Treatment Schedule Research Articles

Mixed effect estimation in deep compartment models: Variational methods outperform first-order approximations

This work focusses on extending the deep compartment model (DCM) framework to the estimation of mixed-effects. By introducing random effects, model predictions can be personalized based on drug measurements, enabling the testing of different treatment schedules on an individual basis. The performance of classical first-order (FO and FOCE) and machine learning based variational inference (VI) algorithms were compared in a simulation study. In VI, posterior distributions of the random variables are approximated using variational distributions whose parameters can be directly optimized. We found that variational approximations estimated using the path derivative gradient estimator version of VI were highly accurate. Models fit on the simulated data set using the FO and VI objective functions gave similar results, with accurate predictions of both the population parameters and covariate effects. Contrastingly, models fit using FOCE depicted erratic behaviour during optimization, and resulting parameter estimates were inaccurate. Finally, we compared the performance of the methods on two real-world data sets of haemophilia A patients who received standard half-life factor VIII concentrates during prophylactic and perioperative settings. Again, models fit using FO and VI depicted similar results, although some models fit using FO presented divergent results. Again, models fit using FOCE were unstable. In conclusion, we show that mixed-effects estimation using the DCM is feasible. VI performs conditional estimation, which might lead to more accurate results in more complex models compared to the FO method.

Critical Issues for Patients and Caregivers in Neuro-Oncology during the COVID-19 Pandemic: What We Have Learnt from an Observational Study.

The COVID-19 pandemic affected neuro-oncological patients and their caregivers regarding tumor care and emotional functioning, including Quality of Life (QoL). This study aimed to understand how COVID-19 affected their psychological state and the relations between patients and health personnel in neuro-oncology. A cross-sectional study was conducted on neuro-oncological patients and their caregivers. A total of 162 patients and 66 caregivers completed the questionnaire. Altogether, 37.5% of patients perceived a greater risk of contracting COVID-19 compared to the general population. On a 0-10 scale, the patients' tumor-related anxiety score was 5.8, and their COVID-19-related score was 4.6. The caregivers reported 7.7 and 5.5, respectively. QoL was described as at least good in 75% of both patients and caregivers; the caregivers' care burden increased in 22.7% of cases during the pandemic, with no correlation with QoL. Future perception often changed, both in patients and caregivers. In 18% of cases, the cancer treatment schedule was changed, either by patient decision or by medical decision. However, 93.5% of patients were satisfied with their overall care. A considerable proportion of patients and caregivers still perceived the tumor disease as more burdensome than the pandemic, and their future as more uncertain. Such data suggest the need to build a productive alliance between patients and health professionals.

Patient accessibility and utilization of behavioral sleep medicine referrals in an academic center.

Behavioral sleep medicine (BSM) is a subspecialty that combines behavioral psychology and sleep medicine specialties. The objective of this study was to analyze referral patterns to a BSM clinic. The 3 specific aims were: (1) describe factors that predict referral acceptance, (2) identify barriers to attending initial appointment, and (3) describe variables associated with the number of visits attended. Retrospective chart reviews were conducted as part of a quality improvement project by this study team's clinical setting. Adults over 21 years of age who were referred to a BSM clinic in an urban Midwestern academic health care system between 2014 and 2019 were included in this study. Sleep medicine was the main referral source for patients with BSM (74.2%), followed by internal medicine (9.3%) and neurology/psychiatry (7.3%). Thirty-eight percent of patients did not schedule an appointment after a referral for BSM was initiated. Younger age, longer distance from clinic, commercial insurance, and out-of-network insurance were all significantly greater for nonschedulers. Eighty-three percent of patients did attend the initial intake session with BSM providers. Older age was associated with lower likelihood of not attending scheduled BSM appointments. Patient characteristics of older age, closer distance from clinic, and in-network insurance coverage were found to significantly increase the likelihood of BSM scheduling, while younger age, Black race and not getting a primary sleep disorder diagnosis (vs a diagnosis of insomnia disorder) and shorter days from referral to appointment were associated with an increased likelihood of not attending the scheduled BSM treatment engagement. Chernyak Y, Ofner S, Williams MK, Bolarinwa C, Manchanda S, Otte JL. Patient accessibility and utilization of behavioral sleep medicine referrals in an academic center. J Clin Sleep Med. 2024;20(11):1793-1806.

Effects of Chemotherapy and Radiation Therapy on Early Laryngeal Cancers.

Treatments for early laryngeal squamous cell carcinoma (SCC) include radiotherapy (RT), chemoradiotherapy (CRT), and larynx-preserving surgery. In this study, early laryngeal SCC was treated with RT in patients with stage I (T1N0) tumors and with CRT and docetaxel (DOC) in patients with stage II (T2N0) tumors and the treatment results and effectiveness of the chemotherapy were compared. A total of 78 patients with early-stage laryngeal SCC were enrolled in this study. The T1N0 patients received radiation for the primary lesions as outpatients at a total dose of 63-70 Gy. By contrast, the T2N0 patients were hospitalized and treated with CRT, receiving a total radiation dose of 66-70 Gy. Docetaxel (DOC, 10 mg/m2) was administered intravenously once a week for 6-8 consecutive weeks concurrently with radiotherapy. The adverse events and survival rates with local control rates were examined. The number of non-glottic T2N0 patients was significantly higher than that of T1N0 patients. Although all patients completed their treatment schedule, significantly more grade 3 adverse events were observed in the T2N0 patients, in particular mucositis and dermatitis, than in T1N0 patients. The 5-year overall survival rate, disease specific survival rate, local control rate, and laryngeal preserve rate of the T1N0 and T2N0 patients were 86.1, 93.3, 88.6, and 94.3% and 85.9, 88.0, 93.1, and 93.1%, respectively. CRT with docetaxel showed the best therapeutic outcomes for the treatment of laryngeal SCC in patients with T2N0 tumours, with a higher local control rate, effective laryngeal preservation, and relatively few adverse events.

Phosphodiesterase type 5 inhibitors as treatment for erectile dysfunction: a webinar-based poll unveiling perceptions of healthcare professionals.

Aim: Erectile dysfunction (ED) is marked by a recurring incapacity to achieve or uphold a satisfactory erection during sexual activities. The study aims to increase awareness about male reproductive health, dispel misconceptions about ED and encourage physician-patient discussions. Materials & methods: A live online poll was conducted during a 3-day webinar titled "Turning the Tide of Men's Health" organized by Viatris™ in collaboration with the Saudi Society of Family and Community Medicine and attended by healthcare professionals (HCPs) from diverse specialties. The attendees voluntarily responded to nine poll questions on adherence to ED medication, use of phosphodiesterase type 5 inhibitors (PDE5is) as cure versus management of ED and patients' challenges. The responses to the poll questions were recorded and assessed to understand the perceptions of HCPs. Results: The poll garnered 10,423 responses from 5831 attendees on the second day of the webinar. The key findings included HCPs' perceptions that PDE5is contribute to ED management not complete cure. The respondents acknowledged that adherence to ED medications might decline on days without planned sexual activity, and long-term adherence on a daily PDE5i is exhibited by a relatively modest percentage of ED patients. The consensus among respondents was that PDE5is do not enhance or generate sexual desire, and the daily schedule of ED treatment may be burdensome for some patients. Conclusion: The findings from this poll offer insights into the perspectives of HCPs regarding the usage of PDE5is to treat ED. Responders of the poll generally agreed that PDE5is can help manage ED without affecting desire, though adherence may be lower on days without planned sexual activity. Furthermore, most respondents acknowledged that adhering to a daily pill regimen posed a greater burden than waiting for the medication to take effect.

Clinical pattern and treatment outcome of cutaneous leishmaniasis patients in Somali region, eastern Ethiopia

AbstractBackgroundNeglected tropical diseases, affecting over a billion people, include leishmaniasis, a protozoan parasite found in over 20 species. It is classified into three types: visceral, cutaneous, and muco‐cutaneous leishmaniasis, with cutaneous leishmaniasis being the most common. Dogs and rodents are the primary reservoirs of leishmaniasis, which is transmitted by infected female sandflies. Cutaneous leishmaniasis, found on exposed parts such as the arms, face and legs, presents with diverse clinical manifestations, including erythematous lesions, large, painless nodules, ulceration and an eventual volcanic form.ObjectiveTo assess the clinical pattern and treatment outcome of cutaneous leishmaniasis patients in the Somali region of eastern Ethiopia.MethodsThis descriptive study was conducted in the Somali region using neglected tropical disease surveillance data collected from 1 September 2023, to 8 February 2024. The data were cleaned and then exported to STATA version 17 for analysis.ResultsFrom 1 September 2023, to 8 February 2024, 900 patients were diagnosed with cutaneous leishmaniasis. Of these, 105 (11.67%) patients had localised cutaneous leishmaniasis, 741 (82.33%) had disseminated cutaneous leishmaniasis, 20 (2.22%) had diffuse cutaneous leishmaniasis, 8 (0.89%) had mucocutaneous leishmaniasis, 12 (1.33%) had mucocutaneous and disseminated leishmaniasis and 14 (1.56%) had localised and mucocutaneous leishmaniasis. All of the cases were male; the most common signs and symptoms the patients showed were papule, nodule, ulcer and crust 791 (87.89%) and itching, fever and discharges 758 (84.22%), respectively. Most of the patients, 823 (93.34%), were given systemic pentavalent antimonials, and the cure rate was 886 (98.44%). Of the patients, 14 (100%) who were defaulted on had diffuse cutaneous leishmaniasis.ConclusionsAll the participants had travelled to an area where sandflies were common. The majority of patients complained of itching, fever and discharges, with over two‐thirds having disseminated cutaneous leishmaniasis (DCL) and 0.89% having mucocutaneous leishmaniasis. The regional health bureau should set up a strong surveillance system and launch educational campaigns to raise awareness about cutaneous leishmaniasis, its transmission, symptoms and preventive measures. Furthermore, patients should be advised to strictly adhere to their treatment schedule and follow‐ups.

PhiHER2: phenotype-informed weakly supervised model for HER2 status prediction from pathological images.

Human epidermal growth factor receptor 2 (HER2) status identification enables physicians to assess the prognosis risk and determine the treatment schedule for patients. In clinical practice, pathological slides serve as the gold standard, offering morphological information on cellular structure and tumoral regions. Computational analysis of pathological images has the potential to discover morphological patterns associated with HER2 molecular targets and achieve precise status prediction. However, pathological images are typically equipped with high-resolution attributes, and HER2 expression in breast cancer (BC) images often manifests the intratumoral heterogeneity. We present a phenotype-informed weakly supervised multiple instance learning architecture (PhiHER2) for the prediction of the HER2 status from pathological images of BC. Specifically, a hierarchical prototype clustering module is designed to identify representative phenotypes across whole slide images. These phenotype embeddings are then integrated into a cross-attention module, enhancing feature interaction and aggregation on instances. This yields a phenotype-based feature space that leverages the intratumoral morphological heterogeneity for HER2 status prediction. Extensive results demonstrate that PhiHER2 captures a better WSI-level representation by the typical phenotype guidance and significantly outperforms existing methods on real-world datasets. Additionally, interpretability analyses of both phenotypes and WSIs provide explicit insights into the heterogeneity of morphological patterns associated with molecular HER2 status. Our model is available at https://github.com/lyotvincent/PhiHER2.

Onychocryptosis: a retrospective study of clinical aspects, inflammation treatment and pain management using Ozoile as a hydrogel and cream formulation.

Ingrown toenails account for roughly 20% of all foot problems in primary care. It is most common in young men, with nail care habits and footwear being major contributors. Onychocryptosis is typically caused by self-treatment attempts to cure the condition in its early stages. Its clinical features are frequently confused with other osseous and soft tissue abnormalities. The goal of this study was to provide perspectives on the management of pain and inflammation in Onychocryptosis using an Ozoile-based hydrogel formulation in a semi-occlusive bandage for 14 days, while incorporating natural pharmacological solutions into established protocols. The primary outcomes measured were pain reduction on NRS and stadiation according to the Al Kline Classification. The reduction was statistically significant, with a mean decrease in VAS score from 10 to 4 (p < 0.05), and Al Kline classification decreased by an average of 1.6 stages. 42% of patients recovered within the first 15 days of treatment, and 93% by the end of the scheduled treatment.

Biological-equivalent-dose-based integrated optimization framework for fast-energy-switching Bragg peak FLASH-RT using single-beam-per-fraction.

When comparing the delivery of all beams per fraction (ABPF) to single beam per fraction (SBPF), it is observed that SBPF not only helps meet the FLASH dose threshold but also mitigates the uncertainty with beam switching in the FLASH effect. However, SBPF might lead to a higher biological equivalent dose in 2Gy (EQD2) for normal tissues. This study aims to develop an EQD2-based integrated optimization framework (EQD2-IOF), encompassing robust dose, delivery efficiency, and beam orientation optimization (BOO) for Bragg peak FLASH plans using the SBPF treatment schedule. The EQD2-IOF aims to enhance both dose sparing and the FLASH effect. A superconducting gantry was employed for fast energy switching within 27ms, while universal range shifters were utilized to improve beam current in the implementation of FLASH plans with five Bragg peak beams. To enhance dose delivery efficiency while maintaining plan quality, a simultaneous dose and spot map optimization (SDSMO) algorithm for single field optimization was incorporated into a Bayesian optimization-based auto-planning algorithm. Subsequently, a BOO algorithm based on Tabu search was developed to select beam angle combinations (BACs) for 10 lung cases. To simultaneously consider dose sparing and FLASH effect, a quantitative model based on dose-dependent dose modification factor (DMF) was used to calculate FLASH-enhanced dose distribution. The EQD2-IOF plan was compared to the plan optimized without SDSMO using BAC selected by a medical physicist (Manual plan) in the SBPF treatment schedule. Meanwhile, the mean EQD2 in the normal tissue was evaluated for the EQD2-IOF plan in both SBPF and ABPF treatment schedules. No significant difference was found in D2% and D98% of the target between EQD2-IOF plans and Manual Plans. When using a minimum DMF of 0.67 and a dose threshold of 4Gy, EQD2-IOF plans showed a significant reduction in FLASH-enhanced EQD2mean of the ipsilateral lung and normal tissue by 10.5% and 11.5%, respectively, compared to Manual plans. For normal tissues that received a dose greater than 70% of the prescription dose, using a minimum DMF of 0.7 for FLASH sparing compensated for the increase in EQD2mean resulting from replacing ABPF with SBPF schedules. The EQD2-IOF can automatically optimize SBPF FLASH-RT plans to achieve optimal sparing of normal tissues. With an energy switching time of 27ms, the loss of fractionate repairing using SBPF schedules in high-dose regions can be compensated for by the FLASH effect. However, when an energy switching time of 500ms is utilized, the SBPF schedule needs careful consideration, as the FLASH effect diminishes with longer irradiation time.

Hit it hard: qualitative patient perspectives on the optimisation of immune checkpoint inhibition

BackgroundImmune checkpoint inhibitors have transformed the treatment landscape of many cancers, including melanoma and renal cell carcinoma (RCC). Randomised trials are evaluating outcomes from reduced ICI treatment schedules with the aim of improving quality of life, tolerability, and cost-effectiveness. This study aims to provide insight into patient and carer’s perspectives of these trials.MethodsSeven focus groups were conducted with 31 people with stage IV melanoma, RCC, or caregivers for people receiving ICI. Transcripts were analysed using reflexive thematic analysis.ResultsThree themes were generated: 1) “Treatment and clinic visits provide reassurance”: reducing hospital visits may not improve quality of life. 2) “Assessment of personal risk versus benefit”: the decision to participate in an ICI optimisation trial is influenced by treatment response, experience of toxicity and perceived logistical benefits based on the individual’s circumstances. 3) “Pre-existing experience and beliefs about how treatment and trials work”, including the belief that more treatment is better, influence views around ICI optimisation trials.ConclusionThis study provides insight into recruitment challenges and recommends strategies to enhance recruitment for ongoing ICI optimisation trials. These findings will influence the design of future ICI optimisation trials ensuring they are acceptable to patients.

Threshold-awareness in adaptive cancer therapy.

Although adaptive cancer therapy shows promise in integrating evolutionary dynamics into treatment scheduling, the stochastic nature of cancer evolution has seldom been taken into account. Various sources of random perturbations can impact the evolution of heterogeneous tumors, making performance metrics of any treatment policy random as well. In this paper, we propose an efficient method for selecting optimal adaptive treatment policies under randomly evolving tumor dynamics. The goal is to improve the cumulative "cost" of treatment, a combination of the total amount of drugs used and the total treatment time. As this cost also becomes random in any stochastic setting, we maximize the probability of reaching the treatment goals (tumor stabilization or eradication) without exceeding a pre-specified cost threshold (or a "budget"). We use a novel Stochastic Optimal Control formulation and Dynamic Programming to find such "threshold-aware" optimal treatment policies. Our approach enables an efficient algorithm to compute these policies for a range of threshold values simultaneously. Compared to treatment plans shown to be optimal in a deterministic setting, the new "threshold-aware" policies significantly improve the chances of the therapy succeeding under the budget, which is correlated with a lower general drug usage. We illustrate this method using two specific examples, but our approach is far more general and provides a new tool for optimizing adaptive therapies based on a broad range of stochastic cancer models.

Physical exercise in haemodialysis patients: which type of exercise is more convenient?

Randomized intra-haemodialysis and home-based exercise trials have demonstrated similar efficacy in improving physical performance, particularly in increasing walking distance. During dialysis sessions, patients can engage in structured, supervised activities such as cycling or resistance exercises, ensuring safety and immediate feedback from healthcare professionals. This structured nature can significantly enhance adherence, making exercise a regular part of the patient's treatment schedule. Home-based exercise offers flexibility and convenience. Patients can incorporate activities like walking, stretching or using resistance bands into their daily lives. This flexibility allows patients to exercise at their own pace and according to their preferences, fostering independence and self-management. By continuing physical activity at home, patients can maintain continuity in their exercise regimen, which is crucial for long-term health benefits. Combining both intra-haemodialysis and home-based exercises has the potential to improve overall adherence to exercise programs. Strategies such as patient education, customized plans, monitoring and feedback, and support systems can help combine these two exercise types. By integrating these two modalities, healthcare providers can create a comprehensive and balanced exercise regimen that enhances adherence, promotes independence and maximizes health benefits for dialysis patients, fostering long-term health and well-being through sustained physical activity. However, this dual approach, which caters to both the need for medical supervision and the desire for personal autonomy, has yet to be tested in randomized trials.

Tributyrin reverses the deleterious effect of saturated fat on working memory and synaptic plasticity in juvenile mice: differential effects in males and females

Short-chain fatty acids, such as butyric acid, derived from the intestinal fermentation of dietary fiber, have been proposed as a treatment for certain pathologies of the central nervous system. Our research group has shown that tributyrin (TB), a butyric acid prodrug, reverses deficits in spatial memory and modulates hippocampal synaptic plasticity. In the present work, diets enriched in either saturated (SOLF; Saturated OiL-enriched Food) or unsaturated (UOLF; Unsaturated OiL-enriched Food) fat were supplied during either 2 h or 8 weeks to 5-week-old male and female mice undergoing a treatment schedule with TB. After the dietary treatment, spatial learning and memory (SLM) was assessed in both the Y-maze and the eight-arm radial maze (RAM). Hippocampal expression of genes involved in glutamatergic transmission as well as synaptic plasticity (long-term potentiation -LTP- and long-term depression -LTD-) were also analyzed. Our results show that 2 h of SOLF intake impaired LTP as well as the performance in the Y-Maze in juvenile male mice whereas no effect was found in females. Moreover, TB reversed both effects in SLM and LTP in males. In the case of chronic intake, both SOLF and UOLF deteriorated SLM measured in the RAM in both sexes whereas TB only reversed LTP impairment induced by SOLF in male mice. These results suggest that TB may have a potentially beneficial influence on learning and memory processes, contingent upon the type of diet and the sex of the individuals.

Evidence to support phytosanitary policies–the minimum effective heat treatment parameters for pathogens associated with forest products

Research on reducing the movement of pests on wood products has led to several options for safer trade including heat treatment of wood to mitigate pests. In this study, pathogenic organisms commonly regulated in the trade of forest products were tested to determine the minimum heat dose (temperature and time) required to cause mortality. The mycelial stage of tree pathogens, Heterobasidion occidentale, Grosmannia clavigera, Bretziella fagacearum, Phytophthora cinnamomi, P. lateralis, P. ramorum and P. xmultiformis, which may be found in untreated wood products, were tested in vitro using the Humble water bath with parameters simulating the rate of heat applied to wood in a commercial kiln. RNA detection using reverse transcription real-time PCR was used to validate pathogen mortality following treatment for: P. ramorum, P. lateralis, P. cinnamomi, P. xmultiformis and G. clavigera. The lethal temperature for all pathogens ranged from 44 to 50°C for a 30-min treatment duration. Using this method to evaluate heat treatment for other forest product pests is recommended to accurately identify the minimum dose required to support phytosanitary trade. With more data potentially lower heat treatment applications may be recommended under specific conditions to produce more efficient and economical heat treatment schedules and reduce environmental impacts.

Nutritional Vitamin D deficiency rickets in children – Challenges in diagnosis, management, and prevention

Nutritional rickets are characterized by under mineralization of the skeleton that leads to bone deformities and poor growth. The balance between Vitamin D and calcium intake is critical for the maintenance of bone health. A few risk factors that contribute to a high prevalence of rickets in India include poor maternal nutrition, poor dietary calcium, and Vitamin D intake and poor sunshine practices. Early features of rickets may be asymptomatic and may be missed without biochemical and radiological investigations. Severe rickets may be the first manifestation of an underlying non-nutritional rickets that may be misdiagnosed in the absence of a complete workup. The treatment of rickets requires Vitamin D therapy with adequate calcium supplementation. The schedule of treatment with Vitamin D is not standardized, but daily therapy is preferable compared to weekly/monthly stoss therapy. Both cholecalciferol and ergocalciferol may be used for treatment as they are efficacious and cost-effective instead of active Vitamin D preparations. Periodic monitoring for the resolution of biochemical deficiency and improvement in skeletal changes should be emphasized. Prolonged treatment with Vitamin D and calcium should be avoided for the risk of Vitamin D toxicity and nephrocalcinosis. An impetus is required toward the prevention of Vitamin D deficiency. At present, nutritional strategies should focus on a life-cycle approach during the antenatal period, early infancy, and childhood and adolescence. Food fortification is likely to be an effective option, but the efficacy and logistics of this in the Indian setting will require further research.

Establishment of a clinical pharmacist-led multiple myeloma clinic with collaborative prescribing model at the national center for cancer care and research in Qatar

BackgroundMultiple myeloma (MM) is a chronic and incurable hematologic malignancy that is prevalent among the elderly. Interprofessional patient care showed superiority over physician-only care in multiple settings, including MM. ObjectiveThe primary objective of this study was to evaluate the impact of clinical pharmacist (CP)-led clinic and CPs interventions on MM patient care. Practice descriptionReal-world analysis of ambulatory patients with MM showed that CPs were central to the optimization of therapy and adherence to treatment schedules and supportive medications. Practice innovationThe CP-led MM Clinic was established with a collaborative prescribing agreement (CPA) in 2022 at the National Center for Cancer Care and Research in Qatar and was the first of its kind in the Middle East and North Africa region. This CPA allowed CPs to issue refills for supportive medications and order required laboratory tests. Evaluation methodsData collected included the number of CP interventions, refills ordered by CPs, documentation of patient education, and medication reconciliations. The data were retrospectively collected and analyzed comparing ambulatory patients with MM treated before (2021) to those treated after the clinic implementation in 2022. ResultsThe study population comprised 22 patients. A higher number of CPs interventions were documented post-clinic than preclinic (343 vs. 76, P = 0.004), with earlier initiation of bisphosphonate post-clinic (25 vs. 206 days, P = 0.008). There were also significant improvements in the introduction of risk appropriate venous thromboembolism prophylaxis (43% vs. 6%, P = 0.001) as well as vitamin D and calcium supplementation (100% vs. 68%, P = 0.02) post-clinic. Twenty-two medication refills for supportive medications and eight prechemotherapy laboratory investigations were ordered by CPs. ConclusionThe CP-led clinic provided a timely link to care optimization for ambulatory MM patients. This innovative CPA model implemented in the clinic could potentially be applied to different cancer settings to optimize safe and effective patient care.

Hepatic arterial infusion chemotherapy combined with toripalimab and surufatinib for the treatment of advanced intrahepatic cholangiocarcinoma.

The aim of the present study is to report the clinical results of patients with advanced intrahepatic cholangiocarcinoma (ICC) who received combination therapy of hepatic arterial infusion chemotherapy (HAIC), toripalimab and surufatinib. The study cohort consisted of 28 patients with advanced ICC who were treated with HAIC (mFOLFOX6 regimen, Q3W) in combination with intravenous toripalimab (240 mg, Q3W) and oral surufatinib (150 mg, once daily). The cohort had 14 male and 14 female patients. The baseline characteristics of the study cohort were obtained. The tumor response and drug-associated toxicity were assessed and reported. During the follow-up period (median follow-up time: 11.3 months; range: 4-19 months), four patients died of tumor progression. The objective response rate and disease control rate were 58% and 79%, respectively. The mPFS was 9.5 months, and the overall survival rate was 83.3%. The most frequent adverse events were nausea and vomiting (100%) and abdominal pain (85.7%). Serious complications related to death were not observed. The combination treatment schedule for advanced ICC demonstrated positive efficacy and safety profiles. This study provides promising clinical guidance for the treatment of advanced cholangiocarcinoma and is expected to modify the treatment strategy for this disease.

Update on GALLANT: A phase 2 study using metronomic gemcitabine, doxorubicin, and docetaxel plus nivolumab in previously treated sarcoma (NCT04535713).

e23569 Background: Metronomic dosing of gemcitabine, doxorubicin and docetaxel causes less severe side effects than standard chemotherapy for advanced sarcoma. Hypothesis: The addition of nivolumab to this regimen will have synergistic effects and improve treatment outcomes. Objectives: Primary objective: To assess progression-free survival (PFS); Secondary objectives: (1) To evaluate best overall response during treatment period confirmed in a 6-week follow-up, (2) PFS rate at 6 and 9 months, (3) Overall survival (OS) rate at 6, 12 months, and (4) Incidence of treatment-related adverse events (TRAEs). Methods: Inclusion criteria: Previously treated male and female subjects, &amp;gt; 18 years of age, pathologically confirmed diagnosis of locally advanced, unresectable, or metastatic sarcoma, measurable disease by RECIST v1.1, and acceptable hematologic and organ functions. Exclusion Criteria: History of autoimmune disorder. Treatment schedule: Metronomic doses of gemcitabine (600 mg/m2 max:1000 mg), doxorubicin (18 mg/m2; max: 32 mg), docetaxel (25 mg/m2; max:42 mg) on Day 1 and Day 8, and nivolumab (240 mg) on Day 1 only. Repeat treatment cycles may be given every three weeks if the toxicity grade is &amp;lt;1. Results: Efficacy (n = 70). This population completed at least one treatment cycle and had a follow-up CT or MRI scan at week 6. Best Overall Response = 14 PR, 47 SD, 9 PD. ORR = 20%; DCR (CR+PR+SD) was 87%. Median PFS was 8.2 (95% CI: 5.85-10.55) months; 6- month PFS rate of 59%. Median OS was 17.6 (95% CI: 13.53-21.67) months, with 6-month OS of 84%. Safety (n = 75): Grade 3/4 TRAEs include thrombocytopenia (n = 26), white blood cell count decreased (n = 17), neutropenia (n = 16), fatigue (n = 15), anemia (n = 13), nausea (n = 9), anorexia (n = 5), diarrhea (n = 2), emesis (n = 1), febrile neutropenia (n = 1), sepsis (n = 1), rectal bleeding (n = 1), transaminitis (n = 1), dizziness (n = 1), shortness of breath (n = 1). There were no unexpected adverse events reported. Conclusions: Taken together, the data suggests that nivolumab plus metronomic doses of gemcitabine, doxorubicin and docetaxel (1) may have synergistic activity, and (2) by indirect comparison, may be as effective as standard first line therapy for advanced sarcoma with manageable toxicity. Clinical trial information: NCT04535713 .

Therapeutic Responses to Efgartigimod for Generalized Myasthenia Gravis in Japan.

Efgartigimod, which has been well tolerated and efficacious in individuals with generalized myasthenia gravis (MG), is available in Japan not only for the treatment of anti-acetylcholine receptor-positive (AChR+) but also anti-muscle-specific receptor tyrosine kinase (MuSK+) and seronegative generalized MG. We report details of the use of efgartigimod for generalized MG in clinical practice in Japan. We included patients with generalized MG in the 2021 survey of Japan Myasthenia Gravis Registry (JAMG-R) study group who received an initial cycle of efgartigimod between May and September 2022. We defined "responders" as patients who achieved a score ≥2 points for MG activities of daily living (MG-ADL) in the first treatment cycle. The MG composite and the Revised scale of the 15-item Myasthenia Gravis-Quality of Life scale (MG-QOL15-r) were also evaluated. Of 1,343 JAMG-R patients, 36 (2.7%) started efgartigimod (female 68%, age 53 years). Their serologic profiles were as follows: AChR+, n = 19 (53%); MuSK+, n = 6 (17%); and seronegative, n = 11 (31%). Twenty-six patients (72%) had refractory MG. There were 81 cycles of efgartigimod during the 26-week observation in 34 patients (average, 2.4 cycles). The mean interval between cycles was 5.9 weeks. A continuous 4-weekly infusion of efgartigimod was performed in 65 (80%) of 81 cycles. In the first cycle, the MG-ADL score of the 34 patients decreased significantly from 10.5 ± 4.3 to 6.9 ± 5.1 (p = 0.003). Similarly, the mean MG composite and MG-QOL15-r decreased from 18.4 ± 13.6 to 11.8 ± 9.6 (p = 0.004) and from 19.2 ± 6.3 to 14.2 ± 8.3 (p = 0.007), respectively. Twenty-one (62%) patients were responders. Therapeutic responses were observed in the subsequent cycles. The duration of effectiveness of efgartigimod was varied among the responders; 4 responders had only a single effective cycle. Significant improvement was observed in the MuSK+ patients. Prednisolone dose of 7 patients was reduced. Our examination of the patients' postintervention status revealed that 6 patients achieved minimal manifestations. COVID-19 occurred in 5 patients. We failed to detect clinical or laboratory findings associated with responders. Efgartigimod can be considered for the treatment of patients with generalized MG who do not achieve minimal manifestations, with a broad flexibility of patient selection and treatment schedules.

Safety and time to response of [177Lu]Lu-DOTATATE in patients with newly diagnosed advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Sub-analysis of the phase 3 randomized NETTER-2 study.

4131 Background: NETTER-2 (NCT03972488) is the first randomized study to evaluate radioligand therapy ([177Lu]Lu-DOTA-TATE; hereafter 177Lu-DOTATATE) at first line (1L) in patients (pts) with advanced, well-differentiated higher grade (G2 and G3) gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Significant improvements in progression-free survival and objective response rate (ORR) were observed for pts receiving 177Lu-DOTATATE. This sub-analysis of NETTER-2 assessed safety and time to response (TTR). Methods: Eligible pts (n=226) were newly diagnosed with somatostatin receptor-positive high G2 or G3 (Ki67 ≥10% and ≤55%) advanced GEP-NETs and were randomized (2:1) to receive 4 cycles of 177Lu-DOTATATE (4 × 7.4 GBq every 8 weeks [Q8W]) plus 30 mg octreotide long-acting repeatable (LAR) Q8W during 177Lu-DOTATATE treatment then Q4W (177Lu-DOTATATE arm), or 60 mg octreotide LAR Q4W (control arm). Hematologic adverse events (AEs) and laboratory toxicities were scored according to CTCAE grade. Response was assessed centrally based on conventional imaging (RECIST 1.1 criteria). Results: The AE pattern in the 177Lu-DOTATATE arm was consistent with the established safety profile. Among laboratory abnormalities, grade 3/4 decreases in lymphocytes (38.1% vs 2.7%), leukocytes (4.1% vs 0), neutrophils (3.4% vs 0), platelets (2.0% vs 0) and hemoglobin (1.4% vs 2.7%) were observed in 177Lu-DOTATATE (n=147) and control (n=73) arms, respectively; median time to first occurrence of hematologic toxicities was 4.4 months among pts with immediate hematotoxicities. These events were transient and manageable. There was no notable difference in infection rates between treatment arms (31.3% 177Lu-DOTATATE and 27.4% control). One case of myelodysplastic syndrome was observed (177Lu-DOTATATE arm ~14 months after first cycle). Five fatal AEs occurred during the randomized treatment period; all considered unrelated to treatment and attributed to GEP-NET progression. AEs leading to 177Lu-DOTATATE dose interruption, reduction and discontinuation occurred in 14 (9.5%), 2 (1.4%) and 3 (2.0%) pts, respectively. Among 65 responders in the 177Lu-DOTATATE arm (ORR 43 %), median TTR (Q1, Q3) was 5.7 months (4.1, 8.3). Most responses occurred during the 4-cycle treatment with 177Lu-DOTATATE. Conclusions: In pts with advanced G2 and G3 (Ki67 ≥10% and ≤55%) GEP-NETs treated with 177Lu-DOTATATE at 1L the most common hematologic toxicity was lymphopenia, but infection rates were similar vs control. With a median TTR of 5.7 months, most responses to 177Lu-DOTATATE occurred during scheduled treatment. Overall, the study confirmed the safety profile of 177Lu-DOTATATE and supports its use at 1L for this pt population. Clinical trial information: NCT03972488 .