Citations

Abstract The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P ≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P ≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.

Abstract Purpose: Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in KIT/PDGFRA and are initially responsive to tyrosine kinase inhibitors (TKI). The acquisition of secondary mutations leads to refractory/relapsed disease. This study reports the results of an analysis from the phase III INVICTUS study (NCT03353753) characterizing the genomic heterogeneity of tumors from patients with advanced GIST and evaluating ripretinib efficacy across KIT/PDGFRA mutation subgroups. Patients and Methods: Tumor tissue and liquid biopsy samples that captured circulating tumor DNA were collected prior to study enrollment and sequenced using next-generation sequencing. Subgroups were determined by KIT/PDGFRA mutations and correlation of clinical outcomes and KIT/PDGFRA mutational status was assessed. Results: Overall, 129 patients enrolled (ripretinib 150 mg once daily, n = 85; placebo, n = 44). The most common primary mutation subgroup detected by combined tissue and liquid biopsies were in KIT exon 11 (ripretinib, 61.2%; placebo, 77.3%) and KIT exon 9 (ripretinib, 18.8%; placebo, 15.9%). Patients receiving ripretinib demonstrated progression-free survival (PFS) benefit versus placebo regardless of mutation status (HR 0.16) and in all assessed subgroups in Kaplan–Meier PFS analysis (exon 11, P < 0.0001; exon 9, P = 0.0023; exon 13, P < 0.0001; exon 17, P < 0.0001). Among patients with wild-type KIT/PDGFRA by tumor tissue, PFS ranged from 2 to 23 months for ripretinib versus 0.9 to 10.1 months for placebo. Conclusions: Ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were previously treated with three or more TKIs.

Pregnancy loss affects approximately 20% of couples. The lack of a clear cause complicates half of all miscarriages. Early evidence indicates the maternal immune system and angiogenesis regulation are both key players in implantation success or failure. Therefore, this prospective study recruited women in the first trimester with known viable intrauterine pregnancy and measured blood levels of immune tolerance proteins galectin-9 (Gal-9) and interleukin (IL)-4, and angiogenesis proteins (vascular endothelial growth factors (VEGF) A, C, and D) between 5 and 9 weeks gestation. Plasma concentrations were compared between groups defined based on (a) pregnancy outcome and (b) maternal history of miscarriage, respectively. In total, 56 women were recruited with 10 experiencing a miscarriage or pregnancy loss in the 2nd or 3rd trimester and 11 having a maternal history or miscarriage. VEGF-C was significantly lower among women with a miscarriage or pregnancy loss. Gal-9 and VEGF-A concentrations were decreased in women with a prior miscarriage. Identification of early changes in maternal immune and angiogenic factors during pregnancy may be a tool to improve patient counseling on pregnancy loss risk and future interventions to reduce miscarriage in a subset of women.

Purpose: To review the current options in the management of Warthin tumors (WTs) and to propose a working management protocol. Methods: A systematic literature search was conducted using PubMed and ScienceDirect database. A total of 141 publications were selected and have been included in this review. Publications were selected based on relevance, scientific evidence, and actuality. Results: The importance of parotid WTs is increasing due to its rising incidence in many countries, becoming the most frequently encountered benign parotid tumor in certain parts of the world. In the past, all WTs were treated with surgery, but because of their slow growth rate, often minimal clinical symptoms, and the advanced age of many patients, active observation has gradually become more widely used. In order to decide on active surveillance, the diagnosis of WT must be reliable, and clinical, imaging, and cytological data should be concordant. There are four clear indications for upfront surgery: uncertain diagnosis; cosmetic problems; clinical complaints, such as pain, ulceration, or recurrent infection; and the patient’s wish to have the tumor removed. In the remaining cases, surgery can be elective. Active surveillance is often suggested as the first approach, with surgery being considered if the tumor progresses and/or causes clinical complaints. The extent of surgery is another controversial topic, and the current trend is to minimize the resection using partial parotidectomies and extracapsular dissections when possible. Recently, non-surgical options such as microwave ablation, radiofrequency ablation, and ultrasound-guided ethanol sclerotherapy have been proposed for selected cases. Conclusions: The management of WT is gradually shifting from superficial or total parotidectomy to more conservative approaches, with more limited resections, and to active surveillance in an increasing number of patients. Additionally, non-surgical treatments are emerging, but their role needs to be defined in future studies.

Abstract Background Ripretinib 150 mg once daily (QD) is indicated for advanced gastrointestinal stromal tumors (GISTs) as at least fourth-line therapy. In INVICTUS, ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. was allowed after progressive disease (PD) on 150 mg QD by blinded independent central review using modified RECIST 1.1. We report the efficacy and safety of ripretinib IPDE to 150 mg b.i.d. after PD among patients randomized to ripretinib 150 mg QD in the INVICTUS study. Materials and Methods Tumor imaging was performed every 28-day cycle for the first four cycles in the ripretinib 150 mg QD period and then every other cycle, including the 150 mg b.i.d. period. Among the ripretinib IPDE patients, progression-free survival (PFS)1 was the time from randomization until PD; PFS2 was the time from the first dose of ripretinib 150 mg b.i.d. to PD or death. Results Among 43 ripretinib IPDE patients, median PFS1 was 4.6 months (95% confidence interval [CI], 2.7–6.4) and median PFS2 was 3.7 months (95% CI, 3.1–5.3). Median overall survival was 18.4 months (95% CI, 14.5–not estimable). Ripretinib 150 mg b.i.d. (median duration of treatment 3.7 months) was well tolerated with new or worsening grade 3–4 treatment-emergent adverse events (TEAEs) of anemia in six (14%) and abdominal pain in three (7%) patients. Ripretinib 150 mg b.i.d. was discontinued because of TEAEs in seven (16%) patients. Conclusion Ripretinib 150 mg b.i.d. after PD on 150 mg QD may provide additional clinically meaningful benefit with an acceptable safety profile in patients with at least fourth-line GISTs. Implications for Practice Of the 85 patients with advanced gastrointestinal stromal tumor having received at least three prior anticancer therapies randomized to ripretinib 150 mg once daily (QD) in the phase III INVICTUS study, 43 underwent ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. after progressive disease (PD). Median progression-free survival was 4.6 months before and 3.7 months after ripretinib IPDE. The safety profile of ripretinib 150 mg b.i.d. was acceptable. These findings indicate ripretinib IPDE to 150 mg b.i.d. may provide additional clinical benefit in patients with PD on ripretinib 150 mg QD, for whom limited treatment options exist.

To determine the effect of Trendelenburg position on the diameter or cross-section area of the internal jugular vein (IJV) a systematic review and metanalysis was performed. Studies that evaluated the cross-sectional area (CSA) and anteroposterior (AP) diameter of the right internal jugular vein (RIJV) with ultrasonography in supine and any degree of head-down tilt (Trendelenburg position) were analyzed. A total of 22 articles (613 study subjects) were included. A >5° Trendelenburg position statistically increases RIJV CSA and AP diameter. Further inclination from 10° does not statistically benefit IJV size. This position should be recommended for CVC placement, when patient conditions allow it, and US-guided cannulation is not available.

AbstractProblemCell‐free fetal DNA (cffDNA) shed from the placenta can be detected in maternal blood and increases incrementally during gestation. Concentrations are further elevated with pregnancy complications. Specific activators of cffDNA release in such complications have not been identified. Here, we use trophoblast cells from early and term placenta to examine cffDNA release following apoptosis, infection, and sterile inflammatory stress.Method of StudyHTR8/SVneo cells were used to model first‐trimester trophoblasts, and term cytotrophoblasts (CTBs) were isolated from placentae collected after uncomplicated deliveries. Trophoblasts were treated with varying concentrations of doxorubicin (DOX), lipopolysaccharide (LPS), or high‐mobility group box protein 1 (HMGB1) for 18 h. Cells or supernatants were quantified for caspase‐3/7 cleavage, pro‐inflammatory cytokine secretion, and cffDNA release.ResultsBoth HTR8/SVneo and CTBs underwent caspase‐3/7 cleavage following DOX treatment, with HTR8/SVneo cells more sensitive to apoptosis than term CTBs. Apoptotic cells released more cffDNA in a dose‐dependent manner. Treatment with LPS resulted in an increase in pro‐inflammatory IL‐6 release, particularly in term CTBs compared to early trophoblasts; however, LPS did not affect cffDNA release. Lastly, while neither cell released more TNF‐α following stimulation with HMGB1, both HTR8/SVneo and CTBs released significantly more cffDNA in the presence of HMGB1.ConclusionsThese data show that apoptosis and sterile inflammation induced by DOX and HMGB1, respectively, cause an increase in cffDNA concentrations in both first‐trimester and term trophoblasts. Understanding physiologic release of cffDNA during healthy and complicated pregnancy can identify new targets for the diagnosis and treatment of gestational complications.