Preferred treatment regimen of aflibercept after treatment interruption in patients with neovascular age-related macular degeneration

BACKGROUND: The efficacy of antiangiogenic therapy in neovascular age-related macular degeneration depends on adherence to the intravitreal injection regimen and regular follow-up. In 2020, the COVID-19 pandemic and associated epidemiological restrictions in ophthalmological care delivery led to a massive lack of appropriate control and management of this condition. AIM: To determine the preferred regimen of intravitreal anti-VEGF therapy in patients with neovascular age-related macular degeneration who experienced treatment interruption due to the COVID-19 pandemic. MATERIAL AND METHODS: Thirty eyes of 26 patients (20 males and 6 females, mean age 73.710.4 years) with neovascular age-related macular degeneration were included; all of them experienced treatment interruption due to the COVID-19 pandemic during the second year of aflibercept therapy. Re-starting therapy, all patients were divided in two groups and received treatment as per the fixed dosing (bimonthly), or as pro re nata (PRN) regimen. All patients underwent standard ophthalmological examination and optical coherence tomography before and after treatment interruption as well as six months after treatment re-start. RESULTS: At six months after treatment re-start, best corrected visual acuity and central retinal thickness did not show statistically significant difference similar between the fixed dosing group and that of PRN dosing regimen (p=0.34 and p=0.85, respectively). However, patients of the fixed dosing group received for one more injection than those of the PRN group (median value 2.0 injections, 95% confidence interval 2.0-2.4; p=0.0001). Preservation of the disease activity according to optical coherence tomography data, in the fixed regimen group was found in 10 eyes (71.4 %) versus 9 eyes (56.2 %) in the PRN group (p=0.63). CONCLUSIONS: For neovascular age-related macular degeneration patients at the second year of treatment, an adequate therapeutic strategy for re-starting anti-VEGF therapy after treatment interruption appears to be the PRN regimen. PRN regimen allows reducing one injection in comparison to fixed dosing regimen with comparable functional outcomes during first 6 month.

Ondansetron and metoclopramide as second-line antiemetics in women with nausea and vomiting in pregnancy: the EMPOWER pilot factorial RCT

Background Around one-third of pregnant women suffer from moderate to severe nausea and vomiting, causing physical and emotional distress and reducing their quality of life. There is no cure for nausea and vomiting in pregnancy. Management focuses on relieving symptoms and preventing morbidity, and often requires antiemetic therapy. National guidelines make recommendations about first-, second- and third-line antiemetic therapies, although care varies in different hospitals and women report feeling unsupported, dissatisfied and depressed. Objectives To determine whether or not, in addition to intravenous rehydration, ondansetron compared with no ondansetron and metoclopramide compared with no metoclopramide reduced the rate of treatment failure up to 10 days after drug initiation; improved symptom severity at 2, 5 and 10 days after drug initiation; improved quality of life at 10 days after drug initiation; and had an acceptable side effect and safety profile. To estimate the incremental cost per treatment failure avoided and the net monetary benefits from the perspectives of the NHS and women. Design This was a multicentre, double-dummy, randomised, double-blinded, dummy-controlled 2 × 2 factorial trial (with an internal pilot phase), with qualitative and health economic evaluations. Participants Thirty-three patients (who were < 17 weeks pregnant and who attended hospital with nausea and vomiting after little or no improvement with first-line antiemetic medication) who attended 12 secondary care NHS trusts in England, 22 health-care professionals and 21 women participated in the qualitative evaluation. Interventions Participants were randomly allocated to one of four treatment groups (1 : 1 : 1: 1 ratio): (1) metoclopramide and dummy ondansetron; (2) ondansetron and dummy metoclopramide; (3) metoclopramide and ondansetron; or (4) double dummy. Trial medication was initially given intravenously and then continued orally once women were able to tolerate oral fluids for a maximum of 10 days of treatment. Main outcome measures The primary end point was the number of participants who experienced treatment failure, which was defined as the need for further treatment because symptoms had worsened between 12 hours and 10 days post treatment. The main economic outcomes were incremental cost per additional successful treatment and incremental net benefit. Results Of the 592 patients screened, 122 were considered eligible and 33 were recruited into the internal pilot (metoclopramide and dummy ondansetron, n = 8; ondansetron and dummy metoclopramide, n = 8; metoclopramide and ondansetron, n = 8; double dummy, n = 9). Owing to slow recruitment, the trial did not progress beyond the pilot. Fifteen out of 30 evaluable participants experienced treatment failure. No statistical analyses were performed. The main reason for ineligibility was prior treatment with trial drugs, reflecting an unpredicted change in prescribing practice at several points along the care pathway. The qualitative evaluation identified the requirements of the study protocol, in relation to guidelines on anti-sickness drugs, and the diversity of pathways to care as key hurdles to recruitment while the role of research staff was a key enabler. No important adverse events or side effects were reported. Limitations The pilot trial failed to achieve the recruitment target owing to unforeseen changes in the provision of care. Conclusions The trial was unable to provide evidence to support clinician decisions about the best choice of second-line antiemetic for nausea and vomiting in pregnancy. Trial registration Current Controlled Trials ISRCTN16924692 and EudraCT 2017-001651-31. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 63. See the NIHR Journals Library website for further project information.

Institutional chart review on same-day pegfilgrastim administration in small cell lung cancer (SCLC) patients receiving myelotoxic chemotherapy.

71 Background: Pegfilgrastim administration is recommended at least 24 hours after the end of chemotherapy (CTX) treatment for prevention of chemotherapy-induced (febrile) neutropenia (CIN/FN). Published studies have found no differences in the risk of FN between same-day and next-day pegfilgrastim administrations in certain cancers. To evaluate the efficacy and safety of same-day compared to next-day pegfilgrastim administration in SCLC patients, we evaluated our own institutional data. Methods: Using ICD-9 and ICD-10 codes for SCLC, electronic health records were reviewed retrospectivey for the period 11/1/2013-8/31/2018 at the University of Arizona Cancer Center (UACC). Inclusion criteria were age 18 or older, biopsy confirmed SCLC diagnosis, treated at UACC, and pegfilgrastim administration on the same day as CTX. Outcomes collected in the first cycle and all cycles of CTX were: FN incidence, CIN grade 3/4, and treatment delay or hospitalizations due to CIN/FN. Results: Out of 1,181 patient records, 34 patients met inclusion criteria. The median age was 67.5 years, 23.5% of patients had stage 3 or 4 SCLC while 50% had 0-1 ECOG status. 44.1% of patients had a risk based on the type of CTX. Average baseline absolute neutrophil count was 5.55x109cells/L (SD=1.27x109cells/L). A total of 104 CTX cycles were given. Outcomes are summarized in the Table below. After the first cycle, the incidence rate of CIN grade 3/4 was 5.88%, but 0% for all other outcomes. Conclusions: After the first cycle, there were s of FN and no patients experienced treatment delays or hospitalizations related to CIN/FN; only two cases for CIN grade 3/4 were observed. Across all cycles, CIN grade 3/4 was observed in 17 cycles. In only two cycles, treatment was delayed or patient was hospitalized due to CIN/FN, not involving same patients. FN was observed in only 3/104 cycles. All observed rate were comparable or lower than known rates for next-day pegfilgrastim administration. Future studies including randomized trials should be further evaluated.[Table: see text]

Human filariasis in travelers and migrants: a retrospective 25-year analysis at the Institute of Tropical Medicine, Antwerp, Belgium

Background Information on human filariasis in international travelers is scarce. We describe the epidemiology, clinical presentation and outcome of these infections in a reference travel clinic over the past decades. Methods We reviewed all cases of filariasis diagnosed at the Institute of Tropical Medicine, Antwerp, Belgium, from 1994 to 2018. Diagnosis was obtained by either parasitological methods (confirmed) or strict clinical case definitions (probable). We assessed the characteristics of cases at diagnosis and response to therapy within three to 12 months. Results A total of 320 patients (median age: 41 years; 71% males) were diagnosed with 327 filarial infections (Wuchereria bancrofti = 6; Onchocerca volvulus = 33, Loa loa = 150, Mansonella perstans = 130; unspecified species = 8). Diagnosis was confirmed in 213/320 (67%) patients. European long-term travelers accounted for 166 patients (52%) and visitors/migrants from tropical countries for another 110 (34%). Central Africa was the likely region of acquisition for 294 (92%) patients. The number of filariasis cases decreased from 21.5/year in average in the nineties to 6.3/year in the last decade, when loiasis became predominant. Cases reported symptoms in &gt; 80% of all filarial infections but mansonellosis (45/123 single infections; 37%). Lymphatic filariasis and onchocerciasis cases responded well to conventional therapy. However, 30% of patients with loiasis and mansonellosis experienced treatment failure (with diethylcarbamazine and levamisole-mebendazole, respectively). Conclusions The burden and species distribution of filariasis in travelers evolved in the past decades. Most presentations were symptomatic. Case management would benefit from more effective therapies for loiasis and mansonellosis.

Magnification of fear and intention of avoidance in non-experienced versus experienced dental treatment in adults

Background Dental fear is associated with the experience of prior dental treatment and avoidance of dental visits. It remains unclear if individuals show an intention of avoidance (IA) towards treatments that they have not received (i.e., non-experienced dental treatment). The study aims to investigated (a) if individuals showed an increased fear and IA to non-experienced, compared to experienced dental treatment, and (b) if fear and IA to non-experienced treatment is associated with dental anxiety. Methods Fear/IA of 12 common conditions of dental treatment of 402 adults were investigated. If subjects have experienced the condition, fear and IA were assessed based on subjects’ prior experience (i.e., ExpFear/ExpIA). If they have not experienced the condition, fear and IA were assessed based on their anticipation (i.e., NExpFear/NExpIA). Trait dental anxiety was assessed using the Index of Dental Anxiety and Fear (IDAF-4C+). Results (A) NExpFear and NExpIA were significantly higher than ExpFear and ExpIA, respectively. (B) The IDAF-4C+ scores are positively correlated with NExpFear/NExpIA and negatively correlated with the magnification of fear (i.e., the discrepancy in the fear/IA of non-experienced vs. experienced conditions). (C) The condition ‘extraction of a wisdom tooth’ and ‘root canal treatment’ showed the highest ratings on NExpFear. Conclusions Individuals may develop a high degree of fear and IA of the treatment they have not received. Trait dental anxiety plays a key role in the fear of non-experienced treatment.

Healthcare needs, expectations, utilization, and experienced treatment effects in patients with hereditary spastic paraplegia: a web-based survey in the Netherlands

Background We aimed to identify healthcare needs, expectations, utilization, and the experienced treatment effects in a population of Dutch patients with hereditary spastic paraplegia (HSP). Methods We distributed an online questionnaire among 194 adult persons with HSP in the Netherlands, of which 166 returned a fully completed version. After applying predefined exclusion criteria, 109 questionnaires from persons with pure HSP were analysed. Results Healthcare needs and expectations were primarily focused on the relief of muscle stiffness and reduction of balance and gait impairments (65–80%), but many participants also expressed needs regarding relief of non-motor symptoms (e.g. pain, fatigue), emotional problems, impaired sleep and self-care capacity, and participation problems (> 60%). Remarkably, despite these frequent needs, relatively few participants (< 33%) expected to be able to improve in these additional domains. Rehabilitation physicians and physiotherapists were more frequently consulted than neurologists and occupational therapists, respectively. Physiotherapy was the most often proposed non-pharmacological intervention (85%), followed by orthopedic footwear (55%) and splints (28%). Approximately one third of the participants was never offered any pharmacological (spasmolytic) treatment. Spasmolytic oral drugs, injections, and intrathecal baclofen were given to 41%, 26%, and 5% of the participants, respectively. Independent of the type of pharmacological intervention, 35–46% of these participants experienced decreased spastiticy and improved general fitness. Other experienced effects differed per type of intervention. Conclusions Based on this web-based survey in the Netherlands, there seems to be ample room for improvement to meet and attune the healthcare needs and expectations of people with HSP concerning both their motor and non-motor symptoms and functional limitations. In addition, the provision of adequate information about non-pharmacological and pharmacological interventions seems to be insufficient for many patients to allow shared decision making. These conclusions warrant a more pro-active attitude of healthcare providers as well as an interdisciplinary approach for a substantial proportion of the HSP population, also involving professionals with a primary occupational and/or psychosocial orientation.

Long-Term Deutetrabenazine Treatment Is Associated With Continued Improvement in Tardive Dyskinesia in the Completed 3-Year Open-Label Extension Study

BackgroundThe 12-week ARM-TD and AIM-TD studies in tardive dyskinesia (TD) patients showed statistically significant improvements in TD symptoms with deutetrabenazine. The completed open-label extension (OLE) study (SD-809-C−20) evaluated long-term efficacy and safety of deutetrabenazine in TD.MethodsPatients who completed ARM-TD or AIM-TD enrolled in the OLE study, with deutetrabenazine dose titrated based on dyskinesia control and tolerability. Change from baseline in Abnormal Involuntary Movement Scale (AIMS) score was assessed by local site raters. Treatment success was evaluated locally as patients being “much improved” or “very much improved” on Clinical Global Impression of Change (CGIC).Results343 patients enrolled in the OLE study; 6 patients were excluded from analyses. At Week 54 (n=249; dose [mean±SE]: 38.7±0.66mg/day), mean change from baseline in AIMS score was –4.8±0.28; 66% of patients experienced treatment success. At Week 106 (n=194; dose: 39.3±0.75mg/day), mean change from baseline in AIMS score was –5.4±0.33; 65% of patients experienced treatment success. At Week 145 (n=160; dose: 39.4±0.83mg/day), mean change from baseline in AIMS score was –6.6±0.37; 73% of patients experienced treatment success. Treatment was generally well tolerated across 723 patient-years of exposure through Week 158, and exposure-adjusted incidence rates (incidence/patient-years) for akathisia/restlessness were 0.01, somnolence/sedation were 0.07, and symptoms which may represent parkinsonism or depression were 0.08 each.ConclusionsPatients who received long-term treatment with deutetrabenazine achieved sustained improvement in AIMS scores. Findings from this open-label trial with response-driven dosing suggest the possibility of increasing benefit over time.FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel

Efficacy and safety of subsequent molecular targeted therapy after immuno-checkpoint therapy, retrospective study of Japanese patients with metastatic renal cell carcinoma (AFTER I-O study)

Objectives Guidelines for treatment of mRCC recommend nivolumab monotherapy (NIVO) for treated patients, and nivolumab plus ipilimumab combination therapy (NIVO+IPI) for untreated IMDC intermediate and poor-risk mRCC patients. Although molecular-targeted therapies (TTs) such as VEGFR-TKIs and mTORi are recommended as subsequent therapy after NIVO or NIVO+IPI, their efficacy and safety remain unclear. Methods Outcome of Japanese patients with mRCC who received TT after NIVO (CheckMate 025) or NIVO+IPI (CheckMate 214) were retrospectively analyzed. Primary endpoints were investigator-assessed ORR of the first TT after either NIVO or NIVO+IPI. Secondary endpoints included TFS, PFS, OS and safety of TTs. Results Twenty six patients in CheckMate 025 and 19 patients in CheckMate 214 from 20 centers in Japan were analyzed. As the first subsequent TT after NIVO or NIVO+IPI, axitinib was the most frequently treated regimen for both CheckMate 025 (54%) and CheckMate 214 (47%) patients. The ORRs of TT after NIVO and NIVO+IPI were 27 and 32% (all risks), and median PFSs were 8.9 and 16.3 months, respectively. During the treatment of first TT after either NIVO or NIVO+IPI, 98% of patients experienced treatment-related adverse events, including grade 3–4 events in 51% of patients, and no treatment-related deaths occurred. Conclusions TTs have favorable antitumor activity in patients with mRCC after ICI, possibly via changing the mechanism of action. Safety signals of TTs after ICI were similar to previous reports. These results indicate that sequential TTs after ICI may contribute for long survival benefit.

Phase Ib/II study of pembrolizumab with lanreotide depot for advanced, progressive gastroenteropancreatic neuroendocrine tumors (PLANET).

369 Background: Pembrolizumab has antitumor activity in a subset of GEP-NETs patients. We hypothesized that the lanreotide, by its antitumor effects and reduction of serotonin, a modulator of immunity, would synergize with pembrolizumab in low/intermediate grade GEPNETs. Methods: GEP-NETs patients who had progressed on a prior somatostatin analogue received lanreotide 90mg sq and pembrolizumab 200mg IV every 3 weeks until progressive disease or intolerable toxicity. The primary endpoint was ORR at any time on study and secondary endpoints were PFS and OS. Results: 22 patients were treated (F/M 10/12; Caucasian/AA/other 10/7/5; GI/pancreatic 14/8; median Ki67 5%, median time since diagnosis 5.3 yrs (IQR 2.3-7.9 yrs)). Prior octreotide LAR/lanreotide/both was administered to 20/1/1. Patients had a median of 2 prior systemic therapies (range 1-9) and six had prior locoregional therapy and 3 external beam radiotherapy. Of the 12 tumors analyzed thus far, 4 had detectable PD-L1 expression and 11 had detectable TILs. A median of 6 pembrolizumab doses (range 2-15) and 7 lanreotide doses (range 2-15) were administered. Six patients experienced treatment related SAEs (abdominal pain, pneumonitis, colitis, and hyperglycemia, all related to the pembrolizumab). Selected treatment related adverse events included: Hypothyroidism 23%, colitis 9%, hyperglycemia 14%, and pneumonitis 5%. Best response by RECIST 1.1 was SD/PD/Not available:39/52/9% and by irRECIST was 43/48/9%. Median PFS was 5.4 months (95% CI 1.7-8.3 mo). The median overall survival at a median follow-up of 15 months was not reached. Peripheral blood immunologic correlates will be reported subsequently. Conclusions: In a population of GEP-NET patients, progressing on a median of 2 prior therapies, including prior somatostatin analogue therapy, a minority of whom had PD-L1 expressing tumors, the combination of lanreotide and pembrolizumab produced stable disease in approximately 40% of patients. No new safety signals were identified. Clinical trial information: NCT03043664.