Tolerability Of Treatment Research Articles

Abstract 121: Gut microbiome association with dietary habits and abemaciclib-induced diarrhea:A multicenter, prospective study

Abstract Background: Abemaciclib, a leading treatment used for HR-positive, HER2-negative metastatic and primary breast cancer patients, often causes diarrhea. Understanding the reasons machinery behind this adverse event leads to reduce the toxicity and improve the quality of life. This study explores a hypothesis that specific gut microbiota profiles are engaged in gastrointestinal toxicities caused by abemaciclib and may be influenced by patients' dietary habits. We assessed it using the Brief Diet History Questionnaire (BDHQ). Materials and Methods: Our research involved collecting blood and stool samples, as well as dietary data through the BDHQ from 39 patients diagnosed with HR-positive, HER2-negative metastatic breast cancer. These were obtained prior to the start of abemaciclib treatment, at the first imaging evaluation, and at either disease progression or treatment discontinuation due to adverse effects. Incidence and severity of diarrhea were evaluated by the Bristol stool scale at baseline, from day 1 to day 14, and at day 90 of treatment. Stool samples were collected at baseline and at day 90 after the start of abemaciclib treatment. We conducted 16S metagenomic sequencing for gut microbiome analysis and used mass cytometry along with RNA-sequencing to profile immune cells. Results: Our findings indicate a significant association between the gut microbiota composition and abemaciclib-induced diarrhea, which also appears to be modulated by dietary patterns. An increase in Dorea was observed with higher Bristol Stool Scale scores, while Bifidobacterium and Sellimonas abundances were inversely related to changes in stool characteristics. The presence of Dorea was also positively associated with the consumption of specific food items such as tea, root vegetables, and dietary minerals. In contrast, Collinsella abundance decreased as the frequency of diarrhea increased and it was associated with the consumption of fried foods and certain fats. Conclusion: The prevalence of diarrhea as a side effect of abemaciclib treatment highlights the need for better management strategies. Our study indicates that gut microbiota, altered by dietary habits, is linked to this adverse effect. The data suggest a possibility of using specific gut bacteria as probiotics to alleviate this condition, pointing towards personalized dietary interventions as a potential avenue for improving treatment tolerance. Citation Format: Yuri Fujimoto, Kosuke Kawaguchi, Yurina Maeshima, Hiroshi Ishiguro, Kazuhiko Yamagami, Sachiko Takahara, Hirofumi Suwa, Masae Torii, Shigenori Nagai, Yasuaki Sagara, Wakako Tsuji, Hiroyasu Yamashiro, Takeshi Kotake, Shinji Fukuda, Kuniaki Saito, Yasuko Yamamoto, Masako Kataoka, Yuki Himoto, Atsushi Yonezawa, Yukiko Fukui, Yuki Nakamura, Wei Li, Sunao Tanaka, Masahiro Takada, Satoshi Morita, Masakazu Toi. Gut microbiome association with dietary habits and abemaciclib-induced diarrhea:A multicenter, prospective study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 121.

A Prospective Evaluation of Tubarial Gland Doses With Acute Dysphagia and Treatment Tolerance in Head and Neck Cancer Patients.

Background This study prospectively analyzed the clinical significance of tubarial glands (TGs) doses in head and neck cancer (HNC) patients. Methods Patients diagnosed with HNC in Ankara Bilkent City Hospital, Turkey were analyzed. TGs volumes and doses were noted. The patients were evaluated in terms of acute dysphagia (AD)and radiation therapy (RT)-associated xerostomia. Results The median volume of the TGs was 3.5(2.1-5.9)cc. No increasedstandardized uptake values (SUV) were observed in the TGs. There was no significant relationship between TGs values and the third orsixth months of xerostomia after RT.There was a significant relationship between grade ≥2 AD and TGs-Dmean(p0.020); TGs-V25(%)(p0.007); TGs-V30(%)(p0.009); TGs-V40%(p0.011); TGs-V50%(p0.010), TGs-V60%(p0.045). In terms of the risk of grade ≥2 AD, the cut-off value of the TGs-Dmeanwas analyzed for 50 Gy, with 75% sensitivity and 73.3% specificity (p 0.020; AUC 0.746; 95% CI 0.561-0.929).Additionally for grade ≥2 AD, the cut-off value of the TGs-V25(%)was analyzed 78with 81.3% sensitivity and 80.0% specificity (p 0.011; AUC 0.769; 95% CI 0.591-0.947). Conclusion A significant correlation was found between TGs doses and AD during RT. TGs-V25(%)value showed higher significance. In future studies, the clinical significance of TGs can be studied especially on this value. The relationship between TGs doses and xerostomia should be evaluated with a larger series.

IV low dose ketamine infusions for treatment resistant depression: Results from a five-year study at a free public clinic in an academic hospital

Individuals with major depressive disorder and treatment resistant depression (MDD-TRD) have limited and sometimes poorly tolerated therapeutic options. Low dose ketamine has presented promising and potent antidepressant effects in this population. To support the existent literature, we conducted a longitudinal study examining five years of real-world clinical data on the use of IV low-dose ketamine alongside standard care for MDD-TRD outpatients. For this study we collected demographic information, clinical scale scores, side effects and dropout data. The data was analyzed using descriptive statistics, effect size using Cohen's D analysis, and multivariate ANOVA (MANOVA) to determine the impact of sociodemographic variables. 71 outpatients (50.28 years old, SD: 14.26; female 74.65%) were included in the analysis. The results showed a significant reduction in depressive symptoms and suicide ideation (SI) by treatment endpoint. 54.93% of patients responded to the treatment, 78.26% experienced transient and mild side effects, and 11.27% of dropped out of the treatment. Multivariate analysis showed that the demographic variables did not impact treatment effect or tolerability. The results of this study suggest that IV low dose ketamine treatment is effective, fast-acting, and well tolerated for the management of depressive symptoms and SI in patients with MDD-TRD in naturalistic clinical practice.

O239: Identification of novel radiosensitisers in colorectal cancer cells

Abstract Introduction Locally advanced rectal cancer is typically treated with neoadjuvant chemoradiotherapy, where chemotherapy acts synergistically to radiosensitise cancer cells. Response to chemoradiotherapy is variable, with 8-20% of cases having a complete pathological response, but 20-30% demonstrate no response or disease progression. Novel radiosensitisers can potentially improve response, tolerability of radiotherapy and de-escalate treatments, including the need for major surgery. This study aims to perform a screen of available FDA-approved drugs to identify novel radiosensitisers in rectal cancer. Methods A drug screen of forty FDA-approved drugs was performed. HCT-116 cells were cultured and treated as a monolayer with 0.3μM and 1.0μM of a specific drug for 16 hours. Clonogenic assays were performed in 24 well plates after photon irradiation at 0 and 1 Gy. Relative colony formation (survival fraction) was employed to measure drug efficacy and radiosensitisation. Following the screen, two drugs were selected for dose optimisation and further mechanistic evaluation with DNA repair kinetics and DNA damage using immunofluorescence of γH2Ax foci. Results Abexinostat and Fomepizole were selected from the screen for dose optimisation based on their radiosensitising capabilities. Dose optimisations determined both drugs had an optimal concentration of 0.5 and 1.0μM and required an optimum of 6 hours of treatment, and showed significant radiosensitisation. Prolonged DNA repair kinetics and significantly more γH2Ax foci in cells treated with Abexinostat and Fomepizole indicated persisting DNA damage. Conclusion Abexinostat and Fomepizole show promise as radiosensitizers. Further experimentation is ongoing to determine the mechanism of action for these drugs and their translational potential.

Evaluation of treatment outcomes and tolerability in older patients with rectal cancer treated with radiotherapy accompanied by the G-8 geriatric score: TROD13–003 multicenter study

IntroductionThe choice of treatment for rectal cancer often differs in older and younger patients, with the rate of radiotherapy use lower among older adults. In our daily practice, when evaluating a frail older patient with rectal cancer, we usually choose to give less treatment. This may be due to concern that the patient will not be able to tolerate radiotherapy. The Geriatric 8 score (G8GS) is a guide to evaluating treatment tolerability as it relates to frailty in older adults with cancer. The aim of this study was to evaluate treatment outcomes and tolerability in older patients with rectal cancer treated with radiotherapy (RT) accompanied by G8GS. Materials and MethodsPatients aged 65 and older with stage I-III rectal adenocarcinoma who were treated with RT and had a G8 evaluation were included in this multicenter retrospective study. Prognostic factors related to G8GS were calculated using Chi-square and logistic regression tests and survival rates were calculated by the Kaplan–Meier test using the SPSS v24.0 software. All p-values ≤0.05 were considered statistically significant. ResultsA total of 699 patients from 16 national institutions were evaluated. The median age was 72 years (range 65–96), and the median follow-up was 43 (range 1-190) months. Four hundred and fifty patients (64%) were categorized as frail with G8GS ≤14 points. Frail patients had higher ages (p = 0.001) and more comorbidities (p = 0.001). Ability to receive concomitant and/or adjuvant chemotherapy rates were significantly higher in fit patients (p = 0.002 and p = 0.001, respectively). No significant difference was observed in terms of grade 3-4 early and late toxicity for both groups. Cancer-related death was higher (p = 0.003), and 5- and 8-year survival rates were significantly lower (p = 0.001), in the frail group. Age and being frail were significantly associated with survival. DiscussionRadiotherapy is a tolerable and effective treatment option for older adults with rectal cancer even with low G8GS. Being in the frail group according to G8GS and having multiple comorbidities was negatively associated with survival. Addressing the medical needs of frail patients through a comprehensive geriatric assessment prior to radiotherapy may improve G8GS, allowing for standard treatment and increased survival rates.

Variables associated with antibiotic treatment tolerance in patients with Mycobacterium avium complex pulmonary disease

BackgroundTreatment of Mycobacterium avium complex pulmonary disease (MAC-PD) involves prolonged courses of multiple antibiotics that are variably tolerated and commonly cause adverse drug reactions (ADR). The purpose of this retrospective, single-center study was to identify demographic and disease-related variables associated with significant ADRs among patients treated with antibiotics against MAC-PD.MethodsWe reviewed all patients treated with antibiotic therapy for MAC-PD at a single center from 2000 to 2021. Patients were included if they met diagnostic criteria for MAC-PD, were prescribed targeted antibiotic therapy for any length of time and had their treatment course documented in their health record. We compared patients who completed antibiotics as originally prescribed (tolerant) with those whose antibiotic treatment course was modified or terminated secondary to an ADR (intolerant).ResultsOver the study period, 235 patients were prescribed antibiotic treatment with their clinical course documented in our center’s electronic health record, and 246 treatment courses were analyzed. One hundred forty-three (57%) tolerated therapy versus 108 (43%) experienced ADRs. Among the 108 intolerant courses, 67 (63%) required treatment modification and 49 (46%) required premature treatment termination. Treatment intolerance was associated more frequently with smear positive sputum cultures (34% vs. 20%, p = 0.009), a higher Charlson Comorbidity Index (CCI) (4 vs. 6, p = 0.007), and existing liver disease (7% vs. 1%, p = 0.03). There was no between-group difference in BMI (21 vs. 22), fibrocavitary disease (24 vs. 19%), or macrolide sensitivity (94 vs. 80%). The use of daily therapy was not associated with intolerance (77 vs. 79%). Intolerant patients were more likely to be culture positive after 6 months of treatment (44 vs. 25%).ConclusionsPatients prescribed antibiotic therapy for MAC-PD are more likely to experience ADRs if they have smear positive sputum cultures at diagnosis, a higher CCI, or existing liver disease. Our study’s rate of early treatment cessation due to ADR’s was similar to that of other studies (20%) but is the first of its kind to evaluate patient and disease factors associated with ADR’s. A systematic approach to classifying and addressing ADRs for patients undergoing treatment for MAC-PD is an area for further investigation.

Translation from Preclinical Research to Clinical Trials: Brain-Gut Photobiomodulation Therapy for Alzheimer's Disease.

Recently, novel non-pharmacological interventions, such as photobiomodulation (PBM) therapy, have shown promise for the treatment of Alzheimer's disease (AD). This article outlines the translation from the preclinical to clinical stages of an innovative brain-gut PBM therapy in a mouse model of AD, a pilot clinical trial involving mild-to-moderate AD patients, and a continuing pivotal clinical trial with a similar patient population. In a mouse model of AD (Aβ25-35), daily application of brain-gut PBM therapy to both the head and the abdomen produced a neuroprotective effect against the neurotoxic effects of an Aβ25-35 peptide injection by normalizing all the modified behavioral and biochemical parameters. The pilot clinical trial to evaluate brain-gut PBM therapy demonstrated the tolerability and feasibility of the novel PBM-based treatment for mild-to-moderate AD patients. Compared to the sham patients, the PBM-treated patients had lower Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) comprehension sub-scores, higher forward verbal spans, and lower Trail Making Test (TMT) Part B (TMT-B) execution times, which suggest an improvement in cognitive functions. This pilot study provided important information for the design of a novel pivotal clinical trial, currently in progress, to assess the efficacy of brain-gut PBM therapy in a larger sample of AD patients. This pivotal clinical trial could demonstrate that brain-gut PBM therapy is a safe, well-tolerated, and efficient disease-modifying treatment for mild-to-moderate AD patients and that it has medical and economic benefits.

Novel prognostic biomarker TBC1D1 is associated with immunotherapy resistance in gliomas.

Glioma, an aggressive brain tumor, poses a challenge in understanding the mechanisms of treatment resistance, despite promising results from immunotherapy. We identified genes associated with immunotherapy resistance through an analysis of The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases. Subsequently, qRT-PCR and western blot analyses were conducted to measure the mRNA and protein levels of TBC1 Domain Family Member 1 (TBC1D1), respectively. Additionally, Gene Set Enrichment Analysis (GSEA) was employed to reveal relevant signaling pathways, and the expression of TBC1D1 in immune cells was analyzed using single-cell RNA sequencing (scRNA-seq) data from GEO database. Tumor Immune Dysfunction and Exclusion (TIDE) database was utilized to assess T-cell function, while Tumor Immunotherapy Gene Expression Resource (TIGER) database was employed to evaluate immunotherapy resistance in relation to TBC1D1. Furthermore, the predictive performance of molecules on prognosis was assessed using Kaplan-Meier plots, nomograms, and ROC curves. The levels of TBC1D1 were significantly elevated in tumor tissue from glioma patients. Furthermore, high TBC1D1 expression was observed in macrophages compared to other cells, which negatively impacted T cell function, impaired immunotherapy response, promoted treatment tolerance, and led to poor prognosis. Inhibition of TBC1D1 was found to potentially synergistically enhance the efficacy of immunotherapy and prolong the survival of cancer patients with gliomas. Heightened expression of TBC1D1 may facilitate an immunosuppressive microenvironment and predict a poor prognosis. BlockingTBC1D1 could minimize immunotherapy resistance in cancer patients with gliomas.

Sex-related similarities and differences in responses to heart failure therapies.

Although sex-related differences in the epidemiology, risk factors, clinical characteristics and outcomes of heart failure are well known, investigations in the past decade have shed light on an often overlooked aspect of heart failure: the influence of sex on treatment response. Sex-related differences in anatomy, physiology, pharmacokinetics, pharmacodynamics and psychosocial factors might influence the response to pharmacological agents, device therapy and cardiac rehabilitation in patients with heart failure. In this Review, we discuss the similarities between men and women in their response to heart failure therapies, as well as the sex-related differences in treatment benefits, dose-response relationships, and tolerability and safety of guideline-directed medical therapy, device therapy and cardiac rehabilitation. We provide insights into the unique challenges faced by men and women with heart failure, highlight potential avenues for tailored therapeutic approaches and call for sex-specific evaluation of treatment efficacy and safety in future research.

Switching from immediate- to extended-release cysteamine in patients with nephropathic cystinosis: from clinical trials to clinical practice.

The purpose of this study is to evaluate the effectiveness and safety of switching from immediate-release (IR) to extended-release (ER) cysteamine in patients with nephropathic cystinosis (NC) in Spain. We conducted an observational, retrospective, multicentre study in NC patients who received IR cysteamine for at least 12months, switched to ER cysteamine, and received it for at least 6months before inclusion. Data were collected from nine patients (four children, five adults) 36months before and after the switch. Despite the highly selected population, an improvement in growth, particularly in children and a significant reduction in hospitalization days was observed. A decrease in halitosis, body odour and gastrointestinal effects was reported in most of the patients who suffered before the switch, and the use of proton pump inhibitors (PPIs) decreased in some patients. The estimated glomerular filtration rate (eGFR) remained stable in patients with preserved kidney function. No significant changes in white blood cell (WBC) cystine levels were observed after the switch. There was no significant difference in the cysteamine dose received. However, some patients were receiving <50% of the recommended dose of cysteamine before and after the switch and showed elevated levels of WBC cystine. Switching from IR to ER cysteamine in clinical practice reduces hospital stays, improves nutritional status and growth in paediatric patients and could help to enhance treatment tolerability by reducing side effects. Furthermore, the dosing of ER cysteamine could promote therapeutic compliance and positively affect the quality of life of the NC population.

Ovarian Cancer in the Older Manitoban Population-Treatment Tolerance and Cancer-Related Outcomes: A Manitoba Ovarian Cancer Outcomes (MOCO) Group Study.

In Canada, individuals with gynecologic reproductive organs (ovaries, fallopian tubes, uterus) over the age of 70 comprise a large proportion of epithelial ovarian cancer patients. These patients often have co-morbidities, polypharmacy, or decreased functional status that may impact treatment initiation and tolerance. Despite this, there is limited evidence to guide treatment for older patients diagnosed with ovarian epithelial carcinoma. This is a retrospective study with data from Manitoba, Canada. The data were obtained from the Manitoba Ovarian Cancer Database, the Manitoba Cancer Registry, and electronic health records. All individuals with epithelial ovarian, fallopian tube, or peritoneal cancer diagnosed between 2009 and 2018 were identified. Patients aged > 70 at the time of diagnosis were included in the study cohort. Four hundred and forty individuals were included. The majority had advanced stage disease (56%). Moreover, 59% of patients received no chemotherapy. Of the patients who received chemotherapy, 20% received <2 cycles and 21% required a dose reduction due to toxicity. Univariable and multivariable analysis identified advanced stage (p < 0.001), treatment modality (p < 0.001), and advanced age at diagnosis (p < 0.001) with poorer overall survival. Our study demonstrated a high rate of chemotherapy dose reduction and discontinuation in the elderly epithelial ovarian cancer population. Further research is needed to identify risk factors for treatment discontinuation and intolerance in this population.

Protocol for a mixed-methods study to develop and feasibility test a digital system for the capture of patient-reported outcomes (PROs) in patients receiving chimeric antigen receptor T-cell (CAR-T) therapies (the PRO-CAR-T study)

IntroductionChimeric antigen receptor (CAR) T-cell therapies are novel, potentially curative therapies for haematological malignancies. CAR T-cell therapies are associated with severe toxicities, meaning patients require monitoring during acute and postacute...

198 treatment tolerance and toxicity in elderly nasopharyngeal cancer patients and implication on outcomes

198 treatment tolerance and toxicity in elderly nasopharyngeal cancer patients and implication on outcomes

TOward a comPrehensive supportive Care intervention for Older men with metastatic Prostate cancer (TOPCOP3): A pilot randomized controlled trial and process evaluation

IntroductionCurrent management of metastatic prostate cancer (mPC) includes androgen receptor axis-targeted therapy (ARATs), which is associated with substantial toxicity in older adults. Geriatric assessment and management and remote symptom monitoring have been shown to reduce toxicity and improve quality of life in patients undergoing chemotherapy, but their efficacy in patients being treated with ARATs has not been explored. The purpose of this study is to examine whether these interventions, alone or in combination, can improve treatment tolerability and quality of life (QOL) for older adults with metastatic prostate cancer on ARATs. Materials and MethodsTOPCOP3 is a multi-centre, factorial pilot clinical trial coupled with an embedded process evaluation. The study includes four treatment arms: geriatric assessment and management (GA + M); remote symptom monitoring (RSM); geriatric assessment and management plus remote symptom monitoring; and usual care and will be followed for six months. The aim is to recruit 168 patients between two cancer centres in Toronto, Canada. Eligible participants will be randomized equally via REDCap. Participants in all arms will complete a comprehensive baseline assessment upon enrollment following the Geriatric Core dataset, as well as follow-up assessments at 1.5, 3, 4.5, and 6 months. The co-primary outcomes will be grade 3–5 toxicity and QOL. Toxicities will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. QOL will be measured by patient self-reporting using the EuroQol 5 dimensions of health questionnaire. Secondary outcomes include fatigue, insomnia, and depression. Finally, four process evaluation outcomes will also be observed, namely feasibility, fidelity, and acceptability, along with implementation barriers and facilitators. DiscussionData will be collected to observe the effects of GA + M and RSM on QOL and toxicities experienced by older adults receiving ARATs for metastatic prostate cancer. Data will also be collected to help the design and conduct of a definitive multicentre phase III randomized controlled trial. This study will extend supportive care interventions for older adults with cancer into new areas and inform the design of larger trials.Trial registration: The trial is registered at clinicaltrials.gov (registration number: NCT05582772).

Feasibility study of a multimodal prehabilitation programme in women receiving neoadjuvant therapy for breast cancer in a major cancer hospital: a protocol

IntroductionNeoadjuvant therapy has become a standard treatment for patients with stage II/III HER2 positive and triple negative breast cancer, and in well-selected patients with locally advanced and borderline resectable high...

Efficacy and safety of bispecific antibodies therapy for relapsed or refractory multiple myeloma: a systematic review and meta-analysis of prospective clinical trials.

Bispecific antibody (BsAbs) therapy represents a promising immunotherapeutic approach with manageable toxicity and noteworthy preliminary efficacy in treating patients with relapsed or refractory multiple myeloma (RRMM). The objective of this systematic review and meta-analysis was to compare the efficacy and safety of B-cell maturation antigen (BCMA)-targeted BsAbs and non-BCMA-targeted BsAbs in the treatment of RRMM patients. PubMed/MEDLINE, Web of Science, EMBASE, Cochrane Library and meeting libraries were searched from inception to August 16th, 2023. The efficacy evaluation included the complete objective response rate (ORR), complete response (CR) rate, stringent CR (sCR) rate, partial response (PR) rate, and very good PR (VGPR) rate. The efficacy evaluation included any grade adverse events (AEs) and grade ≥ 3 AEs. Fourteen studies with a total of 1473 RRMM patients were included. The pooled ORR of the entire cohort was 61%. The non-BCMA-targeted BsAbs group displayed a higher ORR than the BCMA-targeted BsAbs group (74% vs. 54%, P < 0.01). In terms of hematological AEs, BCMA-targeted BsAbs therapy exhibited higher risks of neutropenia (any grade: 48% vs. 18%, P < 0.01; grade ≥ 3: 43% vs. 15%, P < 0.01) and lymphopenia (any grade: 37% vs. 8%, P < 0.01; grade ≥ 3: 31% vs. 8%, P = 0.07). Regarding non-hematological AEs, there were no significant differences in the risks of cytokine release syndrome (CRS, any grade: 64% vs. 66%, P = 0.84; grade ≥ 3: 1% vs. 1%, P = 0.36) and infections (any grade: 47% vs. 49%, P = 0.86; grade ≥ 3: 24% vs. 20%, P = 0.06) between the two groups. However, non-BCMA-targeted BsAbs therapy was associated with a higher risk of immune effector cell-associated neurotoxicity syndrome (ICANS, any grade: 11% vs. 2%, P < 0.01) and lower risks of fatigue (any grade: 14% vs. 30%, P < 0.01) and pyrexia (any grade: 14% vs. 29%, P < 0.01). This analysis suggest that non-BCMA-targeted BsAbs therapy may offer a more favorable treatment response and tolerability, while BCMA-targeted BsAbs therapy may be associated with diminished neurotoxic effects. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42018090768.

Targeting natural killer cells: from basic biology to clinical application in hematologic malignancies.

Natural killer (NK) cell belongs to innate lymphoid cell family that contributes to host immunosurveillance and defense without pre-immunization. Emerging studies have sought to understand the underlying mechanism behind NK cell dysfunction in tumor environments, and provide numerous novel therapeutic targets for tumor treatment. Strategies to enhance functional activities of NK cell have exhibited promising efficacy and favorable tolerance in clinical treatment of tumor patients, such as immune checkpoint blockade (ICB), chimeric antigen receptor NK (CAR-NK) cell, and bi/trispecific killer cell engager (BiKE/TriKE). Immunotherapy targeting NK cell provides remarkable advantages compared to T cell therapy, including a decreased rate of graft versus-host disease (GvHD) and neurotoxicity. Nevertheless, advanced details on how to support the maintenance and function of NK cell to obtain better response rate and longer duration still remain to be elucidated. This review systematically summarizes the profound role of NK cells in tumor development, highlights up-to-date advances and current challenges of therapy targeting NK cell in the clinical treatment of hematologic malignancies.

Drug-Loaded Bacillus Calmette-Guérin Bacteria for Immuno-Chemo Combo Therapy in Bladder Cancer.

Intravesical Bacillus Calmette-Guérin (BCG) is a well-established strategy for managing high-risk nonmuscle-invasive bladder cancer (NMIBC); however, over half of patients still experience disease recurrence or progression. Although the combined intravesical instillation of various chemotherapeutic drugs is implemented in clinical trials to enhance the BCG therapy, the outcome is far from satisfying due to severe irritative effects and treatment intolerance at high doses. Therefore, it is adopted the "biotin-streptavidin strategy" to doxorubicin (DOX)-encapsulated nanoparticles within live BCG bacteria (DOX@BCG) to improve treatment outcomes. Adherence of BCG to the bladder epithelium helps precisely target DOX@BCG to the local tumor cells and simultaneously increases intratumoral transport of therapeutic drugs. DOX@BCG effectively inhibits cancer progression and prolongs the survival of rats/mice with orthotopic bladder cancer owing to synergism between BCG-immunotherapy, DOX-chemotherapy, and DOX-induced immunogenic tumor cell death; furthermore, it exhibits improved tolerance and biosafety, and establishes antitumor immunity in the tumor microenvironment. Therefore, the drug-loaded live BCG bacterial delivery system holds considerable potential for clinical translation in the intravesical treatment of bladder cancer.

Long-term safety and tolerability of ambrisentan treatment for pediatric patients with pulmonary arterial hypertension: An open-label extension study

This open-label, extension study assessed long-term safety, tolerability, and efficacy of ambrisentan in a pediatric population (age 8– < 18 years) with pulmonary arterial hypertension (PAH). Following completion of a 6-month, randomized study, participants entered the long-term extension at individualized ambrisentan dosages (2.5/5/7.5 or 10 mg/day). Safety assessments included adverse events (AEs), AEs of special interest, and serious AEs (SAEs); efficacy outcomes included 6-min walking distance (6MWD) and World Health Organization functional class (WHO FC). Thirty-eight of 41 (93%) randomized study participants entered the extension; 21 (55%) completed (reaching age 18 years). Most participants received concomitant phosphodiesterase-5 inhibitors (n = 25/38, 66%). Median ambrisentan exposure was 3.5 years. Most participants experienced ≥ 1 AE (n = 34/38, 89%), and 21 (55%) experienced SAEs, most commonly worsening PAH (n = 3/38, 8%), acute cardiac failure, pneumonia, or anemia (n = 2/38; 5% each); none considered ambrisentan-related. Seven participants (18%) died, with recorded reasons (MedDRA preferred term): cardiac failure (n = 2), PAH (n = 2), COVID-19 (n = 1), acute right ventricular failure (n = 1), and failure to thrive (n = 1); median time to death: 5.2 years. Anemia and hepatotoxicity AEs were generally mild to moderate and did not require ambrisentan dose adjustment. Assessed at study end in 29 participants (76%), mean 6MWD improved by 17% (standard deviation: 34.3%), and all (29/29, 100%) had improved or unchanged WHO FC. Conclusion: Long-term weight-based ambrisentan dosing, alone or combined with other PAH therapies in children with PAH aged 8– < 18 years, exhibited tolerability and clinical improvements consistent with prior randomized study results. Trial registration: NCT01342952, April 27, 2011.What is Known:•The endothelin receptor antagonist, ambrisentan, is indicated for treatment of pulmonary arterial hypertension (PAH). Previous studies have shown similar efficacy and tolerability in pediatric patients as in adults.What is New:• This open-label extension study assessed the long-term use of ambrisentan in pediatric patients (8–<18 years) with PAH, most of whom were also receiving recommended background PAH treatment. • Weight-based dosing of ambrisentan, given alone or in combination with other PAH therapies, was well tolerated with clinical improvements consistent with prior randomized study results.

Primary Treatment Modification and Treatment Tolerability Among Older Chemotherapy Recipients With Advanced Cancer

Older adults with advanced cancer are less likely to tolerate treatment with cytotoxic chemotherapy compared with younger patients due to their aging-related conditions. Hence, oncologists sometimes opt to employ primary treatment modifications (deviation from standard of care) during the first cycle of chemotherapy. To examine the association between primary treatment modification and treatment tolerability in older adults with advanced cancer who were starting new palliative chemotherapy regimens. This cohort study was a secondary analysis of the GAP70+ (Geriatric Assessment Intervention for Reducing Toxicity in Older Patients with Advanced Cancer) trial, which was conducted between July 2014 and March 2019. The GAP70+ trial included patients aged 70 years or older who had advanced (ie, incurable) cancer, had 1 or more geriatric assessment domain impairments, and planned to start a new palliative chemotherapy regimen. Data analysis was conducted in November 2022. Receipt of standard-of-care chemotherapy regimens vs primary treatment modification defined as any change from National Comprehensive Cancer Network guidelines or published clinical trials (eg, primary dose reduction, schedule change). Tolerability outcomes were assessed within 3 months of treatment. These outcomes included the following: (1) any grade 3 to 5 toxic effect, according to the National Cancer Institute Common Terminology Criteria for Adverse Events; (2) patient-reported functional decline, defined as the development of worse dependency in activities of daily living using scale scores; and (3) a composite adverse outcome (an end point that combined toxic effects, functional decline, and 6-month overall survival). Multivariable cluster-weighted generalized estimating equation models examined the association between primary treatment modification and outcomes adjusting for covariates. This study included 609 patients with a mean (SD) age of 77.2 (5.2) years; more than half (333 [54.7%]) were men. Race and ethnicity was available for 607 patients: 39 (6.4%) were Black, 539 (88.5%) were non-Hispanic White, and 29 (4.8%) were of other race or ethnicity. Nearly half (281 [46.1%]) received a primary modified treatment regimen. The most common cancer types were gastrointestinal cancer (228 [37.4%]) and lung cancer (174 [28.6%]). In multivariable analysis, primary treatment modification was associated with a reduced risk of grade 3 to 5 toxic effects (relative risk [RR], 0.85 [95% CI, 0.77-0.94]) and functional decline (RR, 0.80 [95% CI, 0.67-0.95]). Patients who received primary treatment modification had 32.0% lower odds of having a worse composite adverse outcome (odds ratio, 0.68 [95% CI, 0.48-0.97]). In this cohort study, primary treatment modification was associated with improved tolerability of chemotherapeutic regimens among older adults with advanced cancer and aging-related conditions. These findings may help optimize cancer treatment dosing in older adults with advanced cancer and aging-related conditions.