tbuckley/cabot-search huggingface dataset:
Frailty in relapsed/ refractory multiple myeloma registration trials.
Authors: Meena N. Murugappan, Bellinda King-Kallimanis, Bindu Kanapuru, Ting-Yu Chen, Vishal Bhatnagar, Paul Gustav Kluetz
Journal: Journal of Clinical Oncology (2021)

e20017 Background: Multiple Myeloma (MM) is predominantly a disease of older adults with a median age of onset at 70 years. There is growing interest in using criterion other than chronological age, like frailty, to determine fitness for treatment and ultimately improve clinical outcomes in MM. Frailty is the accumulation of aging-associated diseases and disabilities, making patients more vulnerable to adverse outcomes when exposed to stressors like anti-cancer treatment. MM frailty measures have primarily been developed and tested in newly diagnosed patients. MM patients typically relapse, but there is limited knowledge regarding the prevalence of frailty in the relapsed/refractory (RRMM) setting. The aim of this research was to determine the prevalence of frailty in RRMM commercial clinical trials, at the time of trial enrollment, using the International Myeloma Working Group (IMWG) Frailty Index. Methods: We pooled baseline data from 6 RRMM clinical trials submitted for FDA regulatory review between 2010 and 2020. The IMWG Frailty Index was calculated for each patient based on 4 variables: age (≤75, 75–80, &gt;80 years, score 0, 1, 2, respectively), Charlson Comorbidity Index (CCI; ≤1 or ≥2, score 0 or 1), and (Instrumental) Activities Daily Living (ADL &gt;4 or ≤4, score 0 or 1; IADL &gt;5 or ≤5, score 0 or 1). As ADLs and IADLs are not routinely collected in clinical trials, we substituted this information with corresponding EQ-5D items on self-care and usual activities. Fit, Intermediate-fit, and Frail patients received IMWG scores of 0, 1, and ≥2 respectively. Descriptive statistics for frailty were summarized by age. Results: 2766 RRMM patients were aggregated from six clinical trials. 1502 (54%) patients were Fit, 780 (28%) were Intermediate-fit, and 484 (18%) were Frail. The median age of patients across trials was 65 [range 30-91]. The median CCI was 0 [range 0-7] out of 37. IMWG frailty scores have been presented by age category in Table. Prevalence of frailty at baseline by age in RRMM registration trials. Conclusions: Most patients in RRMM registration trials were classified as Fit at baseline, using the IMWG Frailty Index. This was expected due to stringent trial enrollment criteria which exclude patients with severe comorbidities, as reflected in the low average CCI. The IMWG index heavily weights patient age. As such, there were no Fit patients in the 75 – 80 year old cohort and only Frail patients in the 80+ year old cohort. This is despite the fact that these older patients met stringent trial enrollment criteria and had CCI scores &lt; 7. Chronologic age alone should not be used as an absolute exclusion for treatment, whether in the trial or real-world setting. Future research into frailty indices that do not heavily weight age is warranted.[Table: see text]
Oral etoposide in heavily pre-treated metastatic breast cancer: A retrospective study.
Authors: Agnieszka I. Jagiello-Gruszfeld, Malgorzata Meluch, Michal Kunkiel, Anna Gorniak, Anna Majstrak-Hulewska, Katarzyna Gorska, Aleksandra Konieczna, Zbigniew Nowecki
Journal: Journal of Clinical Oncology (2021)

e13070 Background: Patients with metastatic breast cancer can derive clinical benefit from several subsequent lines of chemotherapy. However, in heavily pre-treated patients, agents with clinical activity, a favourable side effects profile and a convenient administration modality are preferred. Oral etoposide may be an interesting treatment option in this group of patients. Methods: This was a retrospective observational study performed in single institution in 22 patients with MBC refractory to prior anthracycline, taxane, and capecitabine therapy. All patients were treated with oral etoposide at 50 mg/day on days 1-20. Treatment cycles were repeated every 28 days. Results: The median age were 53 years (42-68). The median number of previous chemotherapy lines was 5 (range 2-7). There were no complete or partial responses. Median PFS was 7 months. In 5 patients, the disease stabilized for over 12 months. Interestingly, etoposide activity was unrelated to the number of previous lines and type of metastatic involvement. Oral etoposide was well tolerated with only one patients discontinuing therapy due to toxicity. Conclusions: In real practice oral etoposide is a valuable and safe option for pre-treated metastatic breast cancer patients and might be considered in patients failing other approaches, but still suitable for chemotherapy.
Association of PTPN11 mutation with tumor mutation burden and survival in melanoma patients treated with immune checkpoint inhibitors.
Authors: De Long, Dandan Fan
Journal: Journal of Clinical Oncology (2021)

e21596 Background: Melanoma is a serious skin cancer. Immune checkpoint inhibitors (ICIs) have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. Mutations of PTPN11 (Protein Tyrosine Phosphatase, Non-receptor type11) have been reported to be associated with higher response rate and prolonged survival in advanced Renal Cell Carcinoma, Glioblastoma. The association between PTPN11 mutation and the efficacy of ICIs for melanoma is unknown. Methods: Genomic and survival data of melanoma patients administrated with ICIs were retrieved from publicly accessible data (Melanoma.Allen2015.WES.110) and the association between PTPN11 mutation and progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank tests. At the same time，the association between PTPN11 mutation with TMB was also analyzed in this public immunotherapy-treated cohort(Melanoma.Allen2015.WES.110), Wilcoxon test was used for the comparison of TMB. In addition, Genomic, immune cell infiltration data of 466 patients with Skin Cutaneous Melanoma (SKCM) was obtained from The Cancer Genome Atlas (TCGA). The correlation analysis between immune cell infiltration and PTPN11 mutation status was further analyzed by CIBERSORT. Statistical significance was set at p = 0.05. Results: 3.6% (4/110) patients in the clinical cohort harbored PTPN11 mutation. Survival analysis in the public cohort demonstrated that PTPN11 mutation resulted in significantly longer OS (33.6 vs 8.5 months; HR, 0.16; p = 0.037) and an increasing trend on PFS without significantly difference (9.1 vs 2.8 months; HR, 0.3; P = 0.078) in melanoma patients treated with ICIs. Moreover, PTPN11 mutation is associated with higher TMB in public cohort (p = 0.01). Furthermore, the correlation analysis between immune infiltration and PTPN11 mutation status in melanoma shows that M1 macrophages increased significantly (p = 0.0014), CD8 T cells, plasma B cells and activated NK cells also show an upward trend (p = 0.17, p = 0.17 and p = 0.19) while the resting NK cells decreased significantly (p = 0.016)in melanoma patients with PTPN11 mutation. Conclusions: This study shows that PTPN11 mutation may serve as a potential positive biomarker of ICIs in melanoma since it relatively correlated with higher TMB. In addition, the up regulation of M1 macrophages and the down regulation of resting NK cells may be a potential mechanism for the better efficacy of ICIs in patients with PTPN11 mutation.
Camrelizumab plus chemotherapy as neoadjuvant therapy for resectable, locally advanced esophageal squamous cell carcinoma (NIC-ESCC2019): A multicenter, open-label, single-arm, phase 2 study.
Authors: Jingpei Li, Jun Liu, Zhuoyi Li, Fei Cui, Yuan Zeng, Wenhua Liang, Hengrui Liang, Wei Wang, Ke Xu, Weipeng Cai, JunHui Fu, Jianxing He
Journal: Journal of Clinical Oncology (2021)

4028 Background: Despite multidisciplinary therapies, prognosis of pts with resectable esophageal squamous cell carcinoma (ESCC) remains poor. Combining PD-1 blockade to neoadjuvant chemotherapy might be a feasible and effective strategy. Camrelizumab (an anti-PD-1 antibody) was approved for advanced or metastatic ESCC in the second-line setting and showed improved anti-tumor activity and survival benefit when combined with chemotherapy in multiple advanced tumors. Methods: In this NIC-ESCC2019 phase 2 study, histologically or cytologically confirmed ESCC pts (stage II-IVA) were enrolled to receive two cycles of neoadjuvant chemoimmunotherapy (NIC) with camrelizumab (200 mg on day 1) plus nab-paclitaxel (260 mg/m² in total on day 1 and day 8) and cisplatin (75 mg/m² in total on days 1-3) of each 21-day cycle, followed by esophagectomy. The primary endpoint was complete pathologic response (CPR) rate in the primary tumor. Besides, we also explored the relationship between the tumor genomic profile or primary-tumor microenvironment and the pathological response. Results: Between Jan 17, 2020 and Dec 8, 2020, 56 pts were enrolled. 51 pts underwent surgical resection, and all had complete tumor resection. CPR was achieved in 18 (35.3%; 95% CI, 21.7%-48.9%) pts; 12 (23.5%) pts had major pathologic response (MPR), and 21 (41.2%) had incomplete pathological response (IPR). Of note, 16 (31.4%) pts achieved CPR in both primary tumor and lymph nodes. The objective response rate was 66.7% (95% CI, 40.0-70.4). No in-hospital mortality occurred. The most common treatment-related adverse events (TRAEs) were decreased WBC (20 [36%] of 56 pts), vomiting (19 [34%]), and alopecia (18 [32%]). Grade 3 TRAEs only occurred in 6 (11%) pts, and there were no grade 4 or 5 TRAEs. The most common immune-related AEs included grade 1-2 rash maculo-papular (7 [13%]) and reactive cutaneous capillary endothelial proliferation (5 [9%]). Presence of mutations in CREBBP and KMT2D at treatment-naïve time-point was correlated with non-response group (IPR and stable disease) (CREBBP, p = 0.046; KMT2D, p = 0.047). Among the immune populations, CD8+, CD8+PD-1+ and CD8+PD-L1+ T cells increased significantly after two doses of NIC, especially in the CPR+MPR group (CD8+, p = 0.013; CD8+PD-1+, p &lt; 0.001; CD8+PD-L1+, p = 0.068). Conclusions: The addition of camrelizumab to neoadjuvant chemotherapy in ESCC demonstrated promising efficacy with acceptable toxicity, supporting the further investigation in a randomized phase 3 clinical trial. Clinical trial information: NCT04225364. [Table: see text]
MYC- and MIZ1-Dependent Vesicular Transport of Double-Strand RNA Controls Immune Evasion in Pancreatic Ductal Adenocarcinoma
Authors: Bastian Krenz, Anneli Gebhardt-Wolf, Carsten P. Ade, Abdallah Gaballa, Florian Roehrig, Emilia Vendelova, Apoorva Baluapuri, Ursula Eilers, Peter Gallant, Luana D'Artista, Armin Wiegering, Georg Gasteiger, Mathias T. Rosenfeldt, Stefan Bauer, Lars Zender, Elmar Wolf, Martin Eilers
Journal: Cancer Research (2021)

Abstract Deregulated expression of the MYC oncoprotein enables tumor cells to evade immune surveillance, but the mechanisms underlying this surveillance are poorly understood. We show here that endogenous MYC protects pancreatic ductal adenocarcinoma (PDAC) driven by KRASG12D and TP53R172H from eradication by the immune system. Deletion of TANK-binding kinase 1 (TBK1) bypassed the requirement for high MYC expression. TBK1 was active due to the accumulation of double-stranded RNA (dsRNA), which was derived from inverted repetitive elements localized in introns of nuclear genes. Nuclear-derived dsRNA is packaged into extracellular vesicles and subsequently recognized by toll-like receptor 3 (TLR3) to activate TBK1 and downstream MHC class I expression in an autocrine or paracrine manner before being degraded in lysosomes. MYC suppressed loading of dsRNA onto TLR3 and its subsequent degradation via association with MIZ1. Collectively, these findings suggest that MYC and MIZ1 suppress a surveillance pathway that signals perturbances in mRNA processing to the immune system, which facilitates immune evasion in PDAC. Significance: This study identifies a TBK1-dependent pathway that links dsRNA metabolism to antitumor immunity and shows that suppression of TBK1 is a critical function of MYC in pancreatic ductal adenocarcinoma.
Sex-dependent compensatory mechanisms preserve blood pressure homeostasis in prostacyclin receptor–deficient mice
Authors: Soon Y. Tang, Hu Meng, Seán T. Anderson, Dimitra Sarantopoulou, Soumita Ghosh, Nicholas F. Lahens, Katherine N. Theken, Emanuela Ricciotti, Elizabeth J. Hennessy, Vincent Tu, Kyle Bittinger, Aalim M. Weiljie, Gregory R. Grant, Garret A. FitzGerald
Journal: Journal of Clinical Investigation (2021)

Inhibitors of microsomal prostaglandin E synthase 1 (mPGES-1) are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis, and fails to accelerate thrombogenesis, while suppressing prostaglandin E2 (PGE2), but increasing the biosynthesis of prostacyclin (PGI2). In low-density lipoprotein receptor-deficient (Ldlr-/-) mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE2 accounts for its antiatherogenic effect. However, the effect of mPges-1 depletion on blood pressure (BP) in this setting remains unknown. Here, we show that mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr-/- mice, whereas, despite the direct vasodilator properties of PGI2, deletion of the I prostanoid receptor (Ipr) suppressed this response. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1-/- mice. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high-salt diet (HSD). This is attributable to the protective effect of estrogen in Ldlr-/- mice and in Ipr-/- Ldlr-/- mice. Thus, estrogen compensates for a deficiency in PGI2 to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In male mice, by contrast, the augmented formation of atrial natriuretic peptide (ANP) plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hence, men with hyperlipidemia on a HSD might be at risk of a hypertensive response to mPGES-1 inhibitors.
IMMU-02. CH14.18 IN THE TREATMENT OF HIGH-RISK NEUROBLASTOMA: A META-ANALYSIS
Authors: Sameerah Abdel-Khaleq, Lina Alim, Atholl Johnston, Khloud Adam
Journal: Neuro-Oncology (2021)

Abstract High-risk neuroblastoma (HRNB) is a rare malignancy that mainly affects young children. Long-term survival remains low despite aggressive, multimodal treatment regimens. The aim is to assess the effect of Ch14.18, a novel anti-GD2 antibody, on survival in HRNB. In this meta-analysis, Pubmed/MEDLINE, EMBASE, Cochrane CENTRAL and Clinicaltrials.gov bibliographic databases were searched from inception to 1st July 2018. Prospective or retrospective interventional clinical trials with at least two arms or observational cohort or case-control studies were eligible. Participants had to have HRNB. Ch14.18 was the intervention of choice. Any control, comparator treatments were accepted. Studies were appraised for inclusion by two independent reviewers. Data was extracted from published reports. Primary outcomes assessed were Event-Free Survival (EFS) and Overall Survival (OS) and presented as Weighted Mean EFS (%) ± Standard Error (SE) and Weighted Mean OS (%) ± Standard Error (SE), respectively. Combined effect size was elicited for EFS±SE and OS±SE. The search yielded 367 results of which 7 studies conducted on 1727 patients were eligible for inclusion. The weighted mean EFS±SE for Ch14.18 regimens (n=779) and control regimens (n=787) were 55.6±2.0% and 41.2±1.7%, respectively. The weighted mean OS±SE for Ch14.18 regimens (n=430) and control regimens (n=348) were 63.4±2.3% and 53.6±2.7%, respectively. Results of the meta analysis yielded statistical power &amp;gt;94%. The combined effect size of Ch14.18 regimens for EFS±SE was 0.2907±0.05 [95% CI: 0.19–0.39, p&amp;lt;0.001] and the combined effect size for OS±SE was 0.26±0.07 [95% CI: 0.11- 0.4, p&amp;lt;0.001]. Significant superior survival outcomes were achieved with the use of Ch14.18 in the treatment of HRNB. These findings support using Ch14.18 as an adjunct in maintenance therapy in high-risk neuroblastoma. This meta analysis is the first of its kind. Survival outcomes are to be interpreted with caution due to confounding bias.
RATIONALE-307: Tislelizumab plus chemotherapy versus chemotherapy alone as first-line treatment for advanced squamous NSCLC in patients aged ≥ 65.
Authors: Jie Wang, Shun Lu, Xinmin Yu, Yanping Hu, Yuping Sun, Zhijie Wang, Jun Zhao, Yan Yu, Chunhong Hu, Kunyu Yang, Guosheng Feng, Kejing Ying, Wu Zhuang, Jianying Zhou, Jingxun Wu, Shiang Jiin Leaw, Jing Zhang, Xiao Lin, Nong Yang
Journal: Journal of Clinical Oncology (2021)

9102 Background: Tislelizumab is a humanized, monoclonal antibody with high affinity and specificity for the programmed cell death protein 1 (PD-1). It has demonstrated antitumor activity in advanced lung cancers. We conducted a Phase 3, multicenter, randomized open-label study (NCT03594747) to assess the safety and efficacy of tislelizumab plus chemotherapy in patients (pts) with advanced squamous NSCLC. As previously reported, tislelizumab (TIS) significantly improved progression free survival (PFS) and reduced the risk of progression. Here, we report results from a sub-group of pts aged ≥ 65 years. Methods: Eligible pts (aged 18-75 years) enrolled in China were treatment-naive for locally advanced or metastatic squamous NSCLC. Pts were stratified by disease stage (IIIB vs IV), and programmed death-ligand 1 (PD-L1) expression (&lt;1% vs 1-49% vs 50% tumor cells), and randomized 1:1:1 to Arm A: TIS 200 mg + paclitaxel (P) 175 mg/m 2 and carboplatin (C) area under the plasma concentration 5 (every 3 weeks [Q3W] on day 1); Arm B: TIS + nab-paclitaxel ( nab-P) 100 mg/m 2 (Q3W on days 1, 8 and 15) + C (Q3W on Day 1); or Arm C: P + C (Q3W on day 1). P, nab-P and C were administered for 4 to 6 cycles. TIS was administered until loss of benefit, withdrawal of consent or start of a new anticancer therapy. In this sub-group analysis, pts aged ≥ 65 years were evaluated according to the primary endpoint (PFS) and key secondary endpoints (objective response rate and safety). Results: Overall, 127 pts aged ≥ 65 years were randomized to receive treatment. Median age of pts aged ≥ 65 was 68.0 years and 120 pts (94.5%) were male. In total, 18 (46.2%), 20 (38.5%), and 34 (94.4%) pts in Arms A, B and C, respectively, had discontinued treatment. In Arm C 22/34 pts had completed chemotherapy. The primary and secondary endpoints, PFS and ORR, were longer and higher, respectively, in Arms A and B, compared with Arm C (Table). Grade ≥ 3 treatment related adverse events (TRAEs) occurred in 33 (84.6%), 44 (84.6%) and 28 (82.4%) pts aged ≥ 65 years in Arms A, B and C, respectively, compared with 103 (85.8%), 99 (83.9%) and 94 (80.3%) pts aged ≥ 18 years enrolled in the study. The most commonly reported TRAEs in pts aged ≥ 65 years were anemia, decrease in neutrophil count, and alopecia. Conclusions: In this sub-group analysis, PFS and ORR were longer and higher, respectively, with TIS in pts aged ≥ 65 years with advanced squamous NSCLC. The safety profile of TIS in pts aged ≥ 65 years was similar to the safety profile for all aged pts aged ≥ 18 years. Clinical trial information: NCT03594747. [Table: see text]
Endoscopic ultrasound-guided transportal cholangiography and jejunoduodenostomy to facilitate through-the-stent ERCP and transmural gallbladder drainage in Roux-en-Y gastrectomy
Authors: Esteban Fuentes-Valenzuela, Ramon Sanchez-Ocana, Carlos Chavarría, Carlos de la Serna-Higuera, Manuel Perez-Miranda
Journal: Endoscopy (2021)

Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS)-guided gallbladder drainage can be combined in one session [1] but remain challenging in postsurgical anatomy [2]. EUS-directed transgastric ERCP has led to favorable results in Roux-en-Y gastric bypass; several other through-the-stent endoscopic procedures are also possible in gastric bypass, including EUS [3]. ERCP may similarly be performed in Roux-en-Y hepaticojejunostomy by creating a fistula from the stomach or duodenum to the afferent limb using a lumen-apposing metal stent (LAMS) [4].
Bispecific Immunomodulatory Antibodies for Cancer Immunotherapy
Authors: Belén Blanco, Carmen Domínguez-Alonso, Luis Alvarez-Vallina
Journal: Clinical Cancer Research (2021)

Abstract The recent advances in the field of immuno-oncology have dramatically changed the therapeutic strategy against advanced malignancies. Bispecific antibody-based immunotherapies have gained momentum in preclinical and clinical investigations following the regulatory approval of the T cell–redirecting antibody blinatumomab. In this review, we focus on emerging and novel mechanisms of action of bispecific antibodies interacting with immune cells with at least one of their arms to regulate the activity of the immune system by redirecting and/or reactivating effector cells toward tumor cells. These molecules, here referred to as bispecific immunomodulatory antibodies, have the potential to improve clinical efficacy and safety profile and are envisioned as a second wave of cancer immunotherapies. Currently, there are more than 50 bispecific antibodies under clinical development for a range of indications, with promising signs of therapeutic activity. We also discuss two approaches for in vivo secretion, direct gene delivery, and infusion of ex vivo gene-modified cells, which may become instrumental for the clinical application of next-generation bispecific immunomodulatory antibodies.