Characterization of eomesodermin and T-bet expression by allostimulated CD8+ T cells of healthy volunteers and kidney transplant patients in relation to graft outcome.

Memory T cell (Tmem) responses play a critical role in the outcome of allo-transplantation. While the role of the T-box transcription factor Eomesodermin (Eomes) in the maintenance of antigen-specific Tmem is well studied, little is known about Eomes+ CD8+ T cell responses after transplantation. We evaluated the phenotype and function of allo-reactive Eomes+ CD8+ T cells in healthy volunteers and kidney transplant patients and their relation to transplant outcome. High Eomes expression by steady-state CD8+ T cells correlated with effector and memory phenotype. Following allo-stimulation, the expression of both the T-box proteins Eomes and T-bet by proliferating cells increased significantly, where high expression of Eomes and T-bet correlated with higher incidence of allo-stimulated IFNγ+ TNFα+ CD8+ T cells. In patients with no subsequent rejection, Eomes but not T-bet expression by donor-stimulated CD8+ T cells, increased significantly after transplantation. This was characterized by increased Eomeshi T-bet-/lo and decreased Eomes-/lo T-bethi CD8+ T cell subsets, with no significant changes in the Eomeshi T-bethi CD8+ T cell subset. No upregulation of exhaustion markers programmed-death-1 (PD-1) and cytotoxic-T-lymphocyte-associated-antigen-4 (CTLA4) by donor-stimulated Eomes+ CD8+ T cells was observed. Before transplantation, in patients without rejection, there were higher incidences of Eomeshi T-bet-/lo , and lower incidences of Eomeshi T-bethi and Eomes-/lo T-bethi donor-stimulated CD8+ T cell subsets, compared to those with subsequent rejection. Overall, our findings indicate that high Eomes expression by allo-stimulated T-bet+ CD8+ T cells is associated with enhanced effector function, and that an elevated incidence of donor-stimulated CD8+ T cells co-expressing high levels of Eomes and T-bet before transplantation, may correlate with an increased incidence of acute cellular rejection.

Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB.

The location and/or type of variants in FLNB result in a spectrum of osteochondrodysplasias ranging from mild forms, like spondylocarpotarsal synostosis syndrome and Larsen syndrome, to severe perinatal lethal forms, such as atelosteogenesis I and III and Boomerang dysplasia. Spondylocarpotarsal synostosis syndrome is characterized by disproportionate short stature, vertebral anomalies and fusion of carpal and tarsal bones. Biallelic loss-of-function variants in FLNB are known to cause spondylocarpotarsal synostosis syndrome and 9 families and 9 pathogenic variants have been reported so far. We report clinical features of 10 additional patients from 7 families with spondylocarpotarsal synostosis syndrome due to 7 novel deleterious variants in FLNB, thus expanding the clinical and molecular repertoire of spondylocarpotarsal synostosis syndrome. Our report validates key clinical (fused thoracic vertebrae and carpal and tarsal coalition) and molecular (truncating variants in FLNB) characteristics of this condition.

Renal Transplantation With Final Allocation Based on the Virtual Crossmatch.

Solid phase immunoassays (SPI) are now routinely used to detect HLA antibodies. However, the flow cytometric crossmatch (FCXM) remains the established method for assessing final donor-recipient compatibility. Since 2005 we have followed a protocol whereby the final allocation decision for renal transplantation is based on SPI (not the FCXM). Here we report long-term graft outcomes for 508 consecutive kidney transplants using this protocol. All recipients were negative for donor-specific antibody by SPI. Primary outcomes are graft survival and incidence of acute rejection within 1 year (AR <1 year) for FCXM+ (n = 54) and FCXM- (n = 454) recipients. Median follow-up is 7.1 years. FCXM+ recipients were significantly different from FCXM- recipients for the following risk factors: living donor (24% vs. 39%, p = 0.03), duration of dialysis (31.0 months vs. 13.5 months, p = 0.008), retransplants (17% vs. 7.3%, p = 0.04), % sensitized (63% vs. 19%, p = 0.001), and PRA >80% (20% vs. 4.8%, p = 0.001). Despite these differences, 5-year actual graft survival rates are 87% and 84%, respectively. AR <1 year occurred in 13% FCXM+ and 12% FCXM- recipients. Crossmatch status was not associated with graft outcomes in any univariate or multivariate model. Renal transplantation can be performed successfully, using SPI as the definitive test for donor-recipient compatibility.

Altered breathing mechanics and ventilatory response during exercise in children born extremely preterm.

BACKGROUND: Extreme preterm birth confers risk of long-term impairments in lung function and exercise capacity. There are limited data on the factors contributing to exercise limitation following extreme preterm birth. This study examined respiratory mechanics and ventilatory response during exercise in a large cohort of children born extremely preterm (EP). METHODS: This cohort study included children 8-12 years of age who were born EP (≤28 weeks gestation) between 1997 and 2004 and treated in a large regionalised neonatal intensive care unit in western Canada. EP children were divided into no/mild bronchopulmonary dysplasia (BPD) (ie, supplementary oxygen or ventilation ceased before 36 weeks gestational age; n=53) and moderate/severe BPD (ie, continued supplementary oxygen or ventilation at 36 weeks gestational age; n=50). Age-matched control children (n=65) were born at full term. All children attempted lung function and cardiopulmonary exercise testing measurements. RESULTS: Compared with control children, EP children had lower airway flows and diffusion capacity but preserved total lung capacity. Children with moderate/severe BPD had evidence of gas trapping relative to other groups. The mean difference in exercise capacity (as measured by oxygen uptake (VO2)% predicted) in children with moderate/severe BPD was -18±5% and -14±5.0% below children with no/mild BPD and control children, respectively. Children with moderate/severe BPD demonstrated a potentiated ventilatory response and greater prevalence of expiratory flow limitation during exercise compared with other groups. Resting lung function did not correlate with exercise capacity. CONCLUSIONS: Expiratory flow limitation and an exaggerated ventilatory response contribute to respiratory limitation to exercise in children born EP with moderate/severe BPD.

Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma.

BACKGROUND: We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials. METHODS: Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on-2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice. RESULTS: A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15-17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8-10.0) and 18.7 months (95% CI: 17.5-19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand-foot syndrome (each 7%). CONCLUSION: Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.

Commercially available immunoglobulins contain virus neutralizing antibodies against all major genotypes of polyomavirus BK.

Neutralizing antibodies (NAbs) form the basis of immunotherapeutic strategies against many important human viral infections. Accordingly, we studied the prevalence, titer, genotype-specificity, and mechanism of action of anti-polyomavirus BK (BKV) NAbs in commercially available human immune globulin (IG) preparations designed for intravenous (IV) use. Pseudovirions (PsV) of genotypes Ia, Ib2, Ic, II, III, and IV were generated by co-transfecting a reporter plasmid encoding luciferase and expression plasmids containing synthetic codon-modified VP1, VP2, and VP3 capsid protein genes into 293TT cells. NAbs were measured using luminometry. All IG preparations neutralized all BKV genotypes, with mean EC50 titers as high as 254 899 for genotype Ia and 6,666 for genotype IV. Neutralizing titers against genotypes II and III were higher than expected, adding to growing evidence that infections with these genotypes are more common than currently appreciated. Batch to batch variation in different lots of IG was within the limits of experimental error. Antibody mediated virus neutralizing was dose dependent, modestly enhanced by complement, genotype-specific, and achieved without effect on viral aggregation, capsid morphology, elution, or host cell release. IG contains potent NAbs capable of neutralizing all major BKV genotypes. Clinical trials based on sound pharmacokinetic principles are needed to explore prophylactic and therapeutic applications of these anti-viral effects, until effective small molecule inhibitors of BKV replication can be developed.

Core cell cycle regulatory genes in rice and their expression profiles across the growth zone of the leaf.

Rice (Oryza sativa L.) as a model and crop plant with a sequenced genome offers an outstanding experimental system for discovering and functionally analyzing the major cell cycle control elements in a cereal species. In this study, we identified the core cell cycle genes in the rice genome through a hidden Markov model search and multiple alignments supported with the use of short protein sequence probes. In total we present 55 rice putative cell cycle genes with locus identity, chromosomal location, approximate chromosome position and EST accession number. These cell cycle genes include nine cyclin dependent-kinase (CDK) genes, 27 cyclin genes, one CKS gene, two RBR genes, nine E2F/DP/DEL genes, six KRP genes, and one WEE gene. We also provide characteristic protein sequence signatures encoded by CDK and cyclin gene variants. Promoter analysis by the FootPrinter program discovered several motifs in the regulatory region of the core cell cycle genes. As a first step towards functional characterization we performed transcript analysis by RT-PCR to determine gene specific variation in transcript levels along the rice leaves. The meristematic zone of the leaves where cells are actively dividing was identified based on kinematic analysis and flow cytometry. As expected, expression of the majority of cell cycle genes was exclusively associated with the meristematic region. However genes such as different D-type cyclins, DEL1, KRP1/3, and RBR2 were also expressed in leaf segments representing the transition zone in which cells start differentiation.

Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial.

BACKGROUND: In the AXIS trial, axitinib prolonged progression-free survival (PFS) vs sorafenib in patients with advanced renal cell carcinoma (RCC) previously treated with sunitinib or cytokines. METHODS: In post hoc analyses, patients were grouped by objective response to prior therapy (yes vs no), prior therapy duration (< vs ⩾median), and tumour burden (baseline sum of the longest diameter < vs ⩾median). PFS and overall survival (OS), and safety by type and duration of prior therapy were evaluated. RESULTS: Response to prior therapy did not influence outcome with second-line axitinib or sorafenib. PFS was significantly longer in axitinib-treated patients who received longer prior cytokine treatment and sorafenib-treated patients with smaller tumour burden following sunitinib. Overall survival with the second-line therapy was longer in patients who received longer duration of prior therapy, although not significant in the sunitinib-to-axitinib sequence subgroup; OS was also longer in patients with smaller tumour burden, but not significant in the cytokine-to-axitinib sequence subgroup. Safety profiles differed modestly by type and duration of prior therapy. CONCLUSIONS: AXIS data suggest that longer duration of the first-line therapy generally yields better outcome with the second-line therapy and that lack of response to first-line therapy does not preclude positive clinical outcomes with a second-line vascular endothelial growth factor-targeted agent in patients with advanced RCC.

Outcomes and Health-related Quality of Life following Intensive Care Unit Stay in Barbados.

OBJECTIVES: To evaluate the hospital outcome and health-related quality of life (HRQOL) in adult patients admitted to intensive care units (ICUs) in Barbados. METHODS: A prospective observational study was done in the medical and surgical intensive care units of the Queen Elizabeth Hospital, Barbados, to evaluate the outcomes and HRQOL in adult patients. The acute physiology and chronic health evaluation (APACHE) IV score was applied on admission to one hundred and fifty patients admitted to the ICUs. The HRQOL was evaluated by using Short Form 36 (SF-36) in 63 survivors, three months after ICU discharge. RESULTS: There was no significant difference between medical and surgical ICUs with respect to age, gender, APACHE IV scores, 90-day mortality, and length of stay. The mean (± SD) APACHE IV score was 42.6 (± 23.7). The observed mortality was 32.7% and the standardized mortality ratio (SMR) was 1.85. The APACHE IV scores were significantly higher in non-survivors compared to survivors (p < 0.001). Patients with APACHE IV of > 45, and who were ventilated in the first 24 hours had the highest mortality (66%). The mean ICU length of stay was 7.2 days. CONCLUSION: In this study, the SF-36 scores in all eight dimensions indicated that the HRQOL in the majority of the survivors was average or above average. There was a significant negative correlation between APACHE IV score and the SF-36 score.

Transplanting the highly sensitized patient: trials and tribulations.

PURPOSE OF REVIEW: Humoral sensitization to antigens of the human leukocyte antigen and ABO systems remains one of the largest barriers to further expansion in renal transplantation. This barrier translates into prolonged waiting time and a greater likelihood of death. The number of highly sensitized patients on the renal transplant waiting list continues to increase. This review focuses on the options available to these patients and speculates on future directions for incompatible transplantation. RECENT FINDINGS: Desensitization protocols (to remove antibodies), kidney-paired donation (to circumvent antibodies) or a hybrid technique involving a combination of both have broadened the access to transplantation for patients disadvantaged by immunologic barriers. However, the risk of antibody-mediated rejection may be increased and warrants caution. Technical advances in antibody characterization using sensitive bead immunoassays and the C1q assay and therapeutic modalities such as complement inhibitors and proteasome inhibitors have been used to avoid or confront these antibody incompatibilities. SUMMARY: A growing body of knowledge and literature indicates that these diagnostic and therapeutic modalities can facilitate a safer and more successful treatment course for these difficult-to-treat patients. Rigorous investigations into newer interventions will help in broadening the options for these patients and also expand the living donor pool.

Pre-clinical toxicity & immunobiological evaluation of DNA rabies vaccine & combination rabies vaccine in rhesus monkeys (Macaca mulatta).

BACKGROUND & OBJECTIVES: Pre-clinical toxicology evaluation of biotechnology products is a challenge to the toxicologist. The present investigation is an attempt to evaluate the safety profile of the first indigenously developed recombinant DNA anti-rabies vaccine [DRV (100 µg)] and combination rabies vaccine [CRV (100 µg DRV and 1.25 IU of cell culture-derived inactivated rabies virus vaccine)], which are intended for clinical use by intramuscular route in Rhesus monkeys. METHODS: As per the regulatory requirements, the study was designed for acute (single dose - 14 days), sub-chronic (repeat dose - 28 days) and chronic (intended clinical dose - 120 days) toxicity tests using three dose levels, viz. therapeutic, average (2x therapeutic dose) and highest dose (10 x therapeutic dose) exposure in monkeys. The selection of the model i.e. monkey was based on affinity and rapid higher antibody response during the efficacy studies. An attempt was made to evaluate all parameters which included physical, physiological, clinical, haematological and histopathological profiles of all target organs, as well as Tiers I, II, III immunotoxicity parameters. RESULTS: In acute toxicity there was no mortality in spite of exposing the monkeys to 10XDRV. In sub chronic and chronic toxicity studies there were no abnormalities in physical, physiological, neurological, clinical parameters, after administration of test compound in intended and 10 times of clinical dosage schedule of DRV and CRV under the experimental conditions. Clinical chemistry, haematology, organ weights and histopathology studies were essentially unremarkable except the presence of residual DNA in femtogram level at site of injection in animal which received 10X DRV in chronic toxicity study. No Observational Adverse Effects Level (NOAEL) of DRV is 1000 ug/dose (10 times of therapeutic dose) if administered on 0, 4, 7, 14, 28 th day. INTERPRETATION & CONCLUSIONS: The information generated by this study not only draws attention to the need for national and international regulatory agencies in formulating guidelines for pre-clinical safety evaluation of biotech products but also facilitates the development of biopharmaceuticals as safe potential therapeutic agents.

Comparison of the Efficacy of Opioid-Free Anesthesia With Conventional Opioid-Based Anesthesia for Nasal Surgeries - A Prospective Randomized Parallel Arm Triple-Blinded Study.

Introduction In the setting of nasal surgeries, the use of opioid-free anesthesia involving the use of dexmedetomidine, and lignocaine is being investigated as a potential alternative to opioids. This combination of drugs provides sympatholysis, pain relief, and sedative properties, thereby aiming at reducing the negative effects commonly associated with opioid usage. The objective of this study is to evaluate and compare the effectiveness of opioid-free anesthesia using dexmedetomidine and lignocaine versus conventional opioid anesthesia with fentanyl for nasal surgeries. The comparison will be based on the primary outcome of postoperative visual analog scale (VAS) scores. Secondary outcomes assessed were the amount of rescue analgesic consumption, intraoperative sevoflurane usage, intraoperative blood loss, hemodynamic stability, postoperative nausea and vomiting (PONV) scores, and postoperative Ramsay Sedation Scores. Methods A triple-blind, prospective, randomized, parallel arm study in which 48 patients planned for elective nasal surgery were allocated randomly to one of two groups. In the study, the population labeled as Group D, comprising 24 participants, received dexmedetomidine at a dosage of 1 mcg.kg-1 via intravenous infusion lasting for a duration of 10 minutes prior to the induction of anesthesia. This was followed by a continuous infusion of 0.6 mcg.kg-1 h-1 throughout the intraoperative period, and intravenous Lignocaine 1.5 mg.kg-1 was administered three minutes prior to induction, subsequently an intraoperative infusion of 1.5 mg.kg-1 h-1. In Group F, consisting of 24 participants, intravenous fentanyl of 2 mcg.kg-1 was administered three minutes before the induction. This was subsequently followed by a fentanyl infusion of 0.5 mcg.kg-1h-1 in the intraoperative period. Results The study findings indicate that Group D had considerably lower postoperative VAS scores from 30 minutes to two hours compared to Group F (p<0.05). The utilization of sevoflurane during the intraoperative period was comparatively reduced in Group D in order to achieve the desired bispectral index (BIS) range of 40-60 (p<0.01). Mean intraoperative blood loss was also lower in Group D (85 ml) compared to Group F (115 ml )(p<0.01). Additionally, Group D had significantly lower rescue analgesic consumption and lower incidence of PONV up to 60 minutes compared to Group F (P-value <0.01). A statistically significant difference was observed between Group D and Group F in terms of lower mean values of both mean arterial pressure (MAP) and heart rate in Group D (p<0.01). The results indicate that the postoperative sedation scores within the first two hours were significantly greater in Group D compared to Group F (p<0.01). Conclusion The usage of opioid-free anesthesia has been found to be superior to a traditional opioid-based approach in various aspects, including the provision of sufficient pain relief after surgery, maintenance of stable hemodynamics during the operation, and reduction in occurrences of postoperative nausea and vomiting.

A founder ectodysplasin A receptor (EDAR) mutation results in a high frequency of the autosomal recessive form of hypohidrotic ectodermal dysplasia in India.

BACKGROUND: Hypohidrotic/anhidrotic ectodermal dysplasia (HED) is a rare Mendelian disorder affecting ectodermal tissues. The disease is primarily caused by inactivation of any one of three genes, namely ectodysplasin A1 (EDA-A1), which encodes a ligand belonging to the tumour necrosis factor (TNF) superfamily; ectodysplasin A receptor (EDAR), encoding the EDA-A1 receptor and ectodysplasin A receptor-associated death domain (EDARADD), encoding an adaptor protein. X-linked recessive (EDA-A1), the predominant form of HED, as well as autosomal recessive and dominant (EDAR and EDARADD) inheritance patterns have been identified in affected families. OBJECTIVES: To determine the common genes causing HED in India. METHODS: We performed mutation analysis on 26 HED families from India (including 30 patients). In addition, we carried out sequence and structural analysis of missense/nonsense and insertion/deletion mutations. RESULTS: Among the 26 families analysed, disease-causing EDAR mutations were identified in 12 (46%) while EDA-A1 mutations were detected in 11 (42%). Four novel mutations in EDAR and five in EDA-A1 were identified. More importantly, a possible founder EDAR mutation, namely c.1144G>A, was identified in five independent families, thus accounting for about one-fifth of affected families in whom mutation was detected. A majority of EDA-A1 mutations localized to the TNF-like domain while the location of EDAR mutations was more widespread. CONCLUSIONS: This is the first report of a founder EDAR mutation and of a significantly high frequency of autosomal recessive HED.

Extra-adrenal perirenal myelolipoma. A case report and review of literature.

Myelolipomas are rare tumours which are most commonly found in association with the adrenal glands. However, extra-adrenal sites have been described, but limited to case reports. They are characterized by a normal adrenal gland function and absence of haematopoesis which differentiates them from extramedullary haematopoetic tumours. We present a rare case of perirenal extra-adrenal myelolipoma and we review the imaging characteristics and management options for this condition.

Recent advances in electrochemical sensor developments for detecting emerging pollutant in water environment.

In the latest times, considerable studies have been performed closer to detecting emerging pollutant such as paracetamol in wastewater. Electrochemical sensor developments have recently started to determine in fewer concentrations effectively. The detection of paracetamol using standard protocols corresponding to electroanalytical techniques has a greater impact noticed in directing the detecting process toward biosensors. Non-enzymatic sensors are the peak of all electro analysis approaches. Functionalized materials, such as metal oxide nanoparticles, conducting polymers, and carbon-based materials for electrode surface functionalization have been used to create a fortification for distributing passive enzyme-free biosensors. Synergic effects are possible by enhancing loading capacity and mass transfer of reactants for attaining high analytical sensitivity using a variety of nanomaterials with large surface areas. The main focus of this study is to address the prevailing issues in the identification of paracetamol with the tasks in the non-enzymatic sensors field, followed by the useful methods of electro analysis studies.

Mucinous Signet-Cell Adenocarcinoma of the Ileum: A Diagnostic Challenge-Case Report and Review of the Literature.

Malignancies of the small intestine are rare. Signet-ring cell carcinoma (SRCC) is one of the rarest forms of adenocarcinoma that can arise in the small intestines. We present a case of a patient who originally presented with abdominal pain and radiographic findings suggestive of ileal congestion. The ileal biopsy specimens were nonspecific, and the patient began a trial of corticosteroid treatment for suspected Crohn's disease. A repeat colonoscopy yielded biopsies that were positive for malignancy. The patient then underwent an exploratory laparotomy which led to the diagnosis of SRCC. Given their similar presentations and the extreme rarity of this unusual malignancy, it can be difficult to differentiate between new-onset Crohn's disease and SRCC. A review of the literature was conducted to provide us with an improved understanding of previously documented cases of SRCC.

Perforated left-sided diverticulitis with faecal peritonitis: is the Hinchey classification the best guide for surgical decision making?

BACKGROUND: Although the Hinchey scoring system has guided surgical decision making for perforated diverticulitis, what constitutes optimal surgical management is controversial. We report our experience of selective primary closure of the perforation without use of a transverse colostomy and the specific circumstances in which this may be safe. METHODS: All cases of perforated diverticular disease of the sigmoid colon with Hinchey grade IV (faecal) peritonitis seen over a 4-year period from one surgical unit were reviewed. RESULTS: Primary closure without a diverting stoma was performed in six of the eight patients studied since the bowel was deemed healthy, and resection and primary end-to-end anastomosis were performed in the other two patients because there was associated scarring and stricture formation distally. In the primary closure patients, the site of the perforation was dissected and closed with attendant omentoplasty and a meticulous peritoneal toilet. In one of these cases, a diverting stoma was later fashioned after the patient developed a short-lived faecal fistula. CONCLUSION: The status of the underlying bowel, not the degree of peritoneal soiling, is the most significant consideration in defining the role of minimally invasive surgical treatment options for perforated diverticulitis. A new classification system that remains to be validated, taking into account the degree of colonic scarring and stricture formation, is proposed as a guide for surgical decision making in patients with perforated left-sided diverticulitis with faecal peritonitis.

Exponential stabilization of fixed and random time impulsive delay differential system with applications.

In this work, we study the problem of p-th moment global exponential stability for functional differential equations and scalar chaotic delayed equations under random impulsive effects. Meanwhile, the p-th moment global exponential synchronization for the proposed equations is also discussed, whereas the main results are proved by using Lyapunov function and Razumikhin technique. Furthermore, the impact of fixed and random time impulses are presented by applying the results to Mackey Glass blood cell production model and Ikeda bistable resonator model. Finally, the effectiveness of fixed and random impulses are depicted via graphical representations.

Efficacy and correlative analyses of avelumab plus axitinib versus sunitinib in sarcomatoid renal cell carcinoma: post hoc analysis of a randomized clinical trial.

BACKGROUND: Among patients with advanced renal cell carcinoma (RCC), those with sarcomatoid histology (sRCC) have the poorest prognosis. This analysis assessed the efficacy of avelumab plus axitinib versus sunitinib in patients with treatment-naive advanced sRCC. METHODS: The randomized, open-label, multicenter, phase III JAVELIN Renal 101 trial (NCT02684006) enrolled patients with treatment-naive advanced RCC. Patients were randomized 1 : 1 to receive either avelumab plus axitinib or sunitinib following standard doses and schedules. Assessments in this post hoc analysis of patients with sRCC included efficacy (including progression-free survival) and biomarker analyses. RESULTS: A total of 108 patients had sarcomatoid histology and were included in this post hoc analysis; 47 patients in the avelumab plus axitinib arm and 61 in the sunitinib arm. Patients in the avelumab plus axitinib arm had improved progression-free survival [stratified hazard ratio, 0.57 (95% confidence interval, 0.325-1.003)] and a higher objective response rate (46.8% versus 21.3%; complete response in 4.3% versus 0%) versus those in the sunitinib arm. Correlative gene expression analyses of patients with sRCC showed enrichment of gene pathway scores for cancer-associated fibroblasts and regulatory T cells, CD274 and CD8A expression, and tumors with The Cancer Genome Atlas m3 classification. CONCLUSIONS: In this subgroup analysis of JAVELIN Renal 101, patients with sRCC in the avelumab plus axitinib arm had improved efficacy outcomes versus those in the sunitinib arm. Correlative analyses provide insight into this subtype of RCC and suggest that avelumab plus axitinib may increase the chance of overcoming the aggressive features of sRCC.

Red cell transfusion practices and the impact of phlebotomy in an adult intensive care unit in Trinidad--a prospective observational study.

OBJECTIVES: To determine the pattern of current red cell transfusion practices in an adult intensive care unit (ICU) in Trinidad and the impact of phlebotomy on transfusions. METHODS: A prospective observational study was conducted over a six-month period to include all patients who received transfusions in the ICU of Port-of-Spain General Hospital, Trinidad. Demographic data including age, gender and weight were recorded. Clinical data recorded were the admission APACHE II scores, daily phlebotomy volumes, haemoglobin levels, transfusions and outcome during the first thirty days following ICU admission. Patients were grouped according to diagnoses and transfusion patterns. RESULTS: Of 134 patients admitted, 40 (29.8%) were transfused packed red cells 18 (29%) of the requests were for single unit transfusion. The mean phlebotomy volume was 13.5 +/- 4.3 (SD) mL day. The adjusted phlebotomy volume to body weight did not correlate with the amount of transfusions. The mean haemoglobin level for triggering blood transfusion was 6.73 g dL. The mean transfusion rate was 2.9 +/- 1.8 (SD) units per patient. Ten per cent of the patients received more than 5 units. Twenty nine per cent of the units were transfused on the first day of ICU admission and 69% were transfused during the first week of LCU stay. CONCLUSIONS: Transfusion practices in the study ICU pointed towards a restrictive strategy, although there were some inappropriate transfusions. The phlebotomy volumes did not contribute towards transfusion requirements.