging to this class are presently widely available. These agents differ in their individual mechanisms of action and pharmacokinetic properties. Switching ChEIs can be a reasonable option in cases of intolerance or lack of clinical benefit.Methods: A systematic literature search of switching ChEIs was conducted, and all studies specifically evaluating this issue were identified. Published consensus guidelines were also searched for recommendations on ChEI switching.Results: Eight clinical studies are summarized and discussed. All of these studies are open-label or retrospective and they cannot be readily compared because of heterogeneity in design, number of patients, agents used, and endpoints. Switching in most of these studies was done for both “lack of benefit” or “loss of response” after up to 29 months of treatment. Nevertheless, the majority of studies did not include individuals switched for lack of response after several years of treatment. Lack of satisfactory response or intolerance with the initial agent was not predictive of similar results with the second agent.Conclusions: In light of these findings, we propose the following practical approach to switching ChEIs: (1) in the case of intolerance, switching to a second agent should be done only after the complete resolution of side-effects following discontinuation of the initial agent; (2) in the case of lack of efficacy, switching can be done overnight, with a quicker titration scheme thereafter; (3) switching ChEIs is not recommended in individuals who show loss of benefit several years after initiation of treatment.

QUANTITATIVE ANALYSIS BY PARTICLE INDUCED X- RAY EMISSION (PIXE) OF TRACE ELEMENTS IN LUNG TISSUE OF IDIOPATHIC INTERSTITIAL PNEUMONIA PATIENT

It has been previously shown that activated alveolar macrophage in idiopathic interstitial pneumonia (IIP) played an important role in the process of fibrosing, but the initial agent which activates alveolar macrophages has not been proved. The present study was designed to make quantitative analyses of trace elements in the lung tissue speciments of IIP patients and normal controls. Particle induced X-ray emission (PIXE) was used. The IIP group consisted of 11 patients and the Control group, which had no apparent history for dust inhalation and lung diseases, consisted of 9 subjects. More silicon and magnesium were found in the IIP group than in the normal controls. These data suggested that inhalation of silicon and magnesium might be one of the etiologic factors of IIP.

Nifedipine: Two New Uses

Nifedipine, a calcium channel blocker currently indicated for vasospastic and chronic stable angina, undoubtedly will have many other uses because of its potent peripheral vasodilatory activity and minimal effects on cardiac contractility. These effects of the drug have proved beneficial in treatment of malignant hypertension and Raynaud's phenomenon. Single oral doses of nifedipine 10–20 mg have rapidly and smoothly reduced blood pressure in malignant hypertension, suggesting its use in the emergency room or office setting. Continuous monitoring of the patient is not required. Studies also have demonstrated the efficacy of nifedipine in Raynaud's phenomenon, and the drug should be considered as an initial agent of choice.