Tumor budding outperforms ypT and ypN classification in predicting outcome of rectal cancer after neoadjuvant chemoradiotherapy

BACKGROUND: Budding is a complementary prognostic factor for colorectal cancer. In this study, we aimed to clarify the role of tumor budding in rectal cancer patients after preoperative chemoradiotherapy. METHODS: A total of 124 patients with rectal cancer treated with neoadjuvant chemoradiotherapy and consecutive surgery were included. Surgical specimens were evaluated for budding and routine clinicopathological features. Budding was evaluated on hematoxylin and eosin (H&E)-stained slides and by cytokeratin immunohistochemical (IHC) staining. RESULTS: A budding rate of 36.9% (n = 38) by H&E and 55.6% (n = 55) by IHC was observed. Budding was significantly associated with a high ypT and ypN status, poor differentiation, and low degrees of tumor regression. Moreover, budding was strongly predictive of a worse patient outcome, as measured by tumor recurrence or death. In multivariate analyses, budding remained the only significant parameter for overall survival and was even superior to the ypT and ypN status (budding in H&E: hazard ratio (HR) 2.72, 95% confidence interval (95% CI) 1.15-6.44, p = 0.023; budding in IHC: HR 5.19, 95% CI 1.62-16.61, p = 0.006). CONCLUSION: Budding is a strong prognostic predictor of survival in rectal cancer patients after neoadjuvant therapy. A standardized evaluation of tumor budding after neoadjuvant therapy may thus aid in risk stratification and guide the clinical management of patients with rectal cancer. Immunostaining can help to enhance the diagnostic accuracy and prognostic significance

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

an immunhistochemical expressionanalysis and correlation with clinical risk factors

Hintergrund Ziel dieser Arbeit war es, die prädiktive Relevanz von p53, p21 und der Caspase-3 in verschiedenen Zellkompartimenten hinsichtlich des Ansprechens von Rektumkarzinomen auf die neoadjuvante Radiochemotherapie (Response) zu untersuchen. Zusätzlich wurde der Zusammenhang zwischen klinischen und pathohistologischen Parametern und der Response untersucht. Material und Methode Insgesamt konnte an 104/105 Patienten eine immunhistochemische Expressionsanalyse der präoperativen Biopsate durchgeführt werden, sowie klinische und pathohistologische Daten und die Tumorresponse von 128 Patienten erhoben werden. Die Berechnung der Korrelation zwischen Immunexpression und Response erfolgte mittels Mann-Whitney- und Chi-Quadrat- Test, die Berechnung der Entwicklung der Expression unter der neoadjuvanten Radiochemotherapie erfolgte mittels Wilcoxon- Rank-Test. Eine multivariate Analyse wurde mittels binärer logistischer Regression durchgeführt, um die Unabhängigkeit der einzelnen Faktoren zu testen. Ergebnisse Innerhalb des Patientenkollektivs reagierten 32% der Patienten als „Responder“ und 68% als „Non-Responder“ auf die neoadjuvante Radiochemotherapie. Der nukleäre Expressionsgrad der p21-gefärbten Biopsien korrelierte signifikant mit der Response (p<0,0005). Bei der Bildung eines Cut Off’s von 1% bei der Auswertung der nukleären p21-Expression ergab sich eine Sensitivität von 91,4% und eine Spezifität von 30,4% bei einer signifikanten Korrelation mit der Response (p=0,013). Setzt man den Cut Off bei 5% ergab sich eine Spezifität von 82,6% bei einer signifikanten Korrelation mit der Response (p<0,0005). Die Kombination beider und die Bildung dreier Subgruppen führte zu einem monotonen Anstieg innerhalb der Gruppen: Gruppe eins (0%): 8,6% an Respondern, Gruppe zwei (1-4%): 34,3% an Respondern, Gruppe drei (5% und >): 57,1% an Respondern bei signifikanter Korrelation (p<0,0005). Insgesamt vergrößerte sich der Expressionsgrad der zytoplasmatischen p21-Expression signifikant unter der neoadjuvanten Radiochemotherapie (p<0,0005), die Anzahl an Caspase-3-gefärbten intakten Zellen und die Anzahl der Schmutznekrosen stieg signifikant an (p<0,0005/p=0,028). Die yp-T-Kategorie, die yp-N-Kategorie und der Nikotinabusus korrelierten signifikant mit der Response (p<0,0005/p=0,002/p=0,015). In der multivariaten Analyse stellten sich die Faktoren p21 mit einem Cut Off bei 5% und p21 nukleär in drei Gruppen (0%, 1-4%, 5% und >) als unabhängige Prädiktoren bezüglich der Response dar p=0,002/p=0,006). Schlussfolgerung Eine nukleäre p21-Expression in der Biopsie fungiert als prädiktiver Marker bezüglich der Response auf die neoadjuvante Radiochemotherapie mit geeigneten Cut Off’s bei 1% und bei 5%.Background The predictive relevance of p21, p53 and caspase-3 regarding the response of rectal carcinomas to the preoperative radiochemotherapy was analysed. Additionally the relation of clinical and pathohistological parameters to the response was tested. Material and Methods 104/105 preoperative biopsies were immunhistochemically stained and analysed and clinical and pathohistological data as well as the tumor response of 128 patients were collected. The correlation between the immunexpression and the tumor response was statistically tested using the Mann-Whitney-Test and the Chi-Quadrat-Test. The calculation of the development of the immunexpression during the preoperativ radiochemotherapy was perfomed by the Wilcoxon-Rank- Test. A multivariate analysis was done using the logistic regression, to test the independence of the single factors. Results There were 32% therapy responders and 68% non-responders. The nuclear p21 expression in the biopsies performed before radiochemotherapy correlated significantly with the response to this treatment (p<0,0005). The analysis of p21 revealed a sensitivity of 91,4% and a specificity of 30,4% as well as a significant correlation, if refering to a cut off at 1% (p=0,013). A cut off at 5% resulted in a specificity of 82,6% and a significant correlation with the response (p<0,0005). The implementation of both cut off points generated three groups significantly correlating with the response (p<0,0005): group one (0% expression) in 8,6% of responders, group two (1-4% expression) in 34,3% of responders, group three (5% and >) in 57,1% of the responders. Furthermore after radiochemotherapy there was an increase of the cytoplasmatic p21 expression (p<0,0005), as well as of the number of caspase-3 stained cells and of caspase-3 stained dirty necrosis (p<0,0005, p=0,028). The yp-tcategory and the yp-n-category as well as smoking correlated significantly with the treatment response (p<0,0005, p=0,002, p=0,015). The multivariate analysis showed that the nuclear p21-expression with a cut off point at 5% and p21 divided into three groups (0%, 1-4%, 5% and >) are independent predictors regarding therapy response (p=0,002/p=0,006). Conclusion The nuclear expression of p21 with suitable cut off´s at 1% and 5% can be seen as a predictive marker regarding the response to the preoperative radiotherapy of rectal carcinomas

Characterizing tuberculosis progression in wild meerkats (Suricata suricatta) from fecal samples and clinical signs

Tuberculosis (TB) is an increasing threat to wildlife, yet tracking its spread is challenging because infections often appear to be asymptomatic, and diagnostic tools such as blood tests can be invasive and resource intensive. Our understanding of TB biology in wildlife is therefore limited to a small number of well-studied species. Testing of fecal samples using PCR is a noninvasive method that has been used to detect Mycobacterium bovis shedding amongst badgers, yet its utility more broadly for TB monitoring in wildlife is unclear. We combined observation data of clinical signs with PCR testing of 388 fecal samples to characterize longitudinal dynamics of TB progression in 66 wild meerkats (Suricata suricatta) socially exposed to Mycobacterium suricattae between 2000 and 2018. Our specific objectives were 1) to test whether meerkat fecal samples can be used to monitor TB; 2) to characterize TB progression between three infection states (PCR-negative exposed, PCR-positive asymptomatic, and PCR positive with clinical signs); and 3) estimate individual heterogeneity in TB susceptibility, defined here as the time between TB exposure and detection, and survival after TB detection. We found that the TB detection probability once meerkats developed clinical signs was 13% (95% confidence interval 3–46%). Nevertheless, with an adapted test protocol of 10 PCR replicates per sample we detected hidden TB infections in 59% of meerkats before the onset of clinical signs. Meerkats became PCR positive approximately 14 mo after initial exposure, developed clinical signs approximately 1 yr after becoming PCR positive, and died within 5 mo of developing clinical signs. Individual variation in disease progression was high, with meerkats developing clinical signs from immediately after exposure to 3.4 yr later. Overall, our study generates novel insights into wildlife TB progression, and may help guide adapted management strategies for TB-susceptible wildlife populations

Improved measurement of CPCP violation parameters in Bs0→J/ψK+K−B_s^0\to J/\psi K^+K^- decays in the vicinity of the ϕ(1020)\phi(1020) resonance

The decay-time-dependent $CP$ asymmetry in $B_s^0\to J/\psi(\to \mu^+\mu^-) K^+ K^-$ decays is measured using proton-proton collision data, corresponding to an integrated luminosity of $6 {\rm fb}^{-1}$, collected with the LHCb detector at a center-of-mass energy of 13 TeV. Using a sample of approximately 349 000 $B_s^0$ signal decays with an invariant $K^+ K^-$ mass in the vicinity of the $\phi(1020)$ resonance, the $CP$-violating phase $\phi_s$ is measured, along with the difference in decay widths of the light and heavy mass eigenstates of the $B_s^0$-$\overline{B}_s^0$ system, $\Delta\Gamma_s$, and the difference of the average $B_s^0$ and $B^0$ meson decay widths, $\Gamma_s-\Gamma_d$. The values obtained are $\phi_s = -0.039 \pm 0.022 \pm 0.006$ rad, $\Delta\Gamma_s = 0.0845 \pm 0.0044 \pm 0.0024 ~{\rm ps}^{-1}$ and $\Gamma_s-\Gamma_d = -0.056^{\:+\:0.0013}_{\:-\:0.0015} \pm 0.0014 ~{\rm ps}^{-1}$, where the first uncertainty is statistical and the second systematic. These are the most precise single measurements to date and are consistent with expectations based on the Standard Model and with the previous LHCb analyses of this decay. These results are combined with previous independent LHCb measurements. The phase $\phi_s$ is also measured independently for each polarization state of the $K^+K^-$ system and shows no evidence for polarization dependence.The decay-time-dependent $CP$ asymmetry in $B^0_s\to J/\psi(\to \mu^{+}\mu^{-}) K^{+}K^{-}$ decays is measured using proton-proton collision data, corresponding to an integrated luminosity of 6 $fb^{-1}$, collected with the LHCb detector at a center-of-mass energy of 13 TeV. Using a sample of approximately 349 000 $B^{0}_{s}$ signal decays with an invariant $K^{+}K^{-}$ mass in the vicinity of the $\phi(1020)$ resonance, the $CP$-violating phase $\phi_s$ is measured, along with the difference in decay widths of the light and heavy mass eigenstates of the $B^0_s$-$\bar{B}^0_s$ system, $\Delta\Gamma_s$, and the difference of the average $B^0_s$ and $B^0$ meson decay widths, $\Gamma_s-\Gamma_d$. The values obtained are $\phi_s = \ -0.039 \pm 0.022 \pm 0.006$ rad, $\Delta\Gamma_s = 0.0845 \pm 0.0044 \pm 0.0024$ ps$^{-1}$ and $\Gamma_s-\Gamma_d = -0.0056 ^{+ 0.0013}_{-0.0015} \pm 0.0014$ ps$^{-1}$, where the first uncertainty is statistical and the second systematic. These are the most precise single measurements to date and are consistent with expectations based on the Standard Model and with the previous LHCb analyses of this decay. These results are combined with previous independent LHCb measurements. The phase $\phi_s$ is also measured independently for each polarization state of the $K^{+}K^{-}$ system and shows no evidence for polarization dependence

Search for Bc+→π+μ+μ−B_c^+\to\pi^+\mu^+\mu^- decays and measurement of the branching fraction ratio B(Bc+→ψ(2S)π+)/B(Bc+→J/ψπ+){\cal B}(B_c^+\to\psi(2S)\pi^+)/{\cal B}(B_c^+\to J/\psi \pi^+)

International audienceThe first search for nonresonant $B_c^+\to\pi^+\mu^+\mu^-$ decays is reported. The analysis uses proton-proton collision data collected with the LHCb detector between 2011 and 2018, corresponding to an integrated luminosity of 9 fb$^{-1}$. No evidence for an excess of signal events over background is observed and an upper limit is set on the branching fraction ratio ${\cal B}(B_c^+\to\pi^+\mu^+\mu^-)/{\cal B}(B_c^+\to J/\psi \pi^+) < 2.1\times 10^{-4}$ at $90\%$ confidence level. Additionally, an updated measurement of the ratio of the $B_c^+\to\psi(2S)\pi^+$ and $B_c^+\to J/\psi \pi^+$ branching fractions is reported. The ratio ${\cal B}(B_c^+\to\psi(2S)\pi^+)/{\cal B}(B_c^+\to J/\psi \pi^+)$ is measured to be $0.254\pm 0.018 \pm 0.003 \pm 0.005$, where the first uncertainty is statistical, the second systematic, and the third is due to the uncertainties on the branching fractions of the leptonic $J/\psi$ and $\psi(2S)$ decays. This measurement is the most precise to date and is consistent with previous LHCb results

Probing the nature of the χc1(3872)\chi_{c1}(3872) state using radiative decays

International audienceThe radiative decays $\chi_{c1}(3872)\rightarrow\psi(2S)\gamma$ and $\chi_{c1}(3872)\rightarrow J/\psi\gamma$ are used to probe the~nature of the~$\chi_{c1}(3872)$ state using proton-proton collision data collected with the LHCb detector, corresponding to an~integrated luminosity of~9fb$^{-1}$. Using the~$B^+\rightarrow \chi_{c1}(3872)K^+$decay, the $\chi_{c1}(3872)\rightarrow \psi(2S)\gamma$ process is observed for the first time and the ratio of its partial width to that of the $\chi_{c1}(3872)\rightarrow J/\psi\gamma$ decay is measured to be $$\frac{\Gamma_{\chi_{c1}(3872)\rightarrow \psi(2S)\gamma}} {\Gamma_{\chi_{c1}(3872)\rightarrow J/\psi\gamma}} = 1.67 \pm 0.21 \pm 0.12 \pm0.04 ,$$ where the first uncertainty is statistical, the second systematic and the third is due to the uncertainties on the branching fractions of the $\psi(2S)$ and $J/\psi$ mesons. The measured ratio makes the interpretation of the $\chi_{c1}(3872)$ state as a~pure $D^0\bar{D}^{*0}+\bar{D}^0D^{*0}$ molecule questionable and strongly indicates a sizeable compact charmonium or tetraquark component within the $\chi_{c1}(3872)$ state

Search for Bc+→π+μ+μ−B_c^+\to\pi^+\mu^+\mu^- decays and measurement of the branching fraction ratio B(Bc+→ψ(2S)π+)/B(Bc+→J/ψπ+){\cal B}(B_c^+\to\psi(2S)\pi^+)/{\cal B}(B_c^+\to J/\psi \pi^+)

International audienceThe first search for nonresonant $B_c^+\to\pi^+\mu^+\mu^-$ decays is reported. The analysis uses proton-proton collision data collected with the LHCb detector between 2011 and 2018, corresponding to an integrated luminosity of 9 fb$^{-1}$. No evidence for an excess of signal events over background is observed and an upper limit is set on the branching fraction ratio ${\cal B}(B_c^+\to\pi^+\mu^+\mu^-)/{\cal B}(B_c^+\to J/\psi \pi^+) < 2.1\times 10^{-4}$ at $90\%$ confidence level. Additionally, an updated measurement of the ratio of the $B_c^+\to\psi(2S)\pi^+$ and $B_c^+\to J/\psi \pi^+$ branching fractions is reported. The ratio ${\cal B}(B_c^+\to\psi(2S)\pi^+)/{\cal B}(B_c^+\to J/\psi \pi^+)$ is measured to be $0.254\pm 0.018 \pm 0.003 \pm 0.005$, where the first uncertainty is statistical, the second systematic, and the third is due to the uncertainties on the branching fractions of the leptonic $J/\psi$ and $\psi(2S)$ decays. This measurement is the most precise to date and is consistent with previous LHCb results