Related Events Research Articles

Nivolumab and ipilimumab in the real-world setting in patients with mesothelioma

ObjectivesNivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) is a new first-line treatment combination for patients with pleural mesothelioma. Nivolumab-ipilimumab improved the survival, however, 30.3% of the patients suffered from grade 3–4 treatment related adverse events (TRAE’s) and TRAE’s led to discontinuation in 23.0% of all patients. Here, we present the first real-world data of nivolumab plus ipilimumab in patients with malignant mesothelioma treated in two mesothelioma expert centers. MethodsClinical data of patients with mesothelioma treated with nivolumab and ipilimumab were prospectively collected. Clinical parameters were obtained every visit, CT scans were evaluated every 12 weeks and adverse events were assessed continuously during the treatment. Data on grade 2–5 TRAE’s and activity (overall response rate (ORR), duration of response (DOR), disease control rate (DCR), median progression-free survival (mPFS) and median overall survival (mOS) were reported. ResultsBetween January 2021 and August 2022, 184 patients were treated with nivolumab plus ipilimumab. The median follow-up was 12.1 months (95 %CI 11.1 – 13.1). Grade 3–4 TRAEs were seen in 27.7 % of the patients and 25.0 % discontinued immunotherapy treatment early because of TRAE’s. ORR was 21.7 % (95 % CI 15.7–27.7), median DOR was 5.7 months (IQR 3.2–8.7) and DCR at 12 weeks 56.0 % (95 % CI 48.8–63.2). The mPFS was 5.5 months (95 %CI 4.1–6.9), mOS was 14.1 months (95 % CI 11.1–18.2). ConclusionsNivolumab plus ipilimumab had an equal efficacy in a real-world comparable population but also a high risk of TRAE’s, leading to discontinuation of treatment in 25% of the patients.

Adherence tool for prophylactic haemophilia treatment in adult and adolescent patients: A systematic review and meta-analysis protocol

Hemophilia is a congenital bleeding disorder resulting from a low level or deficiency of clotting factors. It is an x-linked recessive disease and happens almost exclusively in males whereas females are the carrier of the affected gene. The most common types of hemophilia are hemophilia A and Hemophilia B. Hemophilia is classified into mild, moderate and severe. Prophylaxis treatment has more advantages clinically compare to on-demand therapy. It may reduce the bleeding frequency, gives protection from joint damage, may lower the number of total bleeding episodes per year, and may reduce annualised spontaneous and trauma related bleeding events. However, prophylaxis treatment needs regular weekly infusions therefore it is painful to administer especially if the vein is difficult to access. It may cause pain at the site of injections and may lead to non-adherence to treatment. Non-adherence to a regimen will result in insufficient clotting factor levels in the body. The efficacy of the medication is reduced and may lead to a high bleeding tendency. Thus far, the study on adult haemophilic patient adherence tool is scarce and limited; and therefore this review is warranted. The study protocol is conducted as per the PRISMA-P guideline. There are 4 concepts in this systematic review which are Haemophilia, adult and adolescence, preventive treatment and adherence. Articles will be sought from electronic databases PUBMED, Ovid EMBASE, CINAHL, and SCOPUS using the MeSH term, synonym free-text word, truncation, and proximity operators as per each database. The proposed keywords within each concept will be joined using the Boolean operator “OR “and the 4 different concepts combined using the Boolean operator “AND”. Search will be limited to Human, English language, and publication until 2022. Studies will be included if they meet the study inclusion criteria. The quality of the studies will be appraised using the Newcastle-Ottawa quality assessment scale (NOS) for observation-based studies. This systematic review does not require formal ethical approval as data will be extracted from selected published studies. The results will be disseminated through a peer-reviewed publication and relevant conference presentations.(PROSPERO registration CRD42021273813)

A single-blinded randomised controlled trial incentivising adults to increase public transport for health gain: The trips4health study

Incentives-based strategies can improve health behaviour. Public transport use confers individual- and societal-level public health gain but incentivising public transport has been under-explored. The study objective was to assess the effectiveness of financially incentivising public transport use from a public health perspective. trips4health was a single-blinded parallel group randomised controlled trial (RCT) conducted in Hobart, Australia. Participants were 18 + years and infrequent (<3 times/week) bus users who completed surveys and attended study clinics at baseline and post-intervention. Intervention group participants were set weekly bus use targets increasing over 16-weeks. Smartcard credit was awarded if targets were attained. Weekly text messages and educational materials supported incentives. An active control group received educational materials. 110 participants had been randomised to the control (n = 55) or intervention (n = 55) group when the trial was abandoned due to the COVID-19 pandemic; 65 % (n = 71; 34 intervention, 38 control) completed a 16-week intervention period. The percentage of participants using the bus during the 16-week intervention period was higher in the intervention (69 %) than the control (49 %) group, target attainment (intervention) or their equivalent (control) was higher in the intervention (22 %) than the control (15 %) group, and average weekly bus use was higher in the intervention (2.4 bus trips) compared to the control group (1.7). No intervention related adverse events were reported. Preliminary data from this COVID-impacted RCT to increase bus use through incentives demonstrated some evidence of effectiveness. A sufficiently powered trial that broadens participant reach and examines maintenance of longer-term behaviour change is warranted.

Bleeding and thrombotic risk of different antiplatelet regimens posttranscatheter edge-to-edge mitral valve repair in patients with an indication for oral anticoagulation: Results from an all-comers national registry.

Evidence-based recommendations for antithrombotic treatment in patients who have an indication for oral anticoagulation (OAC) after transcatheter edge-to-edge mitral valve repair (TEER) are lacking. To compare bleeding and thrombotic risk for different antithrombotic regimens post-TEER with MitraClip in an unselected population with the need for OACs. Bleeding and thrombotic complications (stroke and myocardial infarction) up to 3 months after TEER with mitraclip were evaluated in 322 consecutive pts with an indication for OACs. These endpoints were defined by the Mitral Valve Academic Research Consortium criteria and were compared between two antithrombotic regimens: single antithrombotic therapy with OAC (single ATT) and double/triple ATT with a combination of OAC and aspirin and/or clopidogrel (combined ATT). Collectively, 108 (34%) patients received single ATT, 203 (63%) received double ATT and 11 (3%) received triple ATT. Bleeding events occurred in 67 patients (20.9%), with access site related events being the most frequent cause (37%). Bleeding complications were observed more frequently in the combined ATT group than in the single ATT group: 24% versus 14% [p = 0.03, adjusted RR: 0.55 (0.3-0.98)]. Within the combined group, the bleeding risk was 23% in the double ATT and 45% in the triple ATT group. Thrombotic complications occurred in only three patients (0.9%), and all belonged to the combined ATT group. In patients with an indication for OACs, withholding of antiplatelet therapy post-TEER with Mitraclip was associated with a 45% reduction in bleeding and without a signal of increased thrombotic risk.

Melatonin enhances waterlogging tolerance of field-grown cotton through quiescence adaptation and compensatory growth strategies

ContextWaterlogging stress inhibits plant growth and development, resulting in significant yield losses. Melatonin, a naturally occurring molecule in plants, has attracted attention in recent years for its potential role in aiding plants in response to abiotic stresses. However, it remains unclear whether melatonin can enhance cotton’s tolerance to waterlogging stress. MethodsTo fill this gap, field-grown cotton plants at early flowering were subjected to a 10-day waterlogging stress and were foliar sprayed with melatonin during waterlogging. The effects of melatonin on the endogenous melatonin concentration, plant biomass, and related physiological and molecular events, as well as the seedcotton yield and yield components, were evaluated over two consecutive years. ResultsIn waterlogged cotton without melatonin treatment (W), melatonin concentration increased by 10.2%, but it increased by 26.9% with melatonin treatment (W+M), compared to the non-waterlogged cotton (NW). Under waterlogging without the application of melatonin, there was a reduction of 27.1% in biological yield and 46.6% in seedcotton yield. However, these reductions were reduced to 21.8% and 39.0%, respectively, following melatonin application. Quantitative real-time PCR analysis revealed that melatonin up-regulated the melatonin biosynthesis genes GhSNAT1 and GhCOMT, as well as the gibberellin biosynthetic gene GhGA20ox1 by 2.1, 3.6 and 1.8 times, respectively, compared to non-waterlogged cotton. However, melatonin down-regulated the ABA synthesis gene GhNCED2, the H2O2 generation related gene GhRBOHC, and the glycolysis and fermentation gene GhADH2 by 61.9%, 65.0% and 40.0%, respectively. Additionally, melatonin increased the leaf chlorophyll content, photosynthetic rate, levels of auxin (IAA) and gibberellic acid (GA), as well as the activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT). Conversely, melatonin reduced contents of hydrogen peroxide (H2O2), malonaldehyde (MDA) and ABA, as well as the activities of alcohol dehydrogenase (ADH) and pyruvate decarboxylase (PDC), compared to waterlogging without application of melatonin. ConclusionsThese findings demonstrate that foliar application of melatonin effectively improved the waterlogging tolerance of field-grown cotton, leading to a reduction in yield loss by 16.5% under waterlogged conditions. This outcome was achieved by a series of physiological, biological and molecular adjustments involved in quiescence adaption and compensatory growth strategies. Therefore, melatonin plays a crucial role in enhancing waterlogging tolerance and mitigating yield loss in waterlogged cotton through these strategies.

Intravenous administration of umbilical cord lining stem cells in left ventricular assist device recipients: Results of the uSTOP LVAD BLEED pilot study

PurposeLeft ventricular assist device (LVAD) implantation improves survival in advanced heart failure. Despite this, angiodysplastic bleeding complications remain a significant driver of costs as well as morbidity. Mechanisms implicated in post LVAD implant bleeding include the dysregulation of angiogenic factors seen in this population. The present pilot study evaluates the safety of umbilical cord lining stem cells (ULSCs) in LVAD recipients while exploring any early evidence of efficacy to improve bleeding. MethodsIn a 3 + 3 design, 9 patients received an intravenous (IV) infusion of ULSCs at escalating doses. The primary endpoint was safety and tolerability, secondary exploratory outcomes included antibodies against hemoglobin to quantify the amount of blood in stool without need for dietary restriction. ResultsThe primary safety and tolerability outcomes were met as no infusion related adverse events or toxic responses were observed. There was no sensitization after administration of ULSCs as assessed by panel reactive antibody. An increase in Angiopoetin-1 levels and a decrease in Angiopoetin-2 levels from baseline to 30 days were observed in 4 patients. Quantitative Faecal Immunochemical Test suggested a decrease in the mean blood content of stool from baseline to 30 days. ConclusionsIn this first ever IV administration of ULSCs in LVAD patients, infusion was noted to be safe and tolerable and did not cause immune sensitization. Half of the patients were noted to have angiogenic stabilization, and there was a trend towards decreasing amounts of blood noted in the stool, suggesting an early signal of efficacy.

Combining Dual Checkpoint Immunotherapy with Ablative Radiation to All Sites of Oligometastatic Non-Small Cell Lung Cancer: Toxicity and Efficacy Results of a Phase 1b Trial

BackgroundAblative local treatment of all radiographically detected metastatic sites in patients with oligometastatic NSCLC increases progression free survival (PFS) and overall survival (OS). Prior studies demonstrated safety of combining stereotactic body radiation therapy (SBRT) with single agent immunotherapy. We investigated the safety of combining SBRT to all metastatic tumor sites with dual checkpoint, anti-CTLA-4 and anti-PD-L1 immunotherapy for patients with oligometastatic NSCLC. MethodsWe conducted a phase Ib clinical trial in patients with oligometastatic NSCLC with up to 6 sites of extracranial metastatic disease. All sites of disease were treated with stereotactic body radiation therapy (SBRT) to a dose of 30 – 50 Gy in 5 fractions. Dual checkpoint immunotherapy was started 7 days following completion of radiation utilizing anti-CTLA-4 (tremelimumab) and anti-PD-L1 (durvalumab) immunotherapy for a total of four cycles followed by durvalumab alone until progression or toxicity. ResultsSeventeen patients were enrolled on study, with 15 patients receiving at least one dose of combination immunotherapy per protocol. The study was closed early (17 of planned 21 patients) due to slow accrual during COVID 19 pandemic. Grade 3+ treatment related adverse events were seen in 6 patients (40%). Of these, only one was felt possibly related to the addition of SBRT to immunotherapy. Median PFS was 42 months while median OS has not yet been reached. ConclusionsDelivering ablative SBRT to all sites of metastatic disease in combination with dual checkpoint immunotherapy did not result in excessive rates of toxicity compared to historical studies of dual checkpoint immunotherapy alone. While not powered for treatment efficacy results, durable PFS and OS results suggest potential therapeutic benefit compared to immunotherapy or radiation alone in this patient population.

Event Segmentation in the Audio Description of Films

To make the content of films available to a visually impaired audience, a sighted translator can provide audio description (AD), a verbal description of visual events. To achieve this goal, the audio describer needs to select what to describe, when to describe it, and how to describe it, as well as to express the information aurally. The efficacy of this communication is critically dependent upon basic cognitive processes of how the sighted audio describer perceives and segments the film’s unfolding chain of events and in what way the visually impaired end users conceive the structure, content, and segmentation of such events in relation to the produced AD. There is, however, virtually no research on this interplay in relation to AD. In this study, we scrutinize live AD of a film from two trained audio describers and examine how events are structured, segmented and construed in their AD. Results demonstrate that the event segmentation experienced from the film is indeed a fundamental part of how AD is structured and construed. It was found that AD at event boundaries was highly sensitive to different spatiotemporal circumstances and this relationship depends on semantic resources for expressing AD. Lay summary In our everyday lives, we naturally organize and remember our experiences as meaningful sequences of events. This happens the same way when we watch movies – we see them as a series of events happening in different places, times, and with changing character dynamics. Now, think about making this cinematic experience accessible to people with visual impairments. This is where a sighted translator, called an audio describer, becomes really important. To make movies understandable for a visually impaired audience, a sighted audio describer describes crucial visual events in the film. Their goal is to create a "narrative equivalence" between the original film and the audio-described version. Thus, the main challenges for audio describers are deciding what information to describe, when to do it, and how to articulate it effectively. In the current case study, we looked at two audio descriptions for the Swedish film "Skumtimmen" (English title: "Echoes from the Dead"). These descriptions were created by trained audio describers. We wanted to see how these narrators organized, broke down, and verbalized the course of events in their audio descriptions. To achieve this, we focused on two important parts of storytelling – changes in time and location – and paid special attention to how often and in what way audio describers verbalized these event boundaries. What we found is that both describers indeed verbalized most event boundaries. This shows that these boundaries are a big part of how audio descriptions are put together. We also learned that the descriptions at these event boundaries were very sensitive to when and where key events unfolded in the story. The way these boundaries were described depended on fundamental cognitive and linguistic resources to talk about space and time. Our findings help us understand how breaking down events in a film is a crucial part of shaping audio descriptions. Plus, our research highlights how important it is to study how events are broken down and verbalized, giving useful insights to improve audio descriptions and train future audio describers. The ultimate goal is to make the experience better for visually impaired viewers, contributing to a more inclusive and enjoyable audiovisual world.

Protocolized Sedation Utilizing COMFORT-B Scale versus Non-protocol-directed Sedation in Mechanically Ventilated Children - An Open-label, Randomized Controlled Trial.

This study aimed to determine the effect of protocolized sedation using the COMFORT-B scale on the duration of mechanical ventilation (DMV). Eighty children with anticipated Duration of mechanical ventilation (DMV) >24h admitted to the Pediatric intensive care unit (PICU) were randomized into one group that received protocolized sedation (PS) using the COMFORT behavioural (COMFORT-B) scale, and another group that received non-protocolized sedation (NPS). The primary outcome was the impact on the DMV. The DMV was significantly lower in PS (PS: 3.5 [3-7] vs. NPS group: 8.5 [4.25-13.75] d; p = 0.008). The cumulative dose and duration of fentanyl in the PS group was significantly lower (median [IQR]; 120 [62.88-279.12] vs. 320.4 [110.88-851.52] μg/kg; p = 0.007 and 4 [2.25-7.75] vs. 8 [4-17.5] d; p = 0.009, respectively). The authors found a decrease in DMV and sedation related adverse events (SRAE) like ventilator associated pneumonia (VAP), accidental extubation, post-extubation stridor and dose and duration of sedative agents with PS.

Memeplex-based memetic algorithm for the multi-objective optimal design of composite structures

Hybrid construction is proposed to decrease costs in lightweight structures using fiber-reinforced plastics (FRP) composite materials. Minimum weight, minimum strain energy (stiffness), and minimum energy variability of the structural system response are the objectives of the robust design optimization approach applied to composite shell structures with stiffeners. The trade-off depends on given stress, displacement, and buckling constraints imposed on composite structures considering non-linear geometric behavior. The design variables are ply angles and ply thicknesses of shell laminates, the cross-section dimensions of stiffeners, and the variables related to the selection of materials and their distribution at the laminate level and subsequently of the laminates along the structure. A Multi-Objective Memetic Algorithm (MOMA) applies multiple learning procedures exploring the synergy of different cultural transmission rules. An enlarged virtual population with a dual age-dominance nature captures and updates the Pareto curve. The concept of memeplex controls the meme selection and their propagation along the hybrid genetic and cultural evolution path. The success of memetic learning procedures is analyzed by measuring each meme's relative and absolute success events according to different approaches, depending on the reference time used in evolutionary history. Results show that MOMA is promising in multi-objective optimization of composite hybrid structures.

Immune Checkpoint Inhibitor-Induced Pancreatic Injury: Clinical and Radiological Profile and Response to Steroids

Background and AimsImmune checkpoint inhibitor therapy causes numerous immune related adverse events, including autoimmune pancreatic injury (AIPI), which results in rapid organ atrophy. We profiled the clinico-radiological features, short-term natural history, and response to steroids of AIPI. MethodsWe retrospectively reviewed medical records of 229/11,165 (2.1%) adult patients with AIPI. 110/229 (48%) had abdominal computerized tomography scan (CT) at lipase elevation; data of 110 without pancreatic metastases were analyzed. We analyzed serial CT-based pancreas volumetry data in 48 patients with AIPI (32 with normal CT and 16 with pancreatitis on CT at lipase elevation). We examined impact of steroids on pain and disease course. ResultsIn AIPI (n=229), median lipase elevation was 4x upper limit of normal (range: 3-40x). The injury was more often asymptomatic than painful (143/229 (62%) vs 86/229 (38%), P<.000). Majority (83/110 (75%) had normal CT, often in painless vs painful disease: 51/57 (90%) vs 32/53 (60%), P<.001); 25% had interstitial pancreatitis. On serial pancreas volumetry, marked volume (cc) loss occurred 1 year after vs 3 months before lipase elevation in both normal CT (median 81.6 vs 61.3, P=.00) and pancreatitis on CT groups (91.8 vs 60.5, P=.00), >20% volume loss occurred in 47% vs 73%, respectively (P=.08). Steroids, when used did not mitigate pain, biochemical relapse, pancreas volume loss or 1-year diabetes incidence (7.2%). ConclusionsAIPI is uniquely characterized by painless lipase elevation, normal pancreas on CT and rapid pancreatic volume loss on follow-up. Steroids do not appear to have a role in management.

Delay in Care Seeking for Menstrual Regulation

In Bangladesh menstrual regulation (MR) services are available at all major government and private hospitals, and even at government primary health care facilities. In spite of wide availability, women who do not use menstrual regulation services from proper facilities may resort to induce unsafe abortion by non-medical or untrained health workers in unhygienic condition. Worldwide, nearly 1 in 10 pregnancies end in unsafe abortion and World Health Organization (WHO) estimates that 18 out of 20 unsafe abortions takes place in developing countries. Induced abortion leading to complication such as bleeding, infection injuries and even death, these deaths could be prevented if women had an access to safe abortion facilities. This cross sectional study was carried out among fifty two women from family planning unit of Institute of Child and Mother Health (ICMH), Dhaka from December 2009 to May 2010. The purpose of this study was to identify the factors for delay in care seeking of menstrual regulation (MR). The data were collected by using the pretested questionnaires and cases were selected from the women who came for seeking care of MR after 10 weeks of amenorrhoea. Duration of amenorrhoea was confirmed by taking history and in some cases by ultrasonography. After incorporation of the socio-demographic data; factors or reasons of delay in MR were found due to personal, social, service and family related events. The mean age of respondents was 22.14 years. About 75% of the respondents were housewives and 79% were illiterate. The mean age of marriage 19.5 years. Regarding husband’s educational level of the respondent, more than one-third (37%) was class I – V, others one-third (33%) was above the primary level rest of the husbands were higher secondary and above. More than two-third (70%) of the respondents delivered 1 to 3 live children and used oral contraceptive pills. Most of the (87%) of women gave right answer about MR and most of them (85%) had knowledge about adverse effect of MR. Nearly two-third (65%) came to know about MR form relatives/neighbors, where one-fourth (25%) from health workers and rest them from mass media/ others. Most of the (87%) respondents answered correctly about advantages of MR, however, 60% did not know about the proper time of performing MR after cessation of menstruation. Most of the respondents (85%) knew about the side effects of MR; among them more than one-third (37%) told excessive bleeding was adverse effects of MR, however 33%, 8%, 6% and rest 4% told pain, sterility, perforation and infection respectively were the adverse effects of MR. Three-fifth (60%) of the patients didn't know about the right time of pursue care for MR and 63% of them were unaware about legal aspects of MR that they have right to seek MR. More than half of the respondents (56%) stated the reasons for the delay due to their personal problem where, 19%, 15% and 10% of them were specified the reasons as social factor, service related reason and family conflict respectively. Among the respondents of personal reason for delaying MR, more than half of them (52%) took oral tablets for abortion at home, 41% failed to understand their amenorrhoea and only 7% were unaware about service facility for MR. Regarding familial reasons for delay of MR, 60% pointed out the security problem and remaining 40% told about resistance by husband/others or absence of husband in the houses. The main (70%) social reasons of delaying MR was due to spiritual bindings and 30% was due to public disgrace. Service facility related reasons for delaying MR were treatment cost (62%), distance of facility (25%) and substandard services (13%). The study findings suggested that women had good knowledge about MR even they made delay due to unawareness of their legal rights, personal issues, social and service related causes. Strengthening of reproductive health services through community clinic at community level with available awareness building program on MR may minimize the delay for care seeking of MR among women. Bangladesh Med J. 2022 May; 51(2): 37-44

Energetic solar flare events in relation with subionospheric impact on 6-10 September 2017: data and modeling

Energetic solar flare events in relation with subionospheric impact on 6-10 September 2017: data and modeling

Abstract LB_A13: Phase 1 dose expansion results of CYT-0851, a monocarboxylate transporter (MCT) inhibitor, in combination with capecitabine (cape) in platinum-resistant ovarian cancer

Abstract Background: The MCT inhibitor CYT-0851 potently inhibits MCT1, has activity against MCT4, and blocks lactate transport resulting in cell death in glycolytic cancer cells. In an in vitro CRISPR screen, thymidylate synthetase was a significant hit in 2 resistant cell models, sensitizing them to CYT-0851. Follow-up in vitro combination studies showed that CYT-0851 synergized with 5-FU to inhibit cancer cell growth. Monotherapy clinical activity of CYT-0851 has been reported previously in lymphoma and solid tumors. In the phase 1 dose escalation trial of CYT-0851 plus cape, 400 mg was identified as the recommended phase 2 dose. In three phase 2 trials, cape had a RECIST response rate of 5-8% in ovarian cancer. Methods: An expansion cohort of 10 patients (pts) with platinum resistant advanced ovarian cancer were treated with CYT-0851, 400 mg QD in combination with cape, 1000 mg/m2 PO BID x 14 days every 21 days and were evaluable. One additional pt treated at the 300 mg dose level was evaluable and added to the analysis. The primary objective was safety, and secondary objectives were pharmacokinetics and preliminary anti-tumor activity by RECIST. Results: As of Aug 21, 2023, 11 pts were treated and evaluable, 9 white, 1 African American black, and 1 American Indian or Alaskan native, with a median age of 64 (range 52-76). Median prior therapies were 6 (range 2-14). All but one had 3 or more prior therapies. Median CYT-0851 dose compliance with continuous daily dosing was 99% (range 91– 100%). There were no treatment discontinuations or CYT-0851 dose reductions for treatment related adverse events. 7 pts (64%) experienced a treatment-related adverse event, all were Grade 1-2. There were no grade 3+ treatment related adverse events. The most common related AEs were fatigue reported in 5 pts (46%), and decreased appetite, diarrhea, nausea, palmar-plantar erythrodysaesthesia syndrome and vomiting, each reported in 2 patients (18%). Exposure of CYT-0851 in combination with capecitabine exhibits dose proportional behavior and was similar between combination therapy and monotherapy. One pt had a confirmed PR with progression on day 294, and 2 additional pts achieved a PR that has not been confirmed yet, with treatment ongoing on day 113 and 41. 7 pts had SD, and one patient PD as best response. The disease control rate was 91%. 5 Pts discontinued for progressive disease with a median of 133 days of treatment (range 43-300), and 2 withdrew consent on days 131-134. 4 patients continue therapy on days 42,47,106, and 113. Median PFS was 170 days (95% CI 79-NA). Conclusions: The oral outpatient combination of CYT-0851 and cape has demonstrated an acceptable safety and tolerability profile without any unanticipated toxicities at clinically active doses. The disease control rate of 91% and unconfirmed response rate of 27% in refractory platinum resistant ovarian cancer is promising and warrants further exploration. Furthermore, this regimen should be evaluated in other tumor types commonly treated with 5-FU, including breast and colorectal cancer. Citation Format: Elizabeth Swisher, Gerald Steven Falchook, Pamela N. Munster, Nina Beri, Kathleen N. Moore, Timothy A. Yap, David R. Spigel, Susan Doleman, William D. Bradley, Thomas J. O'Shea, Markus F. Renschler, Ryan C. Lynch. Phase 1 dose expansion results of CYT-0851, a monocarboxylate transporter (MCT) inhibitor, in combination with capecitabine (cape) in platinum-resistant ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A13.

Recombinant erythropoietin in autoimmune hemolytic anemia with inadequate bone marrow response: a prospective analysis

AbstractUp to 30% of patients with autoimmune hemolytic anemia (AIHA) show inadequate bone marrow (BM) compensatory response with inappropriately low levels of reticulocytes and endogenous erythropoietin. Ineffective BM compensation is associated with more severe anemia, transfusion need, and hospital admission, and treatment with recombinant erythropoietin (rEPO) may be beneficial. Here, we prospectively analyzed the efficacy and safety of rEPO in a single-center cohort of 47 patients with AIHA with inadequate reticulocytosis and endogenous erythropoietin at baseline. Epoetin alpha 40 000 international units per week were administered subcutaneously until hemoglobin (Hb) >11 g/dL and then tapered off. Overall response was 55% at 15 days, 74% at 1 month, 74% at 3 months, 80% at 6 months, and 91% at 12 months. Consistently, Hb values significantly increased from baseline to each subsequent time point (P<.001) with a median increase of +1.4, +2.4, +3.4, +3.8, and +4.4 g/dL, respectively. Transfusion needs reduced from 30% to <10% at 15 days and thereafter (P < .001). Concomitant medications included prednisone or methylprednisolone (N = 40, stable since >2 weeks from enrollment), mycophenolate mofetil (N = 1, ongoing since >3 months from enrollment), and rituximab (N = 7 patients with cold agglutinin disease from day 8). No association between concomitant medications and response to rEPO was found. Treatment was generally safe without rEPO-related severe adverse events. The comparison with an AIHA population not treated with rEPO showed a significant benefit of rEPO at 15 days and 1 month on response and Hb increase. These data support the use of rEPO as an add on to standard immunosuppression in AIHA with inadequate BM compensation. This trial was registered at www.clinicaltrials.gov as #NCT05931718.

Abstract LB_A12: Initial results from 2 Phase I studies of NMS-03305293, a selective PARP1 inhibitor

Abstract Background PARP-1 has a well-established role in DNA repair. PARP-1 selective inhibitors are a new subclass of PARPi that offer potential for improved tolerability. NMS-03305293 (NMS-293) is an oral, brain-penetrant PARP-1 selective inhibitor with strong antitumor activity in BRCA mutated preclinical models. Furthermore, NMS-293 is synergistic with temozolomide (TMZ) in glioblastoma mouse models. Methods Two phase I/I-II dose-escalation/expansion studies assessed safety, tolerability, and preliminary antitumor activity of NMS-293. Both are actively recruiting. In PARPA-293-001 (NCT04182516), NMS-293 was administered orally, ranging from 20 mg (QD) to 160 mg (BID) for 21 or 28 days on 28-day cycle in adult patients with advanced/metastatic, relapsed/refractory solid tumors who have exhausted standard treatment options. In PARPA-293-002 (NCT04910022), NMS-293 was administered in a range of doses orally, QD or BID on days 1-7 plus TMZ 150mg/m2 QD on days 1-5 in repeated 28-day cycle in adult patients with recurrent diffuse gliomas. Tumor responses were measured by investigator-assessed RANO criteria. Results The unpooled safety database at the data-cut-off (02-AUG-23), includes 45 patients in PARPA-001 and 21 patients in PARPA-002. PARPA-001 showed an MTD of 100 mg BID for 28 days on a 28-day cycle, a dose with meaningful PK relative to preclinical activity. PARPA-002 dose finding is ongoing with no DLTs as of cutoff date. The most frequent (≥10%) any-grade treatment related adverse events (TRAEs) in PARPA-001 were reversible QTcF prolongation, nausea, asthenia, decreased appetite and vomiting, mainly mild/moderate. In PARPA-002, with discontinuous NMS-293 plus TMZ, no G≥3 TRAEs were reported. The most frequent (≥10%) any-grade TRAEs were: nausea, fatigue, vomiting, decreased appetite, and platelet count decreased, mainly G1 adverse events. Overall, no dose-dependent trends of myelosuppression have been observed. 14 recurrent glioma patients across dose levels in PARPA-002 were evaluable for tumor response. A patient with glioblastoma had confirmed partial response (PR) with duration 7.6+ weeks, remaining on treatment at cutoff date. A patient with grade 3 IDH-mutant astrocytoma had unconfirmed PR with ongoing tumor shrinkage at 16.1+ weeks. A patient with glioblastoma had complete radiological disappearance of enhancing non-target lesions, remaining on treatment at cutoff date. NMS-293 PK profiles showed an increase in exposure with the dose with approximately 5 to 13 hours half-life. Conclusion NMS-293, a PARP-1 selective, brain penetrant inhibitor was well tolerated in phase I clinical trials with no dose dependent trends of myelosuppression. Furthermore, NMS-293 showed encouraging clinical activity in combination with TMZ in difficult-to-treat recurrent glioma patients. Citation Format: Marjolein Geurts, Dorothee Gramatzki, Sara Merler, Matteo Duca, Fabio Girardi, Ugur T. Sener, Domenico Roberti, Grazia Saturno, Patrizia Crivori, Alessia Montagnoli, Lisa Mahnke, Siqing Fu, Paola Gaviani, Kurt A. Jaeckle, Jian Zhang, Yehui Shi, Valentina Guarneri, Michael Weller, Sani H. Kizilbash, Martin J. van den Bent, Michele Milella, Silvia Damian. Initial results from 2 Phase I studies of NMS-03305293, a selective PARP1 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A12.

Cosmetic use related adverse events and need for cosmetovigilance

Cosmetics are applied to human body for cleansing, beautifying, promoting attractiveness or altering appearance. Cosmetics are causing adverse events to users, yet evidence about its magnitude is limited among students due self-diagnosis and self-medication .To know about the cosmetic use related adverse events and to enhance awareness regarding cosmetovigilance among the students of Nirmala College of pharmacy, Muvattupuzha by an educational intervention. To assess the prevalence of cosmetics, use among the students of Nirmala college of pharmacy, Muvattupuzha.To identify the cosmetics related adverse events and knowledge , To improve the awareness regarding cosmetovigilance. By online survey using google form. The questionnaire consisted of three parts, demographic profile, utilization pattern, participant's experience of cosmetics-related adverse reactions for the last two years.an awareness program about cosmetovigilance system. Access the knowledge of students one month after awareness.502 participants,55.2% with pimple ,55.2% with hair loss,41.4% with allergic reaction, dryness of skin, etc.

Outcome and treatment-related adverse events of combined immune checkpoint inhibition with flipped dosing in a real-world cohort of 79 patients with metastasized melanoma

IntroductionCombined immune checkpoint inhibition (ICI) with ipilimumab and nivolumab is a widely used treatment regimen for metastatic melanoma with non-resectable metastases. Nevertheless, the standard dose of ipilimumab 3 mg/kg bw and nivolumab 1 mg/kg bw is associated with a high rate of treatment-related adverse events (trAEs) (59% grade 3–4). In the CheckMate 511 study, it could be shown that flipped dosing with ipilimumab 1 mg/kg bw and nivolumab 3 mg/kg bw resulted in a significant reduction of trAE.MethodsWe have also used this regimen in the clinical setting and report the trAE, progression-free survival, and overall survival for 79 patients with metastatic melanoma who started combined ICI in the flipped dosing between March 2019 and April 2020.Resultsin total, 40 patients started first-line, 50% of whom had an elevated lactate dehydrogenase level at baseline. The disease control rate of these patients was 50%. The 2-year overall survival rate 67%. Moreover, 33% of the patients suffered grade 3 or 4 treatment related adverse events. DiscussionThe results of our study correspond very well to the results of the CheckMate 511 study (2-year OS: 65%, grade 3-4 immune-related side effects: 35%). Combined ICI with ipilimumab 1 mg/kg bw and nivolumab 3 mg/kg bw seems to be an equally effective but better-tolerated therapy regimen for metastasized melanoma patients, also in a real-world cohort.

Pancreatic Replacement Therapy for Maladaptive Behaviors in Preschool Children With Autism Spectrum Disorder

There is an urgent unmet need for a treatment addressing the core symptoms and associated maladaptive symptoms of autism spectrum disorder (ASD), especially in preschool populations. To evaluate whether treatment of children with ASD aged 3 to 6 years treated with high-protease pancreatic therapy produces long- and short-term improvements in autism-associated maladaptive behaviors. This cohort study at 32 sites across the US used a double-blind parallel group, delayed-start design comprising a 2-week blinded placebo run-in, and a double-blind, randomized, placebo-controlled segment (12 weeks). Children were recruited into the study in 2015, with data collection continuing until 2021. The analyses were completed from June 2021 to February 2022. All participants were randomly assigned to receive either 900 mg high-protease pancreatic replacement therapy or placebo with food 3 times a day for 12 weeks, followed by all receiving 900 mg high-protease pancreatic replacement therapy for 24 weeks. The primary outcome was the irritability/agitation subscale of the Aberrant Behavior Checklist (ABC-I). All potential participants were screened using the Social Communication Questionnaire (SCQ) with diagnosis confirmed by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) for ASD and the Autism Diagnostic Inventory-Revised (ADI-R). Outcomes were measured at the conclusion of the 12-week double-blind segment and at the conclusion of the 24-week open-label segment (total 36 weeks). A total of 190 participants (150 male [79%]), aged 3 to 6 (mean [SD] age, 4.5 [0.8]) years were randomized. Mixed model for repeated measures analysis performed on ABC-I demonstrated statistically significant differences of -2.49 (95% CI, -4.66 to -0.32; Cohen d = 0.364; P = .03) at the 12-week timepoint and -3.07 (95% CI, -5.81 to -0.33; Cohen d = 0.516; P = .03) at 36-week timepoint. No convergence was noted. Our high-protease pancreatic replacement (CM-AT) was well tolerated with no emergent safety concerns or related serious adverse events noted. This cohort study of preschool children sustained cumulative reduction in the maladaptive behavior of irritability in autism. This delayed-start analysis, used to demonstrate disease and condition modification, may prove to be an important tool to evaluate treatments for ASD. ClinicalTrials.gov Identifier: NCT02410902 and NCT02649959.

Platelet Reduction after Aortic Bioprosthesis Implantation: Results from the PORTRAIT Study

Background: Platelet count reduction (PR) is a common but unclear phenomenon that occurs after aortic bioprosthesis valve implantation (bio-AVR). This study aimed to investigate the occurrence and clinical impact of PR in patients receiving stented, rapid deployment (RDV), or stentless bioprostheses. Methods: 1233 adult bio-AVR patients were enrolled. Platelet count variation, early post-operative adverse events, and in-hospital mortality were analysed. Results: 944 patients received a stented valve, an RDV was implanted in 218 patients, and 71 patients had a stentless bioprosthesis. In all groups, the platelet count at discharge was lower than the baseline values (p &lt; 0.001). The percentage of PR was 27% in the stented group, 56% in the RDV group, and 55% in the stentless group. A higher platelet reduction, reaching the minimum platelet value, was observed in the RDV (mean: −30.84, standard error (SE): 5.91, p &lt; 0.001) and stentless (mean: 22.54, SE: 9.10, p = 0.03) groups compared to the stented group. A greater PR occurred as the size of the bioprosthesis increased in RDV (p = 0.01), while platelet count variation was not directly proportional to the stented bioprosthesis size (p &lt; 0.001). PR was not affected by cardiopulmonary bypass (mean: −0.00, SE: 0.001, p = 0.635) or cross-clamp (mean: −0.00, SE: 0.002, p = 0.051) times in any of the groups. RDV subjects experienced more in-hospital adverse events. PR was found to be associated with ischemic strokes in the overall population. Conclusions: Bio-AVR is associated with significant but transient PR. RDV patients more likely experience significant PR and related adverse clinical events. PR is associated with ischemic strokes, regardless of the bioprosthesis type.