A phase Ib randomized multicenter trial of isolated hepatic perfusion in combination with ipilimumab and nivolumab for uveal melanoma metastases (SCANDIUM II trial).

BACKGROUND: Uveal melanoma (UM) is a rare malignancy where 50% of patients develop metastatic disease primarily affecting the liver. Approximately 40% of patients with metastatic UM respond to one-time isolated hepatic perfusion (IHP) with high-dose melphalan. This phase I trial investigates the safety and clinical efficacy of IHP combined with ipilimumab (IPI) and nivolumab (NIVO). PATIENTS AND METHODS: Immunotherapy-naïve patients were randomized in this phase I trial to receive either IHP followed by IPI 3 mg/kg and NIVO 1 mg/kg (IPI3/NIVO1) for four cycles (post-operative arm), or one cycle of preoperative IPI3/NIVO1, IHP and then three cycles of IPI3/NIVO1 (pre-post-operative arm), followed by maintenance therapy with NIVO 480 mg for 1 year. RESULTS: Eighteen patients were enrolled and randomized. Three patients did not undergo IHP as planned. In total, 11/18 patients (6 in the post-operative arm and 5 in the pre-post-operative arm) did not complete the planned four cycles of IPI3/NIVO1. Toxicity to IHP was similar in both groups, but the number of immune-related adverse events (AEs) was higher in the pre-post-operative arm. Among assessable patients, overall response rate was 57% in the post-operative arm (4/7) and 22% in the pre-post-operative arm (2/9). CONCLUSIONS: Combination therapy with IHP and IPI3/NIVO1 was associated with severe AEs. The efficacy of this combination is encouraging with high response rates. One cycle of preoperative IPI/NIVO before IHP did not show potential benefits in terms of safety or efficacy.

The efficacy of immune checkpoint blockade for melanoma in-transit with or without nodal metastases - A multicenter cohort study.

PURPOSE: Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics. METHODS: A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions. RESULTS: A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4-12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively. CONCLUSION: Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.

Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia.

PURPOSE: Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. METHODS: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. RESULTS: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). CONCLUSION: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 × 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 × 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10(-4)), COPD (OR=3.22, P=2.9 × 10(-4)), PAD (OR=3.47, P=9.2 × 10(-3)) and AAA (OR=6.44, P=6.3 × 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10(-5)), particularly for early-onset cases (P=2.1 × 10(-7)). Our results are in agreement with functional studies showing that the human α4ß2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

Altered activity of the serratus anterior during unilateral arm elevation in patients with cervical disorders.

Altered activity in the axioscapular muscles is considered to be an important feature in patients with neck pain. The activity of the serratus anterior (SA) and trapezius muscles during arm elevation has not been investigated in these patients. The objectives of this study was to investigate whether there is a pattern of altered activity in the SA and trapezius in patients with insidious onset neck pain (IONP) (n=22) and whiplash associated disorders (WAD) (n=27). An asymptomatic group was selected for baseline measurements (n=23). Surface electromyography was used to measure the onset of muscle activation and duration of muscle activity of the SA as well as the upper, middle, and lower trapezius during unilateral arm elevation in the three subject groups. Both arms were tested. With no interaction, the main effect for the onset of muscle activation and duration of muscle activity for serratus anterior was statistically significant among the groups. Post hoc comparison revealed a significantly delayed onset of muscle activation and less duration of muscle activity in the IONP group, and in the WAD group compared to the asymptomatic group. There were no group main effects or interaction effects for upper, middle and lower trapezius. This finding may have implications for scapular stability in these patients because the altered activity in the SA may reflect inconsistent or poorly coordinated muscle activation that may reduce the quality of neuromuscular performance and induce an increased load on the cervical and the thoracic spine.

Lentivirus gene transfer in murine hematopoietic progenitor cells is compromised by a delay in proviral integration and results in transduction mosaicism and heterogeneous gene expression in progeny cells.

Human immunodeficiency virus type 1-based lentivirus vectors containing the green fluorescent protein (GFP) gene were used to transduce murine Lin(-) c-kit(+) Sca1(+) primitive hematopoietic progenitor cells. Following transduction, the cells were plated into hematopoietic progenitor cell assays in methylcellulose and the colonies were scored for GFP positivity. After incubation for 20 h, lentivirus vectors transduced 27.3% +/- 6.7% of the colonies derived from unstimulated target cells, but transduction was more efficient when the cells were supported with stem cell factor (SCF) alone (42. 0% +/- 5.5%) or SCF, interleukin-3 (IL-3), and IL-6 (53.3 +/- 1.8%) during transduction. The, vesicular stomatitis virus glycoprotein-pseudotyped MGIN oncoretrovirus control vector required IL-3, IL-6, and SCF for significant transduction (39.3 +/- 9.4%). Interestingly, only a portion of the progeny cells within the lentivirus-transduced methylcellulose colonies expressed GFP, in contrast to the homogeneous expression in oncoretrovirus-transduced colonies. Secondary plating of the primary GFP(+) lentivirus vector-transduced colonies revealed vector PCR(+) GFP(+) (42%), vector PCR(-) GFP(-) (46%), and vector PCR(+) GFP(-) (13%) secondary colonies, indicating true genetic mosaicism with respect to the viral genome in the progeny cells. The degree of vector mosaicism in individual colonies could be reduced by extending the culture time after transduction and before plating into the clonal progenitor cell assay, indicating a delay in the lentiviral integration process. Furthermore, supplementation with exogenous deoxynucleoside triphosphates during transduction decreased mosaicism within the colonies. Although cytokine stimulation during transduction correlates with higher transduction efficiency, rapid cell division after transduction may result in loss of the viral genome in the progeny cells. Therefore, optimal transduction may require activation without promoting intense cell proliferation prior to vector integration.

Pain management practices in children after surgery.

The purpose of this study was to describe the current practice of prescription and administration of pain medication postoperatively to infants and children in the National University Hospital in Iceland to determine whether these patients received therapeutic doses of pain medication. The results in this study support that pain management of infants and children is inadequate. In this retrospective chart review, 38% of the pain medication prescriptions were in therapeutic range. Forty-one percent were below, and 21% were above therapeutic range. Of the administered pain medication doses, 32% were in therapeutic range. Twenty-two percent were below, and 46% were above therapeutic range.

[Views of Icelandic physicians and nurses towards limitation of treatment at the end of life.].

With increasingly advanced life-prolonging technology, the issue of when and how treatment should be limited becomes ever more important. To shed a light on the views of Icelandic physicians and registered nurses a survey was conducted at the Reykjavik Hospital and the National University Hospital. A questionnaire was sent to 184 doctors and 239 nurses. They were asked to respond to several ethical dilemmas regarding limitation of treatment at the end of life. Special emphasis was placed on respect for the patient's autonomy and communication. There were 234 (55%) answers retrieved. The general view was that one should respect patient's autonomy and honor the wish to deny life-prolonging measures. Cost could be an issue in such decisions according to 35% of physicians and 15% of nurses. Under certain conditions, euthanasia could be justified according to five (5%) physicians and 11 (9%) nurses, although only four (2%) could consider themselves as participating in such an act. The majority, 201/230 (87%), supported using written guidelines within hospitals regarding decision-making process in limiting treatment at the end of life. In a case of a dispute between patients or families and health care professionals, 49% of physicians and 84% of nurses were willing to take it to a multidisciplinary ethical committee at the hospital. In a case of a dispute between health care professionals 62% of physicians and 50% of nurses were willing to take it to the Director General of Health.

Psychosocial issues following serious head injury: a case study of an adolescent girl.

This article is a case study of an adolescent girl who sustained a serious head injury following an attack by strangers. The head injury caused an epidural hemorrhage that exerted pressure on her brain stem and resulted in spastic quadriplegia. In this case, the major issues in rehabilitation were the patient's ability to learn to communicate and normalize and gain control over various aspects of her life. Because of the lack of a specialized rehabilitation setting for children and adolescents, rehabilitation took place in an acute care setting, which makes this story unusual in many ways. Staff issues were significant because of the nurses' inexperience with rehabilitation issues and because of the setting. This article describes the primary nurse's experience with this patient over several months. During this phase of rehabilitation, psychosocial issues were a major concern. Fifteen months after rehabilitation began, the patient moved back home and returned to high school. She communicates by using a computer and by using her eyes, and she uses a wheelchair. Despite everything, she is determined to get better and to prepare herself for the future.