Iatrogenic injury of the ureters is a feared complication of abdominal surgery. Zwitterionic near-infrared fluorophores are molecules with geometrically-balanced, electrically-neutral surface charge, ...which leads to renal-exclusive clearance and ultralow non-specific background binding. Such molecules could solve the ureter mapping problem by providing real-time anatomic and functional imaging, even through intact peritoneum. Here we present the first-in-human experience of this chemical class, as well as the efficacy study in patients undergoing laparoscopic abdominopelvic surgery. The zwitterionic near-infrared fluorophore ZW800-1 is safe, has pharmacokinetic properties consistent with an ideal blood pool agent, and rapid elimination into urine after a single low-dose intravenous injection. Visualization of structure and function of the ureters starts within minutes after ZW800-1 injection and lasts several hours. Zwitterionic near-infrared fluorophores add value during laparoscopic abdominopelvic surgeries and could potentially decrease iatrogenic urethral injury. Moreover, ZW800-1 is engineered for one-step covalent conjugatability, creating possibilities for developing novel targeted ligands.
Background
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy ...and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
Methods
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6–8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
Results
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6–69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
Conclusions
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Percutaneous hepatic perfusion with melphalan (M-PHP) is increasingly used in patients with liver metastases from various primary tumors, yet data on colorectal liver metastases (CRLM) are limited. ...The aim of this study was to prospectively evaluate the efficacy and safety of M-PHP in patients with CRLM.
Prospective, single-center, single-arm phase II study of M-PHP with hemofiltration in patients with unresectable CRLM. Proven, extrahepatic metastatic disease was one of the exclusion criteria. Primary outcomes were overall response rate (ORR) and best overall response (BOR). Secondary outcomes were overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
A total of 14 M-PHP procedures were performed in eight patients between March 2014 and December 2015. All patients (median age 56 years, ranging from 46 to 68) had received (extensive) systemic chemotherapy before entering the study. The ORR was 25.0%, with two out of eight patients showing partial response as BOR. Median OS was 17.3 months (ranging from 2.6 to 30.9) with a one-year OS of 50.0%. Median PFS and hPFS were 4.4 and 4.5 months, respectively. No serious adverse events occurred. Grade 3/4 hematologic adverse events were observed in the majority of patients, though all were transient and well-manageable.
M-PHP is a safe procedure with only limited efficacy in patients with unresectable CRLM who already showed progression of disease after receiving one or more systemic treatment regimens.
Incomplete oncologic resections and damage to vital structures during colorectal cancer surgery increases morbidity and mortality. Moreover, neoadjuvant chemoradiotherapy has become the standard ...treatment modality for locally advanced rectal cancer, where subsequent downstaging can make identification of the primary tumor more challenging during surgery. Near-infrared (NIR) fluorescence imaging can aid surgeons by providing real-time visualization of tumors and vital structures during surgery.
We present the first-in-human clinical experience of a novel NIR fluorescent peptide, cRGD-ZW800-1, for the detection of colon cancer. cRGD-ZW800-1 was engineered to have an overall zwitterionic chemical structure and neutral charge to lower nonspecific uptake and thus background fluorescent signal. We performed a phase I study in 11 healthy volunteer as well as a phase II feasibility study in 12 patients undergoing an elective colon resection, assessing 0.005, 0.015, and 0.05 mg/kg cRGD-ZW800-1 for the intraoperative visualization of colon cancer.
cRGD-ZW800-1 appears safe, and exhibited rapid elimination into urine after a single low intravenous dose. Minimal invasive intraoperative visualization of colon cancer through full-thickness bowel wall was possible after an intravenous bolus injection of 0.05 mg/kg at least 2 hours prior to surgery. Longer intervals between injection and imaging improved the tumor-to-background ratio.
cRGD-ZW800-1 enabled fluorescence imaging of colon cancer in both open and minimal invasive surgeries. Further development of cRGD-ZW800-1 for widespread use in cancer surgery may be warranted given the ubiquitous overexpression of various integrins on different types of tumors and their vasculature.
Summary Background & aims Glutamine supplementation in the neonatal period has been associated with increased brain structure volumes at school-age in very preterm children. The aim of this study was ...to clarify the emergence and specificity of differences in brain structure volumes, using growth trajectories of head circumference, weight, and length. Methods Sixty-five very preterm (<32 weeks gestation) children, who originally took part in a randomized controlled trial on glutamine supplementation, participated. Head circumference, weight, and length, were measured at the neonatal intensive care unit, and at routine follow-up assessments at the outpatient clinic and well baby clinics. Magnetic Resonance Imaging was used to determine brain structure volumes at school-age. Growth trajectories were investigated using multilevel modeling analyses. Results Head circumference in the first year of life was positively associated with white matter volume and grey matter volume (range r = 0.55–0.81, all p < 0.002) at school-age. Furthermore, neonatal glutamine supplementation was associated with increased head circumference growth ( p = 0.008) in the first year of life, but not with increased growth in weight ( p = 0.44) and length ( p = 0.73). Conclusions This study indicates a specific increase in head circumference growth in very preterm children that received neonatal glutamine supplementation, and suggests that group differences in brain structure volumes at school-age may have emerged during the first year of life.
Background
Attention‐Deficit/Hyperactivity Disorder (ADHD) is a risk factor for substance use disorders (SUDs) and nicotine dependence (ND). Neurocognitive deficits may predict the increased risk of ...developing SUDs and nicotine dependence.
Methods
This study comprised three groups derived from the Dutch part of the International Multicenter ADHD Genetics (IMAGE) study: ADHD probands (n = 294), unaffected siblings (n = 161), and controls (n = 214). At baseline (age = 12.2), a range of neurocognitive functions was assessed including executive functions (inhibition, working memory, timing), measures of motor functioning (motor timing and tracking) and IQ. After a mean follow‐up of 4.2 years, SUDs and ND were assessed.
Results
None of the neurocognitive functions predicted later SUDs or ND in ADHD probands, even after controlling for medication use and conduct disorder. Slower response inhibition predicted later nicotine dependence in unaffected siblings (OR = 2.06, 95% CI = 1.22–3.48), and lower IQ predicted increased risk for SUDs in controls (OR = 1.96, 95% CI = 1.12–3.44).
Conclusions
Cold executive functions, motor functioning, and IQ did not predict the elevated risk of SUDs and ND in ADHD. Future studies should target ‘hot’ executive functions such as reward processing as risk factors for SUDs or ND.
Aim
To examine visual sensory and perceptive functions, study their interrelations, and explore associations between visual dysfunctions and intelligence in very preterm/very‐low‐birthweight ...(VP/VLBW) children.
Method
One‐hundred and sixteen VP/VLBW children (57 males, 59 females; mean gestational age 30.1wks, SD 2.3; mean corrected age 5y 6mo, SD 1mo) and 73 term‐born children (40 males, 33 females; mean gestational age 39.9wks, SD 1.3; mean age 5y 6mo, SD 3mo) completed visual sensory (acuity, visual field, contrast‐, color‐, and stereovision), perceptive (visual coherence, and Developmental Test of Visual Perception non‐motor scale), and intelligence assessments.
Results
Compared with term‐born children, VP/VLBW children had reduced acuity (d=0.70, p<0.001), inferior visual field (d=0.67, p<0.001), and stereovision (v=0.19, p=0.008). VP/VBLW children showed weaker static coherence (d=0.49, p=0.001) and Position in Space (d=0.41, p=0.006) performance, independent of visual sensory deficits, and showed lower Verbal IQ (VIQ) and Performance IQ (PIQ; p<0.001). Visual perceptive functioning accounted for 13% of variance in VIQ, and for 35% of variance in PIQ.
Interpretation
Visual sensory and perceptive dysfunctions are present in VP/VLBW children and occur largely independently of each other. Visual perceptive dysfunctions are moderately associated with PIQ, and weakly with VIQ.
What this paper adds
Preterm birth is associated with visual sensory and perceptive dysfunctions.
Visual sensory and perceptive dysfunctions occur independently of each other.
Visual sensory and perceptive functioning is moderately related to cognitive functioning.
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