Comprehensive geriatric assessment in older patients with cancer: an external validation of the multidimensional prognostic index in a French prospective cohort study.

BACKGROUND: Older patients with cancer require specific and individualized management. The 3-group Multidimensional Prognostic Index (MPI) based on the Comprehensive Geriatric Assessment (CGA) has shown a predictive interest in terms of mortality. The objective of our study was to assess the prognostic value of MPI for 1-year mortality in an external prospective French cohort of elderly patients with cancer. METHODS: From March 2015 to March 2017 a prospective single-center cohort study enrolled all patients with cancer, aged 75 years and older referred to the geriatric oncology clinic. We used a proportional hazard model for 1-year mortality adjusted for age, sex, tumor sites and metastatic status. C-statistics were used to assess the incremental predictive value of MPI index to these risk factors. RESULTS: overall, 433 patients underwent CGA with MPI (women 42%; mean age 82.8 ± 4.8 years). The most common tumor sites were prostate (23%), skin (17%), colorectum (15%) and breast (12%); 29% of patients had a metastatic disease; 231 patients (53%) belonged to the "MPI-1" group, 172 (40%) to the "MPI-2" group and 30 patients were classified in the "MPI-3" group. One-year mortality rate was 32% (23% in MPI-1, 41% in MPI-2 and 53% in MPI-3, p = 0.024). All domains of MPI except cognition and living status were significantly associated with mortality at one-year, as well as tumor sites and metastatic status. Higher MPI was associated with a higher mortality risk (adjusted HR 1.56 [95%CI 1.70-2.09] and 1.72 [1.33-2.22] for MPI groups 2 and 3 compared to 1; p < 0.0001). CONCLUSIONS: In addition to established risk factors, MPI improves risk prediction of 1-year mortality. This practical prognostic tool may help to optimize management of these vulnerable patients.

Bisphenol A, Chlorinated Derivatives of Bisphenol A and Occurrence of Myocardial Infarction in Patients with Type 2 Diabetes: Nested Case-Control Studies in Two European Cohorts.

A positive association between Bisphenol A (BPA) exposure and coronary heart disease has been shown, but not in patients with type 2 diabetes (T2D). During the treatment of drinking water, chlorination leads to the formation of chlorinated derivatives of Bisphenol A (ClxBPA), that have higher estrogenic activity than BPA. No evidence exists for a relationship between exposure to ClxBPA and myocardial infarction in patients with T2D. The objective of this study was to evaluate the relationship between exposure to BPA, ClxBPA and the occurrence of myocardial infarction (MI) in patients with T2D. Two nested case-control studies in two independent European cohorts were performed. Each case with incident MI during follow-up was matched to one control on age, sex, and personal cardiovascular history in the same cohort. Association between baseline urine concentrations of BPA and of ClxBPA and incident MI was determined. Exposure to BPA was 31% in the ESTHER cohort and 18% in the SURDIAGENE cohort. In a meta-analysis of the two studies, occurrence of MI was significantly associated with urine BPA detection: adjusted OR = 1.97 (1.05-3.70), p = 0.04. Exposure to ClxBPA significantly differed in the SURDIAGENE and ESTHER studies: 24% and 8%, respectively (p = 0.0003). It was very strongly associated with MI in the SURDIAGENE cohort with an adjusted odds ratio (OR) of 14.15 (2.77-72.40) but this association was not replicated in the ESTHER study: adjusted OR: 0.17 (0.02-1.23). Whether these results may be explained by different water chlorination processes in France and Germany, resulting in different ClxBPA exposure levels, requires further investigation.

Combined Analyses of Chloroplast DNA Haplotypes and Microsatellite Markers Reveal New Insights Into the Origin and Dissemination Route of Cultivated Pears Native to East Asia.

Asian pear plays an important role in the world pear industry, accounting for over 70% of world total production volume. Commercial Asian pear production relies on four major pear cultivar groups, Japanese pear (JP), Chinese white pear (CWP), Chinese sand pear (CSP), and Ussurian pear (UP), but their origins remain controversial. We estimated the genetic diversity levels and structures in a large sample of existing local cultivars to investigate the origins of Asian pears using twenty-five genome-covering nuclear microsatellite (simple sequence repeats, nSSR) markers and two non-coding chloroplast DNA (cpDNA) regions (trnL-trnF and accD-psaI). High levels of genetic diversity were detected for both nSSRs (HE = 0.744) and cpDNAs (Hd = 0.792). The major variation was found within geographic populations of cultivated pear groups, demonstrating a close relationship among cultivar groups. CSPs showed a greater genetic diversity than CWPs and JPs, and lowest levels of genetic differentiation were detected among them. Phylogeographical analyses indicated that the CSP, CWP, and JP were derived from the same progenitor of Pyrus pyrifolia in China. A dissemination route of cultivated P. pyrifolia estimated by approximate Bayesian computation suggested that cultivated P. pyrifolia from the Middle Yangtze River Valley area contributed the major genetic resources to the cultivars, excluding those of southwestern China. Three major genetic groups of cultivated Pyrus pyrifolia were revealed using nSSRs and a Bayesian statistical inference: (a) JPs; (b) cultivars from South-Central China northward to northeastern China, covering the main pear production area in China; (c) cultivars from southwestern China to southeastern China, including Yunnan, Guizhou, Guangdong, Guangxi, and Fujian Provinces. This reflected the synergistic effects of ecogeographical factors and human selection during cultivar spread and improvement. The analyses indicated that UP cultivars might be originated from the interspecific hybridization of wild Pyrus ussuriensis with cultivated Pyrus pyrifolia. The combination of uniparental DNA sequences and nuclear markers give us a better understanding of origins and genetic relationships for Asian pear groups and will be beneficial for the future improvement of Asian pear cultivars.

Salutaxel, a Conjugate of Docetaxel and a Muramyl Dipeptide (MDP) Analogue, Acts as Multifunctional Prodrug That Inhibits Tumor Growth and Metastasis.

Salutaxel (3) is a conjugate of docetaxel (7) and a muramyl dipeptide (MDP) analogue. Docetaxel (7) has been recognized as a highly active chemotherapeutic agent against various cancers. MDP and its analogues are powerful potentiators of the antitumor actions of various tumor-necrotizing agents. This article documents the discovery of compound 3 and presents pharmacological proof of its biological function in tumor-bearing mice. Drug candidate 3 was superior to compound 7 in its ability to prevent tumor growth and metastasis. Compound 3 suppressed myeloid-derived suppressor cell (MDSC) accumulation in the spleens of tumor-bearing mice and decreased various serum inflammatory cytokines levels. Furthermore, compound 3 antagonized the nucleotide-binding oligomerization domain-like receptor 1 (NOD1) signaling pathway both in vitro and in vivo.

Comparative pharmacokinetics and bile transformation of R-enantiomer and racemic bambuterol after single-dose intravenous, oral administration in rats and beagle dogs.

This study was to compare pharmacokinetics and bile transformation of R-enantiomer bambuterol with its racemate. Pharmacokinetics of R-enantiomer was investigated after single-dose intravenous and three doses of oral administration to rats and beagle dogs. To compare the pharmacokinetics with racemic bambuterol, the same oral doses of racemic bambuterol were also administrated; the blood and bile samples were collected by cannulation. A validated LC-MS/MS method was used to assess the level of bambuterol in plasma and bile. After single intravenous administration, no significant differences were observed between the two drugs in pharmacokinetic data. After oral dosing of R-bambuterol, the AUCs of R-enantiomer presented linear correlation. After same oral dosing of R-enantiomer and its racemate, all the pharmacokinetic parameters were equivalent. However, the clearance and apparent distribution had different results due to species and administration route difference. The bile transformation of these two compounds was similar and implicated that liver transformation accounted for the major metabolism of them. The bioavailability of R-enantiomer and racemate were comparative and relatively high in beagle dogs. Thus, R-enantiomer had a comparative pharmacokinetic profile and bile transformation with racemic bambuterol in rats and beagle dogs. These findings provided references for further clinical study.

Molecular evolution of Adh and LEAFY and the phylogenetic utility of their introns in Pyrus (Rosaceae).

BACKGROUND: The genus Pyrus belongs to the tribe Pyreae (the former subfamily Maloideae) of the family Rosaceae, and includes one of the most important commercial fruit crops, pear. The phylogeny of Pyrus has not been definitively reconstructed. In our previous efforts, the internal transcribed spacer region (ITS) revealed a poorly resolved phylogeny due to non-concerted evolution of nrDNA arrays. Therefore, introns of low copy nuclear genes (LCNG) are explored here for improved resolution. However, paralogs and lineage sorting are still two challenges for applying LCNGs in phylogenetic studies, and at least two independent nuclear loci should be compared. In this work the second intron of LEAFY and the alcohol dehydrogenase gene (Adh) were selected to investigate their molecular evolution and phylogenetic utility. RESULTS: DNA sequence analyses revealed a complex ortholog and paralog structure of Adh genes in Pyrus and Malus, the pears and apples. Comparisons between sequences from RT-PCR and genomic PCR indicate that some Adh homologs are putatively nonfunctional. A partial region of Adh1 was sequenced for 18 Pyrus species and three subparalogs representing Adh1-1 were identified. These led to poorly resolved phylogenies due to low sequence divergence and the inclusion of putative recombinants. For the second intron of LEAFY, multiple inparalogs were discovered for both LFY1int2 and LFY2int2. LFY1int2 is inadequate for phylogenetic analysis due to lineage sorting of two inparalogs. LFY2int2-N, however, showed a relatively high sequence divergence and led to the best-resolved phylogeny. This study documents the coexistence of outparalogs and inparalogs, and lineage sorting of these paralogs and orthologous copies. It reveals putative recombinants that can lead to incorrect phylogenetic inferences, and presents an improved phylogenetic resolution of Pyrus using LFY2int2-N. CONCLUSIONS: Our study represents the first phylogenetic analyses based on LCNGs in Pyrus. Ancient and recent duplications lead to a complex structure of Adh outparalogs and inparalogs in Pyrus and Malus, resulting in neofunctionalization, nonfunctionalization and possible subfunctionalization. Among all investigated orthologs, LFY2int2-N is the best nuclear marker for phylogenetic reconstruction of Pyrus due to suitable sequence divergence and the absence of lineage sorting.

Long-term outcome of laparoscopic total mesorectal excision for middle and low rectal cancer.

This study aimed to assess the feasibility and long-term outcome of laparoscopic total mesorectal excision for middle and lower rectal cancer. Retrospective assessment was performed on 612 patients with middle and low rectal cancer in the surgery department of our hospital. Three-hundred and three patients underwent laparoscopic total mesorectal excision (LTME), and 309 patients underwent open TME (OTME). All the data regarding patient details, operative variables and the short- and long-term outcomes were collected and compared. The sphincter-preserving rates of the two groups were similar. The conversion rate in LTME was 2.31% (seven cases). Fourteen cases (6.67%) of protective diverting stoma were fashioned in the LTME group compared with 57 cases (26.64%) in the OTME group. The postoperative morbidity was the same in these two groups, while the postoperative period until bowel movement and hospital discharge was shorter in the LTME group (P < 0.01). The median follow-up period was 34 (6-81) months for the LTME group and 36 (6-81) months for the OTME group. Local recurrence rates, the five-year disease-free survival rate and the five-year overall survival rate showed no difference between the two groups. Laparoscopic surgery is feasible and safe in patients with middle and lower rectal cancer and can provide favorable short-term and long-term outcomes.