Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of OC are limited and hard ...to establish. We present a protocol that enables efficient derivation and long-term expansion of OC organoids. Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing all main subtypes of OC. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and interpatient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug-screening assays and capture different tumor subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug-sensitivity assays. Taken together, this demonstrates their potential application for research and personalized medicine.
A highly efficacious vaccine is needed for malaria control and eradication. Immunization with Plasmodium falciparum NF54 parasites under chemoprophylaxis (chemoprophylaxis and sporozoite ...(CPS)-immunization) induces the most efficient long-lasting protection against a homologous parasite. However, parasite genetic diversity is a major hurdle for protection against heterologous strains.
We conducted a double-blind, randomized controlled trial in 39 healthy participants of NF54-CPS immunization by bites of 45 NF54-infected (n = 24 volunteers) or uninfected mosquitoes (placebo; n = 15 volunteers) against a controlled human malaria infection with the homologous NF54 or the genetically distinct NF135.C10 and NF166.C8 clones. Cellular and humoral immune assays were performed as well as genetic characterization of the parasite clones.
NF54-CPS immunization induced complete protection in 5/5 volunteers against NF54 challenge infection at 14 weeks post-immunization, but sterilely protected only 2/10 and 1/9 volunteers against NF135.C10 and NF166.C8 challenge infection, respectively. Post-immunization plasma showed a significantly lower capacity to block heterologous parasite development in primary human hepatocytes compared to NF54. Whole genome sequencing showed that NF135.C10 and NF166.C8 have amino acid changes in multiple antigens targeted by CPS-induced antibodies. Volunteers protected against heterologous challenge were among the stronger immune responders to in vitro parasite stimulation.
Although highly protective against homologous parasites, NF54-CPS-induced immunity is less effective against heterologous parasite clones both in vivo and in vitro. Our data indicate that whole sporozoite-based vaccine approaches require more potent immune responses for heterologous protection.
This trial is registered in clinicaltrials.gov, under identifier NCT02098590 .
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this ...group, but little is known about the immunogenicity of COVID-19 vaccines in these patients.
We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI.
In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency CVID, isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2–specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination.
Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response.
COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations.
Background
Video consultation (VC) is gaining attention as a possible alternative to out-patient clinic visits. However, little is known in terms of attitude, satisfaction and quality of care using ...VC over a face-to-face (F2F) consultation. The aim of this observational survey study was to compare the attitude and satisfaction with VC amongst patients suffering from colorectal cancer and their treating surgeons at the outpatient surgical care clinic in a tertiary referral centre.
Methods
A patient-preference model was chosen following the concept of shared decision making. A total of fifty patients with colorectal cancer were asked to choose between VC- or a F2F-contact during their follow up at the outpatient surgical care clinic and were subsequently assigned to either the VC-group or the F2F-group. Attitude and satisfaction rates of both groups and their surgeons were measured using a questionnaire administered immediately after the consultation.
Results
Out of the 50 patients, 42% chose VC as their preferred follow-up modality. Patients demographics did not differ significantly. Patients who use video calling in their personal life choose VC significantly more often than patients lacking such experience (
p
= 0.010). These patients scored high on both the attitude- and satisfaction scale of the post-VC questionnaire. Patients who chose a F2F-contact seemed to question the ability of the surgeon to properly assess their healthcare condition by using a video connection more (
p
= 0.024). Surgeons were highly satisfied with the use of VC.
Conclusions
Based on patient preference, VC is equivalent to a F2F consultation in terms of patient satisfaction and perceived quality of care. Shared decision making is preferred with regard to which contact modality is used during follow up. For easy uptake in other environments it is to be recommended to facilitate VC using the electronic patient portal.
Objective
Studies on anxiety within oncology show a high prevalence of anxiety both during and after the course of the disease. However, little is known about factors that influence the level of ...anxiety in the diagnostic phase. This study examines the presence of anxiety during diagnosis and treatment planning and explores how a monitoring (ie, information seeking) coping style and the suggested treatment plan (ie, with or without chemotherapy) interact with anxiety.
Methods
Anxiety scores (6‐item State‐Trait Anxiety Inventory) were collected from 81 colorectal cancer patients before and after their visit to the outpatient Gastrointestinal Oncological Center Amsterdam. A cut‐off score (>44) was used to indicate highly anxious patients.
Results
More than half (59%) of the patients were classified as highly anxious before consultation. Although anxiety scores significantly decreased after consultation (t = 3.149, P = .002), 37% of the patients remained highly anxious. Reductions in anxiety were specifically observed for patients with a higher monitoring coping style and patients for whom a treatment plan without chemotherapy was proposed. Interestingly, high monitors for whom treatment without chemotherapy was proposed showed a major decrease in anxiety, whereas low monitors for whom treatment starting with chemotherapy was proposed showed a great increase in anxiety.
Conclusions
The diagnostic phase is associated with high levels of anxiety. Distinct patterns of anxiety were identified, depending on patients' coping style and the suggested treatment plan. Remarkably, patients with a lower monitoring coping style became particularly anxious when they were advised to start treatment with chemotherapy.
Purpose
Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective long-term protection against COVID-19 is therefore of great ...importance in these patients, but little is known about the decay of the immune response after primary vaccination. We studied the immune responses 6 months after two mRNA-1273 COVID-19 vaccines in 473 IEI patients and subsequently the response to a third mRNA COVID-19 vaccine in 50 patients with common variable immunodeficiency (CVID).
Methods
In a prospective multicenter study, 473 IEI patients (including X-linked agammaglobulinemia (XLA) (
N
= 18), combined immunodeficiency (CID) (
N
= 22), CVID (
N
= 203), isolated or undefined antibody deficiencies (
N
= 204), and phagocyte defects (
N
= 16)), and 179 controls were included and followed up to 6 months after two doses of the mRNA-1273 COVID-19 vaccine. Additionally, samples were collected from 50 CVID patients who received a third vaccine 6 months after primary vaccination through the national vaccination program. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T cell responses were assessed.
Results
At 6 months after vaccination, the geometric mean antibody titers (GMT) declined in both IEI patients and healthy controls, when compared to GMT 28 days after vaccination. The trajectory of this decline did not differ between controls and most IEI cohorts; however, antibody titers in CID, CVID, and isolated antibody deficiency patients more often dropped to below the responder cut-off compared to controls. Specific T cell responses were still detectable in 77% of controls and 68% of IEI patients at 6 months post vaccination. A third mRNA vaccine resulted in an antibody response in only two out of 30 CVID patients that did not seroconvert after two mRNA vaccines.
Conclusion
A similar decline in IgG titers and T cell responses was observed in patients with IEI when compared to healthy controls 6 months after mRNA-1273 COVID-19 vaccination. The limited beneficial benefit of a third mRNA COVID-19 vaccine in previous non-responder CVID patients implicates that other protective strategies are needed for these vulnerable patients.
Adherence to antihypertensive drugs (AHDs) is crucial for controlling blood pressure (BP). We aimed to determine the effectiveness of measuring AHD concentrations using a dried blood spot (DBS) ...sampling method to identify nonadherence, combined with personalized feedback, in reducing resistant hypertension.
We conducted a multicenter, randomized, controlled trial (RHYME-RCT, ICTRP NTR6914) in patients with established resistant hypertension. Patients were randomized to receive either an intervention with standard of care (SoC) or SoC alone. SoC consisted of BP measurement and DBS sampling at baseline, 3 months (t3), 6 months (t6), and 12 months (t12); AHD concentrations were measured but not reported in this arm. In the intervention arm, results on AHD concentrations were discussed during a personalized feedback conversation at baseline and t3. Study endpoints included the proportion of patients with RH and AHD adherence at t12.
Forty-nine patients were randomized to receive the intervention+SoC, and 51 were randomized to receive SoC alone. The proportion of adherent patients improved from 70.0 to 92.5% in the intervention+SoC arm ( P = 0.008, n = 40) and remained the same in the SoC arm (71.4%, n = 42). The difference in adherence between the arms was statistically significant ( P = 0.014). The prevalence of resistant hypertension decreased to 75.0% in the intervention+SoC arm ( P < 0.001, n = 40) and 59.5% in the SoC arm ( P < 0.001, n = 42) at t12; the difference between the arms was statistically nonsignificant ( P = 0.14).
Personalized feedback conversations based on DBS-derived AHD concentrations improved AHD adherence but did not reduce the prevalence of RH.
BACKGROUND:Abdominoperineal resection is associated with a high incidence of perineal complications, and whether this is reduced by an omentoplasty is still unclear.
OBJECTIVE:This study aimed to ...investigate the impact of omentoplasty on pelviperineal morbidity in patients undergoing abdominoperineal resection for rectal cancer.
DESIGN:This was a retrospective comparative cohort study using propensity score analyses to reduce potential confounding.
SETTING:The study was undertaken in 2 teaching hospitals and 1 university hospital.
PATIENTS:Patients who underwent abdominoperineal resection for primary rectal cancer between 2000 and 2017 were included.
MAIN OUTCOME MEASURES:The main end points were primary perineal wound healing at 30 days and overall and specific pelviperineal morbidity until the end of the study period.
RESULTS:Among 254 included patients, 106 had an omentoplasty. The primary perineal wound healing rate at 30 days was similar for omentoplasty and no omentoplasty (65% vs 60%; p = 0.422), also after adjusting for potential confounding by propensity score analysis (OR, 0.89; 95% CI, 0.45–1.75). Being free from any pelviperineal complication at 6 months (75% vs 79%; p = 0.492), absence of any pelviperineal morbidity until 1 year (54% vs 49%; p = 0.484), and incidence of persistent perineal sinus (6% vs 10%; p = 0.256) were also similar in both groups. The unadjusted higher perineal hernia rate after omentoplasty (18% vs 7%; p = 0.011) did not remain statistically significant after regression analysis including the propensity score (OR, 1.34; 95% CI, 0.46–3.88). Complications related to the omentoplasty itself were observed in 8 patients, of whom 6 required reoperation.
LIMITATIONS:This study was limited by the retrospective and nonrandomized design causing some heterogeneity between the 2 cohorts.
CONCLUSION:In this multicenter study using propensity score analyses, the use of omentoplasty did not lower the incidence or the duration of pelviperineal morbidity in patients undergoing abdominoperineal resection for rectal cancer, and omentoplasty itself was associated with a risk of reoperation. See Video Abstract at http://links.lww.com/DCR/A918.
The incidence of central venous catheter (CVC)-related bloodstream infections is high in patients requiring a long-term CVC. Therefore, infection prevention is of the utmost importance. The aim of ...this study was to provide an updated overview of randomized controlled trials (RCTs) comparing the efficacy of taurolidine containing lock solutions (TL) to other lock solutions for the prevention of CVC-related bloodstream infections in all patient populations. On 15th February 2021, PubMed, Embase and The Cochrane Library were searched for RCTs comparing the efficacy of TLs for the prevention of CVC-related bloodstream infections with other lock solutions. Exclusion criteria were non-RCTs, studies describing <10 patients and studies using TLs as treatment. Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. A random effects model was used to pool individual study incidence rate ratios (IRRs). Subgroup analyses were performed based on the following factors: CVC indication, comparator lock and bacterial isolates cultured. A total of 14 articles were included in the qualitative synthesis describing 1219 haemodialysis, total parenteral nutrition and oncology patients. The pooled IRR estimated for all patient groups together (nine studies; 918 patients) was 0.30 (95% confidence interval 0.19–0.46), favouring the TLs. Adverse events (10 studies; 867 patients) were mild and scarce. The quality of the evidence was limited due to a high risk of bias and indirectness of evidence. The use of TLs might be promising for the prevention of CVC-related bloodstream infections. Large-scale RCTs are needed to draw firm conclusions on the efficacy of TLs.
Purpose
Resection of pediatric osteosarcoma in the extremities with soft tissue involvement presents surgical challenges due to difficult visualization and palpation of the tumor. Therefore, an ...adequate image-guided surgery (IGS) system is required for more accurate tumor resection. The use of a 3D model in combination with intraoperative tracked ultrasound (iUS) may enhance surgical decision making. This study evaluates the clinical feasibility of iUS as a surgical tool using a porcine cadaver model.
Methods
First, a 3D model of the porcine lower limb was created based on preoperative scans. Second, the bone surface of the tibia was automatically detected with an iUS by a sweep on the skin. The bone surface of the preoperative 3D model was then matched with the bone surface detected by the iUS. Ten artificial targets were used to calculate the target registration error (TRE). Intraoperative performance of iUS IGS was evaluated by six pediatric surgeons and two pediatric oncologic orthopedists. Finally, user experience was assessed with a post-procedural questionnaire.
Results
Eight registration procedures were performed with a mean TRE of 6.78 ± 1.33 mm. The surgeons agreed about the willingness for clinical implementation in their current clinical practice. They mentioned the additional clinical value of iUS in combination with the 3D model for the localization of the soft tissue components of the tumor. The concept of the proposed IGS system is considered feasible by the clinical panel, but the large TRE and degree of automation need to be addressed in further work.
Conclusion
The participating pediatric surgeons and orthopedists were convinced of the clinical value of the interaction between the iUS and the 3D model. Further research is required to improve the surgical accuracy and degree of automation of iUS-based registration systems for the surgical management of pediatric osteosarcoma.
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