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. Keywords: Immune checkpoint inhibitor; In-transit metastasis; Ipilimumab; Melanoma; Nivolumab; PD-1; Pembrolizumab

Treatment with Anti-HER2 Chimeric Antigen Receptor Tumor-Infiltrating Lymphocytes (CAR-TILs) Is Safe and Associated with Antitumor Efficacy in Mice and Companion Dogs

Patients with metastatic melanoma have a historically poor prognosis, but recent advances in treatment options, including targeted therapy and immunotherapy, have drastically improved the outcomes for some of these patients. However, not all patients respond to available treatments, and around 50% of patients with metastatic cutaneous melanoma and almost all patients with metastases of uveal melanoma die of their disease. Thus, there is a need for novel treatment strategies for patients with melanoma that do not benefit from the available therapies. Chimeric antigen receptor-expressing T (CAR-T) cells are largely unexplored in melanoma. Traditionally, CAR-T cells have been produced by transducing blood-derived T cells with a virus expressing CAR. However, tumor-infiltrating lymphocytes (TILs) can also be engineered to express CAR, and such CAR-TILs could be dual-targeting. To this end, tumor samples and autologous TILs from metastasized human uveal and cutaneous melanoma were expanded in vitro and transduced with a lentiviral vector encoding an anti-HER2 CAR construct. When infused into patient-derived xenograft (PDX) mouse models carrying autologous tumors, CAR-TILs were able to eradicate melanoma, even in the absence of antigen presentation by HLA. To advance this concept to the clinic and assess its safety in an immune-competent and human-patient-like setting, we treated four companion dogs with autologous anti-HER2 CAR-TILs. We found that these cells were tolerable and showed signs of anti-tumor activity. Taken together, CAR-TIL therapy is a promising avenue for broadening the tumor-targeting capacity of TILs in patients with checkpoint immunotherapy-resistant melanoma

Extending the Minimum Information About BIobank Data Sharing Terminology to Describe Samples, Sample Donors, and Events

Introduction: The Minimum Information About BIobank data Sharing (MIABIS) was initiated in 2012. MIABIS aims to create a common biobank terminology to facilitate data sharing in biobanks and sample collections. The MIABIS Core terminology consists of three components describing biobanks, sample collections, and studies, in which information on samples and sample donors is provided at aggregated form. However, there is also a need to describe samples and sample donors at an individual level to allow more elaborate queries on available biobank samples and data. Therefore the MIABIS terminology has now been extended with components describing samples and sample donors at an individual level. Materials and Methods: The components were defined according to specific scope and use cases by a large group of experts, and through several cycles of reviews, according to the new MIABIS governance model of BBMRI-ERIC (Biobanking and Biomolecular Resources Research Infrastructure-European Research Infrastructure Consortium). The guiding principles applied in developing these components included the following terms: model should consider only samples of human origin, model should be applicable to all types of samples and all sample donors, and model should describe the current status of samples stored in a given biobank. Results: A minimal set of standard attributes for defining samples and sample donors is presented here. We added an "event" component to describe attributes that are not directly describing samples or sample donors but are tightly related to them. To better utilize the generic data model, we suggest a procedure by which interoperability can be promoted, using specific MIABIS profiles. Discussion: The MIABIS sample and donor component extensions and the new generic data model complement the existing MIABIS Core 2.0 components, and substantially increase the potential usability of this terminology for better describing biobank samples and sample donors. They also support the use of individual level data about samples and sample donors to obtain accurate and detailed biobank availability queries

Middle Eastern mothers in Sweden, their experiences of the maternal health service and their partner's involvement

<p>Abstract</p> <p>Background</p> <p>Traditional patterns relating to how to handle pregnancy and birth are often challenged due to migration. The purpose of this study was to describe Middle Eastern mothers' experiences of the maternal health care services in Sweden and the involvement of their male partner.</p> <p>Methods</p> <p>Thirteen immigrant mothers from the Middle East who had used the maternal health services in Sweden were interviewed using focus group discussions and individual interviews. These were taped, transcribed and analysed according to Content analysis.</p> <p>Results</p> <p>The four main categories that developed were:</p> <p>• Access to the professional midwife</p> <p>• Useful counselling</p> <p>• Stable motherhood in transition</p> <p>• Being a family living in a different culture</p> <p>Conclusion</p> <p>According to the respondents in this study, understanding the woman's native language or her culture was not vital to develop a good relationship with the midwife. Instead the immigrant woman developed trust in the midwife based on the knowledge and the empathy the midwife imparted.</p> <p>Increasing the amount of first trimester antenatal visits could avoid spontaneous visits to the emergency clinic. There was a greater need for involvement and support by the father during the perinatal period, such as caring for older children and carrying out household chores since the mothers' earlier female network was often lost.</p> <p>Clinical implications</p> <p>There is a need to involve immigrant parents in the available parental education in order to prepare them for parenthood in their new country as well as to explore their altered family situation. Collecting immigrant women and their partner's, experiences of maternal health care services offers a possibility to improve the existing care, both in content, access and availability where the timing of visits and content require further evaluation.</p

Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE

Positive Health Outcomes of Fathers’ Involvment in Pregnancy and Childbirth Paternal Support : A Scope Study Literature Review

This study reviewed the literature concerning the involvement by European men in pregnancy and childbirth and examined how this is related to health outcomes; for the men themselves, their partners, and their children. The study also reflects on the literature in relation to other existing research on men, masculinities, and fatherhood. The literature review support the idea that the father’s involvement during pregnancy and delivery can positively influence health outcomes for the man, his partner, and their children. However, little help is offered to the majority of men regarding parenting. It is therefore crucial for the maternal and child healthcare services to develop new ways of reaching out to men. In order to develop new knowledge earlier research needs to be complemented with a multidisciplinary approach where the existing research material, on social science regarding men, masculinities, and fatherhood is also taken into consideration

Carbon monoxide-induced relaxation and distribution of haem oxygenase isoenzymes in the pig urethra and lower oesophagogastric junction

1. The distribution of the carbon monoxide (CO) producing enzymes haem oxygenase (HO)-1 and -2 was studied by immunohistochemistry in the pig's lower urinary tract, including bladder extramural arteries, and the oesophagogastric junction (OGJ). In isolated smooth muscle from the urethra and the OGJ, the mechanisms for CO-induced relaxations were characterized by measurement of cyclic nucleotide levels and by responses to the guanylate cyclase inhibitor methylene blue and some K(+) channel inhibitors. 2. HO-2 immunoreactivity was observed in coarse nerve trunks within the smooth muscle of the urethra and OGJ, and in nerve cell bodies of the enteric plexuses of the OGJ. Furthermore, the vascular endothelium of the intramural vessels of the urethra, bladder and OGJ, and the extramural vessels of the bladder, displayed HO-2 immunoreactivity. Two different antisera against HO-1 were used, but only one displayed immunoreactivity in neuronal structures. HO-1 immunoreactivity, as displayed by this antiserum, was seen in nerve cells, coarse nerve trunks and varicose nerve fibres in the smooth muscle of the urethra and OGJ. Some HO-2 and/or HO-1 (as displayed by both HO-1 antisera) immunoreactive cells with a non-neuronal appearance were observed within the smooth muscle of the OGJ, bladder and urethra. 3. In the urethral preparations, exogenously applied CO (72 μM) evoked a relaxation amounting to 76±6%. The relaxation was associated with an increase in cyclic GMP, but not cyclic AMP, content. CO-evoked relaxations were not significantly reduced by treatment with methylene blue, or by inhibitors of voltage-dependent (4-aminopyridine), high (iberiotoxin, charybdotoxin) and low (apamin) conductance Ca(2+)-activated, and ATP-sensitive (glibenclamide) K(+) channels. Bladder strips, and ring preparations from the extramural arteries of the bladder, did not respond to exogenously administered CO (12–72 μM). 4. In the OGJ, exogenously applied CO evoked a relaxation of 86±6%, which was associated with an increase in cyclic GMP, but not cyclic AMP, content. Treatment with 30 μM methylene blue raised the spontaneously developed muscle tone, and reduced the maximum relaxation evoked by CO to 33±9%. Addition of 4-aminopyridine, apamin, glibenclamide, iberiotoxin, charybdotoxin or glibenclamide had no effect on the relaxations. 4-aminopyridine (0.1–1 mM), iberiotoxin (0.1 μM) and charybdotoxin (0.1 μM) increased the spontaneously developed tone, and a combination of charybdotoxin and apamin reduced CO-induced (24 μM CO) relaxations. 5. The present findings demonstrate the presence of HO in both neuronal and non-neuronal cells in the pig OGJ and lower urinary tract. CO produces relaxation of the smooth muscle in the OGJ and urethra, associated with a small increase in cyclic GMP concentration in both regions. Relaxations evoked by CO in the urethra do not seem to involve voltage-dependent, low and high conductance, or ATP-dependent K(+) channels. However, in the OGJ relaxations evoked by CO can be attenuated by methylene blue and a combination of charybdotoxin and apamin