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Neoadjuvant treatment (nTx) for rectal cancer is commonly reserved for UICC stages II/III. Patients with stage I tumours (T1-2N0M0) are not candidates for nTx. The accuracy of treatment allocation depends on the precision of clinical staging, which is liable to understaging and overstaging. The study aimed at exploring changes in the proportion of stage pI patients with the introduction of nTx over a 26-year period.All consecutive patients with histologically proven rectal cancer excluding carcinoma in situ were retrieved from a prospective database of our colorectal unit. Time periods were defined as per the use of nTx: baseline phase 1994-1997; implementation phase 1998-2005 and guideline phase 2006-2019. Trends over time regarding proportion of applied nTx and stage pI tumours were investigated.Overall, 1468 patients met the inclusion criteria. There were no major differences in patients' characteristics, especially proportion of synchronous metastases (stage IV) over time. nTx was applied to 1.2% of patients without metastases in the baseline phase, to 29.6% in the implementation phase, and to 59.6% in the guideline phase (p 0.001). Corresponding proportions for patients with stage pI were 31.0%, 26.3% and 14.2%, respectively (p 0.001).With a stable proportion of stage IV carcinomas indicating no major changes in the patient cohorts, we could document a significant decrease of stage pI patients with increasing use of nTx. This trend clearly signals overtreatment caused by clinical T- and N-staging. More precise criteria are needed to better select patients with rectal cancer for nTx.

Centralization of cancer care is expected to yield superior results. In Germany, the national strategy is based on a voluntary certification process. The effect of centre certification is difficult to prove because quality data are rarely available prior to certification. This observational study aims to assess outcomes for rectal cancer patients before and after implementation of a certified cancer centre. All consecutive patients treated for rectal cancer in our certified centre from 2009 to 2017 were retrieved from a prospective database. The dataset was analyzed according to a predefined set of 19 quality indicators comprising 36 quality goals. The results were compared to an identical cohort of patients, treated from 2000 to 2008 just before centre implementation. In total, 1059 patients were included, 481 in the 2009–2017 interval and 578 in the 2000–2008 interval. From 2009 to 2017, 25 of 36 quality goals were achieved (vs. 19/36). The proportion of anastomotic leaks in low anastomoses was improved (13.5% vs. 22.1%, p = 0.018), as was the local 5-year recurrence rate for stage (y)pIII rectal cancers (7.7% vs. 17.8%, p = 0.085), and quality of mesorectal excision (0.3% incomplete resections vs. 5.5%, p = 0.002). Furthermore, a decrease of abdominoperineal excisions was noted (47.1% vs. 60.0%, p = 0.037). For the 2009–2017 interval, local 5-year recurrence rate in stages (y)p0-III was 4.6% and 5-year overall survival was 80.2%. Certification as specialized centre and regular audits were associated with an improvement of various quality parameters. The formal certification process has the potential to enhance quality of care for rectal cancer patients.

International audience; Understanding demographical processes underlying abundance and population size fluctuations is critical to species management. Knowing key parameters and responses to observed changes can reduce the number of realistic management scenarios. In hunted species, survival might be the targeted parameter for effective plans. The red-legged partridge Alectoris rufa is a native species in Mediterranean countries. The species is hunted, especially in France where some release plans are implemented. However, survival estimates are scarce there and most studies were conducted in Spain. Here, we took advantage of a radio-tracking experiment in southern France (200 birds surveyed) to estimate monthly and annual survival rates of both wild and released red-legged partridge and to investigate the temporal, spatial and individual variations in survival. We found very high annual survival rate in our island site (0.70) and low survival elsewhere (range: 0.25–0.29). We showed that age and sex were a significant source of variation in annual survival of wild birds with lower estimates for young and for females. The close survival between mainland sites with different mortality sources suggests that compensation may occur between predation and hunting mortality. However, a stronger assessment of this point is needed. Our study suggests that environment characteristics, especially landscape mosaic and predation pressure, was a driver of survival. On the island site, the red-legged partridge shows a different demographic tactics (higher survival, lower reproduction) than in mainland, suggesting an adaptation to the context (lower predation). Regarding hand-reared birds released just before the hunting season, their survival to the next spring was lower than 0.05. Such a low value raises the issue of using release before the hunting season for reinforcement purpose, especially due to negative impact through the general increase in hunting pressure it promotes. Habitat and hunting management may thus be a key to favour the red-legged partridge.

Bacillus thuringiensis var. israelensis (Bti) has become the most commonly used larvicide to control mosquitoes worldwide. Bti is considered non-toxic to most organisms, except some Diptera such as chironomids, which are a major prey in wetland food webs. Although Odonata are important predators of mosquitoes and chironomids at the larval and adult stages, no study has ever considered the potential indirect effects of Bti on Odonata abundance through trophic interactions. We addressed this topic in the Camargue where 2500 of the 25 000 ha of mosquito larval biotopes are Bti-sprayed (aqueous solution of VectoBac 12AS at 2.5 L ha−1) whenever mosquito larvae appear in water bodies (i.e. 30–50 aerial treatments overall annually). Adult Odonata were surveyed along a 100-m line transect in spring, summer and autumn at three control and three treated sites over a 5-year period. Mean number of species (9.9 vs. 5.2) and of individuals (100 vs. 50) detected per year were significantly higher in control areas compared to Bti-sprayed areas. Bti treatment contributed to 87.3% of the explained variance in Odonata richness, compared to 2.9% for site, 6.8% for year and 3.0% for salinity effects. These results are coherent with other studies carried out in the same area and time period highlighting a lower abundance of chironomids, and a lower intake of odonates by breeding birds in treated areas. We conclude that mosquito control using Bti should be acknowledged as a potential threat to Odonata.

The reliability of long-term population estimates is crucial for conservation and management purposes. Most game species population monitoring programs assume that count indices are proportionally related to abundance. However, this assumption is untenable when detection varies spatially and temporally. We assessed whether N-mixture models, which allow detection modeling using spatially and temporally repeated count data, were relevant for monitoring the population of red-legged partridge (Alectoris rufa). Unbiased estimates are needed for calculating hunting quotas for this game species. We used the simple aural playback point-count method and adatasetof 121 point-transects(n ¼16,288 counts) collected from 1992 to 2010. Covariates such as date, hour, wind, rain, and vegetation density influenced detection probability. Estimated abundance ranged from 0 to 15 males per point and exhibited variable coefficients of variation depending on sites (range: 0.14-1.31, mean: 0.44). We found a positive and linear relationship between the abundance estimated by the N-mixture model and the densities provided by 2 other counting methods, square sampling and kilometric abundance index, but not with blank beat. We established a maximum detection radius for the playback surveys, which enabled conversion of abundance at the points into density. The N-mixture modeling approach is more cost-effective for game species monitoring than capture-recapture methods or square sampling, and more reliable than indices of relative abundances. 2014 The Wildlife Society.

The tumor microenvironment plays a pivotal role during cancer development and progression. The balance between suppressive and cytotoxic responses of the tumor immune microenvironment has been shown to have a direct effect on the final outcome in various human and experimental tumors. Recently, we demonstrated that the oxygen sensor HIF-prolyl hydroxylase-2 (PHD2) plays a detrimental role in tumor cells, stimulating systemic growth and metastasis in mice. In our current study, we show that the conditional ablation of PHD2 in the hematopoietic system also leads to reduced tumor volume, intriguingly generated by an imbalance between enhanced cell death and improved proliferation of tumor cells. This effect seems to rely on the overall downregulation of protumoral as well as antitumoral cytokines. Using different genetic approaches, we were able to confine this complex phenotype to the crosstalk of PHD2-deficient myeloid cells and T-lymphocytes. Taken together, our findings reveal a multifaceted role for PHD2 in several hematopoietic lineages during tumor development and might have important implications for the development of tumor therapies in the future.

Summary The mammalian-target of rapamycin (also termed mechanistic target of rapamycin, mTOR) pathway integrates various pro-proliferative and anti-apoptotic stimuli and is involved in regulatory T-cell (TREG) development. As these processes contribute to the pathogenesis of myelodysplastic syndromes (MDS), we hypothesized that mTOR modulation with temsirolimus (TEM) might show activity in MDS. This prospective multicentre trial enrolled lower and higher risk MDS patients, provided that they were transfusion-dependent/neutropenic or relapsed/refractory to 5-azacitidine, respectively. All patients received TEM at a weekly dose of 25 mg. Of the 9 lower- and 11 higher-risk patients included, only 4 (20%) reached the response assessment after 4 months of treatment and showed stable disease without haematological improvement. The remaining patients discontinued TEM prematurely due to adverse events. Median overall survival (OS) was not reached in the lower-risk group and 296 days in the higher-risk group. We observed a significant decline of bone marrow (BM) vascularisation (P = 0·006) but were unable to demonstrate a significant impact of TEM on the balance between TREG and pro-inflammatory T-helper-cell subsets within the peripheral blood or BM. We conclude that mTOR-modulation with TEM at a dose of 25 mg per week is accompanied by considerable toxicity and has no beneficial effects in elderly MDS patients.

Successful management practices for declining bird species depend often on long-term surveys acquired by point counts. Despite high standardization of field protocols, uncertain detection probability remains an important source of variability and bias in point-count data. This effect is of main importance in low-responsive species as the Red-legged partridge (Alectoris rufa), but it can be counterbalanced, increasing detection probability. In this 2-year study, we sampled using traditional point-count methods, followed by playback sessions for each repetition. We measured detection probability and the efficiency of playback for detectability in the context of a feasibility study on long-term point-count surveys for a harvested game bird, the Red-legged partridge. The results for both study years show a distinct increase in detection probability (23% and 45%, respectively) when using playback vs. the traditional point-count method. We also tested our results for heterogeneity, trap dependence, and time dependence, and no effect was detected. Thus, we suggest that the future design of long-term surveys on Red-legged partridges should consider abundance indices using playback sessions.

In locally advanced rectal cancer, neoadjuvant 5-fluorouracil (5-FU)-based long-term chemoradiotherapy leads to marked tumor reduction and decrease of local recurrence rate. Thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are known to be important biomarkers to predict tumor response to 5-FU-based therapy. The aim of this study was to examine the correlation between TS, TP, and DPD protein expression and histopathologic tumor regression after neoadjuvant chemoradiotherapy. The results were compared with the recently published mRNA data. Preoperative biopsies (n = 25) and resection specimens (n = 40) from patients with rectal carcinoma (clinical UICC stage II/III) receiving neoadjuvant 5-FU-based chemoradiotherapy were studied for TS, TP, and DPD protein expression by immunohistochemistry using three different scoring systems (intensity, pattern, intensity + pattern). Results were compared with histopathologic tumor regression. A significant correlation between protein expression and tumor response was only seen when both staining intensity and staining pattern were considered. With this method, a significant association was seen between high TS expression in tumor biopsies as well as resection specimens and nonresponse of the tumor to therapy (P = 0.04). Furthermore, low TP expression in the resection specimens was significantly associated with lack of response (P = 0.02). For DPD no significant correlations were found at all. In conclusion, these results suggest that immunohistochemistry like RT-PCR is a suitable method to determine the correlation between TS, TP, and DPD expression and histopathologic tumor regression. However, precise results can only be achieved if staining intensity as well as staining pattern within the tumors are evaluated.

Pre-operative 5-fluorouracil (5-FU)-based chemoradiotherapy in locally advanced rectal cancer (UICC-II/III) may significantly reduce local tumour mass. Response to pre-operative treatment, however, varies significantly. Thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are thought to be important predictors for the efficiency of 5-FU-based treatment. The aim of this study was to determine the correlation between TS-, TP-, and DPD-gene expression and the response to 5-FU-based long-term pre-operative chemoradiotherapy assessed by histopathological tumour regression. Additionally, the predictive value of intra-tumoural TS-, TP-, and DPD-gene expression in pre-operative rectal tumour biopsies was assessed by correlation with the histopathological regression grade. Formalin-fixed, paraffin wax-embedded pre-operative biopsies (n = 14) and surgical resection specimens (n = 40) from patients with rectal carcinoma (clinical UICC stage II/III) receiving neo-adjuvant 5-FU-based chemoradiotherapy were studied for TS-, TP-, and DPD-gene expression by quantitative TaqMan real-time PCR after laser microdissection. Results were compared with standardized histopathological tumour regression analysis. There was a significant association between low TS-gene expression in pre-operative tumour biopsies and tumour response (p = 0.02). TS- and TP-gene expression was significantly lower in resection specimens of responders than of non-responders (p = 0.02) when microdissection was used. Statistical significance was even higher when TS and TP were combined (p = 0.0001). For the DPD gene, no significance was found at all. In conclusion, this study shows that TS gene expression in a pretreatment biopsy predicts the response of local rectal cancer to neo-adjuvant 5-FU-based chemoradiotherapy in a high percentage. Moreover, intra-tumoural TS- and TP-gene expression in surgical rectal specimens after neo-adjuvant chemoradiotherapy correlates significantly with histopathological tumour regression when microdissection is applied.

We studied age at maturity, longevity, and growth in a marbled newt (Triturus marmoratus) population in southwestern France. Parameters of the life cycle such as date of migration, reproductive period, and terrestrial activity were documented for three neighbouring temporary ponds. This Mediterranean marbled newt population was characterized by aestivation and hibernation periods, a prolonged aquatic phase in adults, and a presence of juveniles in water. Aestivation and hibernation lead to distinct growth periods as determined by skeletochronology. Minimum age at maturity was 2 and 3 years, whereas maximum age observed was 8 and 9 years in males and females, respectively. A higher growth rate and a lower survival rate were found in this Mediterranean population compared with other populations exposed to variable environmental conditions in western Europe.

Summary Background and Aim: In recent years, much research interest has been rightfully directed towards modelling human disease. The increasing demand of laboratory animals has led to a major impetus in small animal imaging. We evaluated the feasibility of using multislice spiral CT (MSCT) technology in a severe combined immunodeficiency (SCID) mouse model for non-small cell lung cancer. Materials and Methods: Mice (n = 14) were implanted orthotopically with the human non-small cell lung adenocarcinoma cell line A 549. Mice were scanned with MSCT and sacrificed 7 days (n = 3), 14 days (n = 3), and 21 days (n = 5) after tumor cell implantation, respectively. Histopathology was performed. Tumor size as revealed by imaging and pathology was correlated. A group of animals (n = 3) received anti-cancer treatment with seco-CBI-Q-galatoside. Those mice were scanned with MSCT 21 days after tumor implantation and sacrificed, and histopathologic work-up was performed. Results: A total of 14 mice with 14 macroscopically visible and 5 microscopically appreciable adenocarcinomas of the lung were examined. All macroscopically visible tumors were readily depicted with MSCT except from 2 lesions of 1 mm in diameter. MSCT accurately displayed the different tumor sizes in treated vs. non-treated animals. Discussion: MSCT proved to be a valuable tool for imaging of a murine lung cancer model. This evidences a potential use of this technology in small animal lung cancer imaging.

The molecular mechanisms that lead to autoantibody production and autoimmune disease remain poorly defined. Based on a clinical observation in a patient with lupus erythematosus and autoimmune hepatitis we here provide the first evidence that (i) a particular cytogenetic aberration (deletion (13)(q14)) could be detected in a proportion of plasma cells and that (ii) the surface marker CD56 could be used to enrich for plasma cells with this cytogenetic aberration.

NLM proteins (NOD26-like major intrinsic proteins) from plants contain amino acid sequence signatures which can be found in aquaporins including plant plasma membrane intrinsic proteins and tonoplast intrinsic proteins and glycerol permeases such as the Escherichia coli GlpF and the yeast FPS1 proteins. Heterologous expression of two members of the NLM subgroup from Arabidopsis thaliana (AtNLM1 and AtNLM2) in baker’s yeast demonstrated the glycerol permease activity in addition to the previously described aquaporin activity of AtNLM1. The transport was non-saturable up to 100 mM extracellular glycerol concentration. Longer-chain sugar alcohols did not compete with the transport of radiolabelled glycerol and hexoses were also not transported through the pore.

Human papillomavirus (HPV) infection is common in cervical intraepithelial neoplasia (CIN). This study investigates HPV detection and typing assay based on polymerase chain reaction amplification of L1 open reading frame with general primers GP5/GP6, followed by enzyme-linked immunosorbent assay detection with type-specific DNA probes. To determine the sensitivity of this assay, formalin-fixed CaSki cells were used as reference cell lines. Fifty copies of viral DNA diluted in DNA from 100,000 noninfected cells could be detected. This assay was also investigated for HPV detection and typing of 67 cervical specimens diagnosed with with CIN III or carcinoma in situ (CIS) and their adjacent squamous epithelium. The CIN III lesions were infected in approximately 80% of the samples, 81% in the neighboring CIN II, and 68% in CIN I. The HPV infection was even detectable in 54% of nondysplastic epithelium located near a CIN III lesion.

Seven species of amphibians have been recorded at the Roque-Haute Nature Reserve, two newt species : Triturus marmoratus and T. helveticus and five frog species : Hyla meridionalis, Pelodytes punctatus, Pelobates cultripes, Bufo calamita, Rana perezi. Many of these species have a geographic distribution restricted to southern France and the Iberian Peninsula, and are considered as vulnerable. Only 25% of the pools of the Roque-Haute Nature Reserve are used for amphibian reproduction. The larval period lasts from autumn to the end of the following summer. Two species have a reproduction in autumn as well as in spring : Pelodytes punctatus and Pelobates cultripes. More studies are needed on the demography and the genetics of these amphibian populations in order to assess their viability and to ensure their conservation., Sept espèces d’amphibiens ont été dénombrées dans la Réserve Naturelle de Roque-Haute, deux urodèles : Triturus marmoratus et T. helvéticas et cinq anoures : Hyla meridionalis, Pelodytes punctatus, Pelobates cultripes, Bufo calamita, Rana perezi. Beaucoup de ces espèces ont une distribution géographique restreinte au sud de la France et à la Péninsule ibérique et la plupart sont considérées comme vulnérables. Seulement 25% des mares de Roque-Haute sont utilisées par les amphibiens pour leur reproduction. La période larvaire dure de l’automne à l’été suivant. Deux espèces ont à la fois une reproduction automnale et printanière, ce sont Pelodytes punctatus et Pelobates cultripes. De nouvelles études sur le fonctionnement démographique et la génétique de ces populations d’amphibiens sont nécessaires afin d’évaluer leur viabilité et d’assurer leur protection., Jakob Christiane, Veith Michael, Seitz Alfred, Crivelli Alain J. Données préliminaires sur la communauté d’amphibiens de la Réserve Naturelle de Roque-Haute dans le sud de la France. In: Ecologia mediterranea, tome 24 n°2, 1998. pp. 235-240.

Regulated migration of hematopoietic stem cells is fundamental for hematopoiesis. The molecular mechanisms underlying stem cell trafficking are poorly defined. Based on a short hairpin RNA library and stromal cell-derived factor-1 (SDF-1) migration screening assay, we identified the histone 3 lysine 27 demethylase UTX (Kdm6a) as a novel regulator for hematopoietic cell migration. Using hematopoietic stem and progenitor cells from our conditional UTX knockout (KO) mice, we were able to confirm the regulatory function of UTX on cell migration. Moreover, adult female conditional UTX KO mice displayed myelodysplasia and splenic erythropoiesis, whereas UTX KO males showed no phenotype. During development, all UTX KO female and a portion of UTX KO male embryos developed a cardiac defect, cranioschisis, and died in utero. Therefore, UTY, the male homolog of UTX, can compensate for UTX in adults and partially during development. Additionally, we found that UTX knockdown in zebrafish significantly impairs SDF-1/CXCR4-dependent migration of primordial germ cells. Our data suggest that UTX is a critical regulator for stem cell migration and hematopoiesis.

One of the major prognostic factors in rectal cancer is lymph node metastasis. The formation of lymph node metastases is dependent on the existence of a premetastatic niche. An important factor preceding metastasis are lymph vessels which are located in the lymph node. Accordingly, the occurrence of intranodal lymphangiogenesis is thought to indicate distant metastasis and worse prognosis. To evaluate the significance of lymph node lymphangiogenesis, we studied formalin fixed, paraffin embedded adenocarcinomas and regional lymph nodes of 203 rectal cancer patients who were treated with neoadjuvant radiochemotherapy and consecutive curative surgery with cancer free surgical margins (R0). Regional lymph node lymph vessels were detected by immunohistochemistry for podoplanin (D2-40). Our results show that the presence of lymphatic vessels in regional lymph nodes significantly affects the disease-free survival in univariate and multivariate analyses. In contrast, there was no correlation between peritumoral or intratumoral lymph vessel density and prognosis. Indeed, our study demonstrates the importance of lymphangiogenesis in regional lymph nodes after neoadjuvant radiochemotherapy and consecutive surgery as an independent prognostic marker. Staining for intranodal lymphangiogenesis and methods of intravital imaging of lymphangiogenesis and lymphatic flow may be a useful strategy to predict long-term outcome in rectal cancer patients. Furthermore, addition of VEGF-blocking agents to standardized neoadjuvant treatment schemes might be indicated in advanced rectal cancer.

We report the case of a 32-year-old woman having developed two cervical cancers synchronously, an adenocarcinoma and a squamous cell carcinoma. Polymerase chain reaction with the general primers GP5/GP6 and a subsequent enzyme-linked immunosorbent assay to detect human papillomaviruses (HPV) resulted in isolation of HPV 33 in the squamous cell carcinoma and HPV 18 in the adenocarcinoma. This is the first reported case of two histologically different synchronous cervical cancers with this distinct HPV expression pattern, and further confirms the association of certain ‘high-risk’ HPV genotypes to different histological features of carcinoma. Furthermore, the important role of microdissection for gaining tumor tissue of different areas in molecular diagnostics is supported.

Purpose According to the CAO-/ARO-/AIO-94 trial of the German Rectal Cancer Study Group, pre-operative 5-fluorouracil (5-FU)-based long-term chemoradiotherapy (CT/RT) is recommended for patients with rectal cancer UICC stage II/III. However, despite the local benefit of neoadjuvant treatment, the overall prognostic value remains uncertain in comparison to adjuvant CT/RT. We assessed the impact of standardized pre-operative CT/RT and intratumoural mRNA levels and polymorphisms of the TS gene on histopathological tumour regression. Patients and methods 40 patients with rectal cancer UICC stage II/III, receiving pre-operative 5-FU-based CT/RT followed by standardized surgery, including total mesorectal excision, were investigated. TS gene expression and TS polymorphisms of surgical specimens were correlated with the grade of histopathological tumour regression (0–4). Patients achieved regression grades 2–4 were determined as responders. Results TS polymorphisms (5′-28 bp repeat + G/C SNP and TS1494del6) could be determined in 39/40 (97.5%) and in 38/40 (95%) patients, respectively. Quantification of TS mRNA expression was successful in 36/40 (90%) patients. There was a highly significant linkage disequilibrium between 5′- and 3′-TS polymorphisms ( p = 0.0013). Interestingly, the majority of patients (82.1%) with 5′-TS genotypes known to be associated with low mRNA expression (2R/2R, 2R/3RC, 3RC/3RC) also possessed the TS1494del6 +6 bp/+6 bp genotype correlating with high TS mRNA expression. TS1494del6 polymorphism was significantly associated with TS mRNA expression. Patients with TS1494del6 −6 bp/−6 bp or −6 bp/+6 bp genotypes showed significantly lower mean TS mRNA expression with 0.55 (range:0.33;0.84) as compared to +6 bp homozygotes with a mean expression of 0.90 (range:0.20;1.91) ( p = 0.025). Furthermore, all patients with TS 3′-UTR −6 bp/−6 bp or −6 bp/+6 bp genotype (11/11) were responders as compared to only 20/26 (77%) of patients with TS 3′-UTR +6 bp/+6 bp genotype ( p = 0.082). TS 5′-polymorphisms were not associated with neither tumour regression nor gene expression. Conclusion Our data suggest that the TS1494del6 polymorphism may be an important predictor for histopathological tumour regression in UICC II/III rectal cancer patients receiving neoadjuvant 5-FU-based CT/RT.

Purpose According to the CAO/ARO/AIO-94 trial of the German Rectal Cancer Study Group, preoperative combined fluorouracil (FU) -based long-term chemoradiotherapy (CT/RT) is recommended for patients with International Union Against Cancer (UICC) stage II/III rectal cancer. However, despite the local benefit of neoadjuvant treatment, the overall prognostic value remains uncertain in comparison with adjuvant CT/RT. Furthermore, the prognostic value of molecular biomarkers, such as thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD), all of which are involved in the FU metabolism, is unknown in neoadjuvant settings. We assessed the impact of standardized preoperative CT/RT and intratumoral TS, TP, and DPD levels on patient outcome. Patients and Methods Forty patients with rectal cancer pretherapeutic UICC stage II/III, receiving preoperative FU-based CT/RT (CAO/ARO/AIO-94 trial) followed by standardized surgery, including total mesorectal excision, were investigated. Downsizing, downstaging, tumor regression, as well as TS, TP, and DPD gene expression of post-treatment surgical specimens were correlated with disease-free survival (DFS) and overall survival (OS). Results Significant downsizing (P < .001) and downstaging (P = .001) were achieved with preoperative CT/RT. During a median follow-up of 49 months (95% CI, 43 to 58 months), the cancer recurrence rate was 28.2%. DFS and OS were significantly increased in patients with downstaging (P < .001 and P = .003, respectively), compared with patients without downstaging. All patients who developed cancer recurrence had a persistent positive lymph node status after preoperative CT/RT (P < .001) and a significantly higher TS gene expression (P = .035) compared with those patients without recurrence. Conclusion Persistent positive lymph node status and high intratumoral TS expression after preoperative CT/RT are predictive of an unfavorable prognosis in rectal cancer UICC stage II/III.

Histologic tumor regression (TR) in rectal cancer after preoperative chemoradiotherapy (CT/RT) may be useful as a surrogate end point for early treatment efficacy, but little is known about its prognostic value. The aim of this follow-up study was to evaluate whether TR is able to predict prognosis in rectal cancer patients. Furthermore, the prognostic value of thymidylate synthase (TS)-gene, thymidine phosphorylase (TP)-gene, and dihydropyrimidine dehydrogenase (DPD)-gene expression after neoadjuvant CT/RT was determined. Forty patients with rectal cancer cUICC stage II/III, receiving preoperative 5-fluorouracil (5-FU) based CT/RT were studied for therapy-induced TR and categorized as "responders" or "nonresponders" according to their TR-grade. Posttherapeutical TS-gene, TP-gene, and DPD-gene expression on surgical resection specimens was quantified by TaqMan real-time PCR after microdissection. During a median follow-up of 58 months, cancer recurrence occurred in 28%. A significant correlation was seen between disease-free survival and lymph node status (P0.001). All patients, who developed cancer recurrence had a posttherapeutical positive lymph node status. The majority of patients with cancer recurrence were "responders" (91%) after CT/RT. There was a significant correlation between posttherapeutical TS-gene expression and cancer recurrence within the subgroup of "responders." TS-gene expression was significantly higher in patients with cancer recurrence than in those, who are disease-free up to date (P=0.028). In conclusion, lymph node status remains the most important prognostic marker in rectal cancer patients, whereas posttreatment TR by itself has no prognostic significance. Furthermore, measurement of posttherapeutical TS-gene expression may help to identify patients at higher risk for cancer recurrence.

Eltrombopag fails to improve severe thrombocytopenia in late-stage dyskeratosis congenita and diamond-blackfan-anaemia

Papillary squamous cell carcinoma (SCC) of the uterine cervix has been defined as a malignant squamous cell lesion characterized by a papillary architecture with fibrovascular cores and moderate to severe dysplasia devoid of frank keratinization and koilocytic change. Papillary SCC should be histopathologically delineated from other rare variants of SCC with papillary features including verrucous and condylomatous carcinoma and the recently recognized (squamo-)transitional cell carcinoma of the uterine cervix. We report three cases of papillary SCC (FIGO stages IB, IV, and IVB) in postmenopausal women. Each tumor tested was positive for human papillomavirus (HPV) 16 and negative for HPV 6, 11 and 18 by general primer mediated polymerase chain reaction and subsequent enzyme-linked immunosorbent assay (PCR-ELISA). These findings 1) support the hypothesis that papillary SCCs (unlike verrucous carcinoma) are similar with regard to risk factors to (squamo-)transitional and condylomatous carcinoma; 2) suggest that HPV may play an etiologic role in at least some of these tumors; and 3) suggest that papillary SCC is the only subtype among squamous/(squamo-)transitional carcinomas that is associated with high-risk HPV infection in the absence of HPV-related histopathologic alterations.

The major intrinsic protein (MIP) gene family encodes membrane transporters with aquaporin and glycerol permease activity as the predominant transport characteristics. However, functional expression of these proteins also showed that some of the MIPs are mixed-functional pores with transport activity for water, glycerol, urea and other small uncharged solutes (review: Borgnia et al., 1999). In Arabidopsis thaliana, a model organism in plant biology, the MIP gene family consists of at least three major subgroups, the tonoplast intrinsic proteins (TIPs), the plasma membrane intrinsic proteins (PIPs), and the NOD26-like MIPs (NLMs; Weig et al., 1997). While each of these subgroups contains functional aquaporins, the primary sequence analysis of the NLM cluster exhibits significant similarity to glycerol permeases of bacteria and yeast. Recently, aquaporin and glycerol permease activity of NOD26 from soybean has been demonstrated by heterologous expression in Xenopus oocytes (Rivers et al., 1997) and functional reconstitution (Dean et al., 1999).

Introduction Enhanced progenitor proliferation, bone marrow (BM) hypervascularization and disturbed immune regulation contribute to the pathogenesis of myelodysplastic syndromes (MDS). Inhibition of mammalian-target of rapamycin (mTor) by temsirolimus (TEM) might be a promising strategy to target these disease-specific cellular alterations. We report on the effects of single agent TEM on the clinical course as well as on immune composition and BM vascularization of MDS patients treated within the prospective, multicenter “TEMDS”-trial (NCT01111448). Patients, Materials and Methods Twenty patients being either IPSS low/int-1 MDS (n = 9) or IPSS int-2/high after azacitidine failure were treated with TEM at a dose of 25 mg/week in the absence of toxicity or disease progression. BM was reevaluated after 4 months of treatment with the option of TEM continuation for a maximum of 12 months in responding patients. Translational research within this study included flowcytometry-based measurement of changes in T-cell composition as well as determination of cytokine levels and BM-vascularization prior to and after TEM. Results Of 20 patients treated, 15 discontinued TEM treatment prematurely due to intolerable side effects (n = 11), infectious complications (n = 3), or progression to AML (n = 1). Fatigue, stomatitis and profound leukopenia were the most frequent adverse events. A total of 13 severe adverse events were encountered in 10 patients and 1 patient died of infectious complications during TEM treatment. Of the 5 patients who were treated for at least 4 months and underwent regular BM reevaluation, none showed signs of response according to IWG criteria. TEM treatment resulted in a remarkable, although non-significant, decrease in total number of lymphocytes in the pB (pre: 74.6%, post: 48.4%, p = 0,083) and BM (pre: 23.5% post: 20.1%, p = 0.123). Within the T-helper cell compartment a trend towards an increase in regulatory T-cell (Treg) frequency was observed (pB: pre: 6.0 %, post: 6.4 %, p = 0.083). Moreover, the balance between naive (CD45RA+/CD45RO-) and activated/memory (CD45RA-/CD45RO+) Treg shifted significantly in favor of the latter (p = 0.004). Plasma analysis in BM and pB revealed, that these changes were obviously not mediated by alterations in TGFβ plasma levels. In a total of 12 assessable patients, a significant (p = 0.006) decrease of BM vascularization was observed after treatment with TEM for a median of 5 weeks (Fig. 1). There were, however, no changes in the medullary or peripheral blood VEGF concentration (data not shown). Conclusions Selective inhibition of the mTOR signaling cascade in MDS patients results in specific alterations of the composition of T-cell subsets as well as BM vascularization. Given the absence of any hematological response we suggest that these drug-induced modifications cannot alter the natural course of the disease. Disclosures: Wermke: Pfizer: Research Funding. Off Label Use: Temsirolimus is licensend for the treatment of MCL and RCC but not MDS. Platzbecker:Pfizer: Research Funding.

One of the major prognostic factors in rectal cancer is lymph node metastasis. The formation of lymph node metastases is dependent on the existence of a premetastatic niche. An important factor preceding metastasis are lymph vessels which are located in the lymph node. Accordingly, the occurrence of intranodal lymphangiogenesis is thought to indicate distant metastasis and worse prognosis. To evaluate the significance of lymph node lymphangiogenesis, we studied formalin fixed, paraffin embedded adenocarcinomas and regional lymph nodes of 203 rectal cancer patients who were treated with neoadjuvant radiochemotherapy and consecutive surgery. Regional lymph node lymph vessels were detected by immunohistochemistry for podoplanin (D2-40). Our results show that the presence of lymphatic vessels in regional lymph nodes significantly affects the disease-free survival in univariate and multivariate analyses. In contrast, there was no correlation between peritumoral or intratumoral lymph vessel density and prognosis. Indeed, our study demonstrates the importance of lymphangiogenesis in regional lymph nodes after neoadjuvant radiochemotherapy and consecutive surgery as an independent prognostic marker. Staining for intranodal lymphangiogenesis and methods of intravital imaging of lymphangiogenesis and lymphatic flow may be a useful strategy to predict long-term outcome in rectal cancer patients. Furthermore, addition of VEGF-blocking agents to standardized neoadjuvant treatment schemes might be indicated in advanced rectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5526. doi:1538-7445.AM2012-5526

Abstract 5038 Case Report We report of a 53 year old woman who presented repeatedly with syncopes over a period of 3 months. Laboratory results revealed severe pancytopenia (Hb 4.6 mmol/l (7.4 g/dl), WBC 1.22 Gpt/L, platelet count 13 Gpt/L) and severe hemolysis (haptoglobin < 0.20 g/l, normal range 0.3–2.0 g/l; LDH 33.1 μmol/s*l, normal range 2.25–3.55 μmol/s*l). Routine examination of the bone marrow aspirate showed typical features of megaloblastic erythropoiesis, which could be confirmed by a low serum cobalamin level (53 pg/ml, normal 211–911 pg/ml) and the presence of anti-intrinsic factor antibody (16.84 U/ml). Additionally, atrophic gastritis was seen in biopsies taken of gastric mucosa. The diagnosis of pernicious anemia was suspected and the patient treated with cobalamin. Except for hemoglobin, the peripheral blood counts recovered within one week. Meanwhile, cytogenetics from the bone marrow revealed metaphases with del(3p) and histopathological results were suspicious of an increased number of blast cells with highly expression of CD163 possibly mimicking MDS or (acute) monocytic leukemia. Therefore, bone marrow examination was repeated two weeks after recovery, which still showed dysplastic changes paralleling hematopoietic recovery but no increased number of blast cells. Additionally, the cytogenetic aberration had disappeared. Discussion Diagnostic work-up for megaloblastic anemia rarely includes cytogenetic analysis of bone marrow cells. Therefore, the finding of a transient cytogenetic aberration has possibly not reported frequently before in the literature. In our case, the initial finding of del(3p) appears to be due to ineffective hematopoiesis caused by vitamin B12 deficiency which leads to impaired DNA synthesis and genomic instability. This might be an explanation for this cytogenetic abnormality which disappeared after substitution of cobalamin. CD163 is exclusively expressed on monocytes and macrophages and with signs of (slightly) increased blast counts might mimic (acute) monocytic leukemia. However, in pernicious anemia with severe hemolysis as seen in this case it might reflect an acute phase reaction, as CD163 represents a signal-inducing macrophage receptor that scavenges haemoglobin by mediating endocytosis of haptoglobin-hemoglobin complexes. In conclusion, vitamin B12 deficiency might be associated with cytogenetic abnormalities and thus in addition to the bone marrow morphology feign certain haematological diseases. Disclosures: No relevant conflicts of interest to declare.

CONCLUSION: Ki67 has, like TS, predictive value in rectal cancer patients after neoadjuvant 5-FU based chemoradiotherapy. The close correlation between Ki67 and TS indicates that TS is involved in active cell cycle processes.

Mortality during emergence in two species of dragonfly, Onychogomphus uncatus and Orthetrum coerulescens, was studied at a Mediterranean irrigation canal in France. Overall mortality was 5.2% (n =1901) and 5.7% (n =611), respectively. Predation was low in both species. The prime cause of mortality was incomplete ecdysis resulting from different factors among which heavy wind was the most important in O. coerulescens and lack of suitable emergence supports in O. uncatus. Besides data on mortality the emergence curves of both species are provided.