Prognostic value of baseline seric Syndecan‐1 in initially unresectable metastatic colorectal cancer patients: a simple biological score

In first‐line metastatic colorectal cancer (mCRC), baseline prognostic factors allowing death risk and treatment strategy stratification are lacking. Syndecan‐1 (CD138) soluble form was never described as a prognostic biomarker in mCRC. We investigated its additional prognostic value for overall survival (OS). mCRC patients with unresectable disease at diagnosis were treated with bevacizumab‐based chemotherapy in two independent prospective clinical trials (development set: n = 126, validation set: n = 51, study NCT00489697 and study NCT00544011, respectively). Serums were collected at baseline for CD138 measurement. OS determinants were assessed and, based on the final multivariate model, a prognostic score was proposed. Two independent OS prognostic factors were identified: Lactate Dehydrogenase (LDH) high level (p = 0.0066) and log‐CD138 high level (p = 0.0190). The determination of CD138 binary information (cutoff: 75 ng/mL) allowed the assessment of a biological prognostic score with CD138 and LDH values, identifying three risk groups for death (median OS= 38.9, 30.1 and 19.8 months for the low, intermediate and high risk groups, respectively; p < 0.0001). This score had a good discrimination ability (C‐index = 0.63). These results were externally confirmed in the validation set. Our study provides robust evidence in favor of the additional baseline soluble CD138 prognostic value for OS, in mCRC patients. A simple biological scoring system is proposed including LDH and CD138 binary status values.     

Efficacy and Safety of Two Neoadjuvant Strategies With Bevacizumab in MRI-Defined Locally Advanced T3 Resectable Rectal Cancer: Final Results of a Randomized,Noncomparative Phase 2 INOVA Study

BackgroundRecurrence and distant metastases remain a significant issue in locally advanced rectal cancer (LARC). Several multimodal strategies are assessed in clinical trials.Patients and MethodsPatients with mid/low magnetic resonance imaging–defined high-risk LARC were randomized to arm A (12-week bevacizumab + FOLFOX-4 then bevacizumab–5-fluorouracil [5-FU]–radiotherapy [RT] before total mesorectal excision [TME]) or arm B (bevacizumab-5-FU–RT then TME). Long-term efficacy and safety up to 5 years’ follow-up are reported. No comparison between arms was planned.ResultsOverall, 91 patients (46 in arm A and 45 in arm B) were included. Main results have been presented previously. During the late follow-up period (> 4 weeks after surgery), 4 patients (8.7%) in arm A and 4 (8.9%) in arm B experienced grade 3/4 adverse events related to bevacizumab; the most frequent were 2 anastomotic fistulas (both in arm A) and abscesses (1 in arm A and 2 in arm B). At 5 years’ follow-up, 9 (19.6%) and 11 (24.4%) patients in arms A and B developed a fistula in the year after surgery, and 2 (4.3%) in arm A at > 1 year after surgery. Most resolved before study end. Five-year disease-free survival was 70% and 64.3% in arms A and B, respectively. Five-year overall survival was 90.5% (95% confidence interval, 76.7, 96.3) in arm A and 72.7% (95% confidence interval, 56.0, 83.9) in arm B.ConclusionNeoadjuvant bevacizumab + FOLFOX-4 may have the potential to increase survival outcomes when followed by bevacizumab–5-FU–RT and TME in LARC. Bevacizumab–5-FU–RT then TME was associated with a higher-than-projected rate of anastomotic fistulas. Further research of neoadjuvant strategies in LARC is encouraged.     

A tailored lifestyle intervention to reduce the cardiovascular disease risk of individuals with Familial Hypercholesterolemia (FH): design of the PRO-FIT randomised controlled trial

Background  

Because of a high cardiovascular disease (CVD) risk in people with Familial Hypercholesterolemia (FH), early prevention of cardiovascular disease is important for health gain and cost reduction. This project focuses on the development and evaluation of an innovative intervention aiming to reduce CVD risk by promoting a healthy lifestyle among people with FH.     

D-dimer in the diagnostic workup of suspected pulmonary thrombo-embolism at high altitude

Background

Pulmonary thrombo-embolism (PTE) is relatively common in high altitude areas where radiological diagnostic facilities are usually not available. So this study was undertaken to use the results of D-dimer assay to determine the need for imaging studies in patients suspected of having PTE at high altitude.

Methods

A total of 101 patients at an altitude of > 3,000 m suspected of having PTE were evacuated. D-dimer and imaging studies were carried out to confirm the diagnosis.

Results

A total of 101 patients suspected of having PTE underwent D-dimer level estimation and imaging studies for PTE. Sixty-eight of these had negative findings) on D-dimer assay. All these patients with negative findings on D-dimer assay had negative findings on pulmonary imaging studies also. So this test is very sensitive with very high negative predictive value (NPV). Whereas, 17 out of 33 patients positive for D-dimer, had positive findings on imaging studies, indicating a relatively less specific test.

Conclusion

Clinical assessment in combination with D-dimer assay can be used for timely differentiation of PTE from other conditions such as high altitude pulmonary oedema (HAPO) especially at isolated high altitude areas/military posts, so that patients could be evacuated as early as possible by fastest means to save the precious lives and in hospital settings this test identifies patients to whom anticoagulant therapy should not be given or patients who should not be subjected to invasive imaging tests.Key Words: D-dimer test, PTE     

Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects.

A high level of polycystin-1 expression is detected in kidneys of all patients with autosomal dominant polycystic kidney disease (ADPKD). Mice that overexpress polycystin-1 also develop renal cysts. Whether overexpression of polycystin-1 is necessary for cyst formation is still unclear. Here, we report the generation of a targeted mouse mutant with a null mutation in Pkd1 and its phenotypic characterization in comparison with the del34 mutants that carry a 'truncation mutation' in Pkd1. We show that null homozygotes develop the same, but more aggressive, renal and pancreatic cystic disease as del34/del34. Moreover, we report that both homozygous mutants develop polyhydramnios, hydrops fetalis, spina bifida occulta and osteochondrodysplasia. Heterozygotes also develop adult-onset pancreatic disease. We show further that del34 homozygotes continue to produce mutant polycystin-1, thereby providing a possible explanation for increased immunoreactive polycystin-1 in ADPKD cyst epithelia in the context of the two-hit model. Our data demonstrate for the first time that loss of polycystin-1 leads to cyst formation and defective skeletogenesis, and indicate that polycystin-1 is critical in both epithelium and chondrocyte development.     

Safety, tolerability and immunogenicity of VAQTA given concomitantly versus nonconcomitantly with other pediatric vaccines in healthy 12-month-old children

BACKGROUND: The objective of this study is to assess whether hepatitis A vaccine is immunogenic and well tolerated when administered to 12-month-old children alone or concomitantly with other routinely administered pediatric vaccines. METHODS: Six hundred seventeen healthy 12-month-old children were randomized to receive dose 1 of hepatitis A vaccine given alone or concomitantly with measles-mumps-rubella vaccine and varicella vaccine and dose 2 of hepatitis A vaccine given alone or concomitantly with diphtheria-tetanus-acellular pertussis vaccine and optionally with oral or inactivated poliovirus vaccine. Participants were followed for clinical adverse experiences and serologic responses to all vaccine antigens. Antibody responses were compared with historical controls for some indices. RESULTS: The safety profile was generally comparable whether hepatitis A vaccine was administered alone or concomitantly with other vaccines. When administered alone, the hepatitis A seropositivity rate was 98.3% and 100% for dose 1 and dose 2, respectively, and after dose 2 was similar to historical rates and the geometric mean titers were similar between initially seropositive and initially seronegative subjects (6207 and 6810 mIU/mL, respectively). After concomitant administration with hepatitis A vaccine, antibody responses to measles, mumps, rubella, diphtheria, tetanus and filamentous hemagglutinin (98.8%, 99.6%, 100%, 98.6%, 100% and 83.3%, respectively) were similar to historical controls and response to poliovirus was demonstrated, but immune responses to varicella zoster virus (79%) and pertussis toxoid (76%) were inferior to historical controls. CONCLUSIONS: Hepatitis A vaccine is highly immunogenic and generally well tolerated when administered to healthy children as young as 12 months of age regardless of initial hepatitis A serostatus and can be administered concomitantly with measles-mumps-rubella vaccine and oral or inactivated poliovirus vaccine.     

安心酮注射剂研制及其稳定性研究

以正交设计筛选处方,研制了安心酮注射剂,考察了制剂的稳定性,有效期为２．８５年。采用酸性染料比色法测定注射剂中安心酮的含量,平均回收率为９８．７％（ＲＳＤ＝０．４４％）。本品对离体灌流豚鼠心脏的作用与原药相似。