The MELFO (MELanoma FOllow-up) study is an international phase III randomized controlled trial comparing an experimental low-intensity schedule against current national guidelines.
Evidence-based ...guidelines for the follow-up of sentinel node-negative melanoma patients are lacking.
Overall, 388 adult patients diagnosed with sentinel node-negative primary melanoma patients were randomized in cancer centers in the Netherlands and United Kingdom between 2006 and 2016. The conventional schedule group (control: n=196) was reviewed as per current national guidelines. The experimental schedule group (n=192) was reviewed in a reduced-frequency schedule. Quality of life was the primary outcome measurement. Detection rates and survival outcomes were recorded. Patient satisfaction rates and compliance with allocated schedules were compared.
At 5 years, both arms expressed high satisfaction with their regimens (>97%). This study found no significant group effect on any patient-reported outcome measure scores between the follow-up protocols. In total, 75/388 (19.4%) patients recurred, with no difference in incidence found between the 2 arms (hazard ratio=0.87, 95% confidence interval: 0.54-1.39, P =0.57). Self-examination was the method of detection for 25 experimental patients and 32 control patients (75.8% vs. 76.2%; P =0.41). This study found no difference in any survival outcomes between the 2 study arms (disease-free survival: hazard ratio=1.00, 95% confidence interval: 0.49-2.07, P =0.99).
A reduced-intensity, American Joint Committee on Cancer (AJCC) stage-adjusted follow-up schedule for sentinel node-negative melanoma patients is a safe strategy, and patient self-examination is effective for recurrence detection with no evidence of diagnostic delay. Patients' acceptance is very high.
Rh antigens can provoke severe alloimmune reactions, particularly in high-risk transfusion contexts, such as sickle cell disease. Rh antigens are encoded by the paralogs, RHD and RHCE, located in one ...of the most complex genetic loci. Our goal was to characterize RH genetic variation in multi-ethnic cohorts, with the focus on detecting RH structural variation (SV).
We customized analytical methods to estimate paralog-specific copy number from next-generation sequencing (NGS) data. We applied these methods to clinically characterized samples, including four World Health Organization (WHO) genotyping references and 1135 Asian and Native American blood donors. Subsequently, we surveyed 1715 African American samples from the Jackson Heart Study.
Most samples in each dataset exhibited SV. SV detection enabled prediction of the immunogenic RhD and RhC antigens in concordance (>99%) with serological phenotyping. RhC antigen expression was associated with exon 2 hybrid alleles (RHCE*CE-D(2)-CE). Clinically relevant exon 4-7 hybrid alleles (RHD*D-CE(4-7)-D) and exon 9 hybrid alleles (RHCE*CE-D(9)-CE) were prevalent in African Americans.
This study shows custom NGS methods can accurately detect RH SV, and that SV is important to inform prediction of relevant RH alleles. Additionally, this study provides the first large NGS survey of RH alleles in African Americans.
Prostate cancer growth is dependent upon androgen receptor (AR) activation, regulated via phosphorylation. Protein kinase C (PKC) is one kinase that can mediate AR phosphorylation. This study aimed ...to establish if AR phosphorylation by PKC is of prognostic significance.
Immunohistochemistry for AR, AR phosphorylated at Ser-81 (pARS81), AR phosphorylated at Ser-578 (pARS578), PKC and phosphorylated PKC (pPKC) was performed on 90 hormone-naïve prostate cancer specimens. Protein expression was quantified using the weighted histoscore method and examined with regard to clinico-pathological factors and outcome measures; time to biochemical relapse, survival from biochemical relapse and disease-specific survival.
Nuclear PKC expression strongly correlated with nuclear pARS578 (c.c. 0.469, p=0.001) and cytoplasmic pARS578 (c.c. 0.426 p=0.002). High cytoplasmic and nuclear pARS578 were associated with disease-specific survival (p<0.001 and p=0.036 respectively). High nuclear PKC was associated with lower disease-specific survival when combined with high pARS578 in the cytoplasm (p=0.001) and nucleus (p=0.038). Combined high total pARS81 and total pARS578 was associated with decreased disease-specific survival (p=0.005).
pARS578 expression is associated with poor outcome and is a potential independent prognostic marker in hormone-naïve prostate cancer. Furthermore, PKC driven AR phosphorylation may promote prostate cancer progression and provide a novel therapeutic target.
To describe the prevalence of and factors associated with different thyroid dysfunction phenotypes in women who are asymptomatic preconception.
Observational cohort study.
A total of 49 hospitals ...across the United Kingdom between 2011 and 2016.
Women aged 16 to 41years with history of miscarriage or subfertility trying for a pregnancy.
Prevalences and 95% confidence intervals (CIs) were estimated using the binomial exact method. Multivariate logistic regression analyses were conducted to identify risk factors for thyroid disease.
None.
Rates of thyroid dysfunction.
Thyroid function and thyroid peroxidase antibody (TPOAb) data were available for 19213 and 19237 women, respectively. The prevalence of abnormal thyroid function was 4.8% (95% CI, 4.5-5.1); euthyroidism was defined as levels of thyroid-stimulating hormone (TSH) of 0.44 to 4.50 mIU/L and free thyroxine (fT4) of 10 to 21 pmol/L. Overt hypothyroidism (TSH > 4.50 mIU/L, fT4 < 10 pmol/L) was present in 0.2% of women (95% CI, 0.1-0.3) and overt hyperthyroidism (TSH < 0.44 mIU/L, fT4 > 21 pmol/L) was present in 0.3% (95% CI, 0.2-0.3). The prevalence of subclinical hypothyroidism (SCH) using an upper TSH concentration of 4.50 mIU/L was 2.4% (95% CI, 2.1-2.6). Lowering the upper TSH to 2.50 mIU/L resulted in higher rates of SCH, 19.9% (95% CI, 19.3-20.5). Multiple regression analyses showed increased odds of SCH (TSH > 4.50 mIU/L) with body mass index (BMI) ≥ 35.0 kg/m2 (adjusted odds ratio aOR 1.71; 95% CI, 1.13-2.57; P = 0.01) and Asian ethnicity (aOR 1.76; 95% CI, 1.31-2.37; P < 0.001), and increased odds of SCH (TSH ≥ 2.50 mIU/L) with subfertility (aOR 1.16; 95% CI, 1.04-1.29; P = 0.008). TPOAb positivity was prevalent in 9.5% of women (95% CI, 9.1-9.9).
The prevalence of undiagnosed overt thyroid disease is low. SCH and TPOAb are common, particularly in women with higher BMI or of Asian ethnicity. A TSH cutoff of 2.50 mIU/L to define SCH results in a significant proportion of women potentially requiring levothyroxine treatment.
Compared to other patient population groups, the field of amputation research in Canada lacks cohesion largely due to limited funding sources, lack of connection among research scientists, and loose ...ties among geographically dispersed healthcare centres, research institutes and advocacy groups. As a result, advances in clinical care are hampered and ultimately negatively influence outcomes of persons living with limb loss.
To stimulate a national strategy on advancing amputation research in Canada, a consensus-workshop was organized with an expert panel of stakeholders to identify key research priorities and potential strategies to build researcher and funding capacity in the field.
A modified Delphi approach was used to gain consensus on identifying and selecting an initial set of priorities for building research capacity in the field of amputation. This included an anonymous pre-meeting survey (N = 31 respondents) followed by an in-person consensus-workshop meeting that hosted 38 stakeholders (researchers, physiatrists, surgeons, prosthetists, occupational and physical therapists, community advocates, and people with limb loss).
The top three identified research priorities were: (1) developing a national dataset; (2) obtaining health economic data to illustrate the burden of amputation to the healthcare system and to patients; and (3) improving strategies related to outcome measurement in patients with limb loss (e.g. identifying, validating, and/or developing outcome measures). Strategies for moving these priorities into action were also developed.
The consensus-workshop provided an initial roadmap for limb loss research in Canada, and the event served as an important catalyst for stakeholders to initiate collaborations for moving identified priorities into action. Given the increasing number of people undergoing an amputation, there needs to be a stronger Canadian collaborative approach to generate the necessary research to enhance evidence-based clinical care and policy decision-making.
IMPLICATIONS FOR REHABILITATION
Limb loss is a growing concern across North America, with lower-extremity amputations occurring due to complications arising from diabetes being a major cause.
To advance knowledge about limb loss and to improve clinical care for this population, stronger connections are needed across the continuum of care (acute, rehabilitation, community) and across sectors (clinical, advocacy, industry and research).
There are new surgical techniques, technologies, and rehabilitation approaches being explored to improve the health, mobility and community participation of people with limb loss, but further research evidence is needed to demonstrate efficacy and to better integrate them into standard clinical care.
An aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial “hit” established 5 as a ...viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model.
Abstract Background Optimizing resuscitation to reduce inflammation and organ dysfunction following human trauma-associated hemorrhagic shock is a major clinical hurdle. This is limited by the short ...duration of pre-clinical studies and the sparsity of early data in the clinical setting. Methods We sought to bridge this gap by linking preclinical data in a porcine model with clinical data from patients from the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study via a three-compartment ordinary differential equation model of inflammation and coagulation. Results The mathematical model accurately predicts physiologic, inflammatory, and laboratory measures in both the porcine model and patients, as well as the outcome and time of death in the PROMMTT cohort. Model simulation suggests that resuscitation with plasma and red blood cells outperformed resuscitation with crystalloid or plasma alone, and that earlier plasma resuscitation reduced injury severity and increased survival time. Conclusions This workflow may serve as a translational bridge from pre-clinical to clinical studies in trauma-associated hemorrhagic shock and other complex disease settings.
Liquid preserved packed red blood cell (LPRBC) transfusions are used to treat anemia and increase end-organ perfusion. Throughout their storage duration, LPRBCs undergo biochemical and structural ...changes collectively known as the storage lesion. These changes adversely affect perfusion and oxygen off-loading. Cryopreserved RBCs (CPRBC) can be stored for up to 10 years and potentially minimize the associated storage lesion. We hypothesized that CPRBCs maintain a superior biochemical profile compared with LPRBCs.
This was a prospective, randomized, double-blinded study. Adult trauma patients with an Injury Severity Score (ISS) greater than 4 and an anticipated 1-U to 2-U transfusion of PRBCs were eligible. Enrolled patients were randomized to receive either CPRBCs or LPRBCs. Serum proteins (haptoglobin, serum amyloid P, and C-reactive protein), proinflammatory and anti-inflammatory cytokines, d-dimer, nitric oxide, and 2,3-DPG concentrations were analyzed. Mann-Whitney U-test and Wilcoxon rank sum test were used to assess significance (p < 0.05).
Fifty-seven patients were enrolled (CPRBC, n = 22; LPRBC, n = 35). The LPRBC group's final interleukin 8, tumor necrosis factor α, and d-dimer concentrations were elevated compared with their pretransfusion values (p < 0.05). After the second transfused units, 2,3-DPG was higher in the patients receiving CPRBCs (p < 0.05); this difference persisted throughout the study. Finally, serum protein concentrations were decreased in the transfused CPRBC units compared with LPRBC (p < 0.01).
CPRBC transfusions have a superior biochemical profile: an absent inflammatory response, attenuated fibrinolytic state, and increased 2,3-DPG. A blood banking system using both storage techniques will offer the highest-quality products to critically injured patients virtually independent of periodic changes in donor availability and transfusion needs.
Therapeutic study, level II.
We developed a complex combat-relevant model of abdominal and extremity trauma, hemorrhagic shock, hypothermia, and acidosis. We then simulated injury, preoperative, and operative phases. We ...hypothesized that this model is reproducible and useful for randomized multicenter preclinical trials. Yorkshire swine were anesthetized, intubated, and instrumented. They then underwent femur fracture, 60% total blood volume hemorrhage, a 30-min shock period, induced hypothermia to 33 degrees C, and hemorrhage volume replacement with 3:1 isotonic sodium chloride solution (NS) at each of three centers. Hemodynamic parameters were measured continuously. Thromboelastography, arterial blood gas, and laboratory values were collected at baseline, after the shock period, and after NS replacement. Thirty-seven animals were used for model development. Eight (21%) died before completion of the study period. Twenty-nine survivors were included in the analysis. MAP (+/-SEM) after the shock period was 32 +/- 2 mmHg and was similar between centers (P = 0.4). Mean pH, base deficit, and lactate levels were 7.29 +/- 0.02, 8.20 +/- 0.65 mmol/L, and 5.29 +/- 0.44 mmol/L, respectively, after NS replacement. These were similar between centers (P > 0.05). Prothrombin time values increased significantly over time at all centers, reflecting a progressive coagulopathy (P < 0.02). Thromboelastography maximum amplitude values were similar among centers (P > 0.05) and demonstrated progressively weakened platelet interaction over time (P < 0.03). Hematocrit was similar after controlled hemorrhage (P = 0.15) and dilution (P = 0.9). The pH, lactate, base deficit, and coagulation tests reflect a severely injured state. A complex porcine model of polytrauma and shock can be used for multi-institutional study with excellent reproducibility. A consistent severe injury profile was achieved, after which experimental interventions can be applied. This is the first report of a reproducible multicenter trauma and resuscitation-related animal model.
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