Dosimetric and Clinical Predictors for Acute and Late Gastrointestinal Toxicity Following Chemoradiotherapy of Locally Advanced Anal Cancer.

AIMS: To analyse dosimetric and clinical predictors for acute and late gastrointestinal toxicity following chemoradiotherapy of anal cancer. MATERIALS AND METHODS: Consecutive patients with locally advanced (T2 ≥4 cm - T4 or N+) anal cancer were selected from an institutional database (n = 114). All received intensity-modulated radiotherapy with concomitant 5-fluorouracil and mitomycin C. Gastrointestinal toxicity was retrospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and bowel cavity, small bowel and large bowel were contoured. Dosimetric and clinical variables were tested for associations with acute grade ≥3 gastrointestinal toxicity and late grade ≥2 gastrointestinal toxicity using the Mann-Whitney test, area under receiver operating characteristic curve (AUC) and logistic regression. RESULTS: The median follow-up was 40 months. Acute grade ≥3 gastrointestinal toxicity was seen in 51 (44.7%) of the patients; late grade ≥2 gastrointestinal toxicity was seen in 36 of the patients (39.6% of 91 patients with >1 year recurrence-free follow-up). Bowel cavity V30Gy was the best dosimetric predictor for acute gastrointestinal toxicity (AUC 0.633; P = 0.02). Large bowel V20Gy was the best dosimetric predictor for late gastrointestinal toxicity (AUC 0.698; P = 0.001) but showed no association with acute gastrointestinal toxicity. In multivariate logistic regression, increasing age was significantly associated with acute gastrointestinal toxicity; smoking and large bowel V20Gy were significantly associated with late gastrointestinal toxicity. Patients who experienced acute grade ≥3 gastrointestinal toxicity were not at an increased risk of late grade ≥2 gastrointestinal toxicity (odds ratio 1.3; P = 0.55). CONCLUSIONS: Factors of importance for acute and late gastrointestinal toxicity were not the same. Bowel cavity V30Gy is a good metric to use for the prediction of acute gastrointestinal toxicity, but the results of our study indicate that individual large and small bowel loops need to be contoured for better prediction of late gastrointestinal toxicity. The role of the large bowel as an important organ at risk for late gastrointestinal toxicity merits further research.

QUANTIFICATION OF PULMONARY PATHOLOGY IN CYSTIC FIBROSIS-COMPARISON BETWEEN DIGITAL CHEST TOMOSYNTHESIS AND COMPUTED TOMOGRAPHY.

PURPOSE: Digital tomosynthesis (DTS) is currently undergoing validation for potential clinical implications. The aim of this study was to investigate the potential for DTS as a low-dose alternative to computed tomography (CT) in imaging of pulmonary pathology in patients with cystic fibrosis (CF). METHODS: DTS and CT were performed as part of the routine triannual follow-up in 31 CF patients. Extent of disease was quantified according to modality-specific scoring systems. Statistical analysis included Spearman's rank correlation coefficient (r) and Krippendorff's alpha (α). MAJOR FINDINGS: The median effective dose was 0.14 for DTS and 2.68 for CT. Intermodality correlation was very strong for total score and the subscores regarding bronchiectasis and bronchial wall-thickening (r = 0.82-0.91, P < 0.01). Interobserver reliability was high for total score, bronchiectasis and mucus plugging (α = 0.83-0.93) in DTS. CONCLUSION: Chest tomosynthesis could be a low-dose alternative to CT in quantitative estimation of structural lung disease in CF.

A RAC-GEF network critical for early intestinal tumourigenesis.

RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2-/- Vav3-/- Tiam1-/-), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.

A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial.

BACKGROUND: Maintenance treatment (mt) with bevacizumab (bev) ± erlotinib (erlo) has modest effect after induction chemotherapy in metastatic colorectal cancer (mCRC). We hypothesized the efficacy of erlo to be dependent on KRAS mutational status and investigated this by exploring mt strategies with bev ± erlo and low-dose capecitabine (cap). PATIENTS AND METHODS: Included patients had mCRC scheduled for first-line therapy, Eastern Cooperative Oncology Group (ECOG) 0-1 and no major comorbidities. Treatment with XELOX/FOLFOX or XELIRI/FOLFIRI + bev was given for 18 weeks. After induction, patients without progression were eligible for randomization to mt; KRAS wild-type (wt) patients were randomized to bev ± erlo (arms wt-BE, N = 36 versus wt-B, N = 35), KRAS mutated (mut) patients were randomized to bev or metronomic cap (arms mut-B, N = 34 versus mut-C, N = 33). Primary end point was progression-free survival (PFS) rate (PFSr) at 3 months after start of mt. A pooled analysis of KRAS wt patients from the previous ACT study was performed. RESULTS: We included 233 patients. Median age was 64 years, 62% male, 68% ECOG 0, 52% with primary tumor in situ. A total of 138 patients started mt after randomization. PFSr was 64.7% versus 63.6% in wt-B versus wt-BE, P = 1.000; and 75% versus 66.7% in mut-B versus mut-C, P = 0.579, with no significant difference in median PFS and overall survival (OS). In the pooled cohort, median PFS was 3.7 months in wt-B (N = 64) and 5.7 months in wt-BE (N = 62) (hazard ratios 1.03, 95% confidence interval 0.70-1.50, P = 0.867). The frequency of any grade 3/4 toxicities during mt was: 28%/58%/18%/15% (wt-B/wt-BE/mut-B/mut-C). CONCLUSIONS: Addition of erlo to bev as mt in KRAS wt mCRC did not significantly improve PFS or OS, but it did increase toxicity. KRAS status does not seem to influence the outcome of treatment with erlotinib. Metronomic cap warrants further investigation in mt strategies, given our explorative results. CLINICALTRIALSGOV: NCT01229813.

The Swedish CArdioPulmonary BioImage Study: objectives and design.

Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large-scale 'omics' and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started.

Tet3 mediates stable glucocorticoid-induced alterations in DNA methylation and Dnmt3a/Dkk1 expression in neural progenitors.

Developmental exposure to excess glucocorticoids (GCs) has harmful neurodevelopmental effects, which include persistent alterations in the differentiation potential of embryonic neural stem cells (NSCs). The mechanisms, however, are largely unknown. Here, we investigated the effects of dexamethasone (Dex, a synthetic GC analog) by MeDIP-like genome-wide analysis of differentially methylated DNA regions (DMRs) in NSCs isolated from embryonic rat cortices. We found that Dex-induced genome-wide DNA hypomethylation in the NSCs in vitro. Similarly, in utero exposure to Dex resulted in global DNA hypomethylation in the cerebral cortex of 3-day-old mouse pups. Dex-exposed NSCs displayed stable changes in the expression of the DNA methyltransferase Dnmt3a, and Dkk1, an essential factor for neuronal differentiation. These alterations were dependent on Tet3 upregulation. In conclusion, we propose that GCs elicit strong and persistent effects on DNA methylation in NSCs with Tet3 playing an essential role in the regulation of Dnmt3a and Dkk1. Noteworthy is the occurrence of similar changes in Dnmt3a and Dkk1 gene expression after exposure to excess GC in vivo.

Earth-like aqueous debris-flow activity on Mars at high orbital obliquity in the last million years.

Liquid water is currently extremely rare on Mars, but was more abundant during periods of high obliquity in the last few millions of years. This is testified by the widespread occurrence of mid-latitude gullies: small catchment-fan systems. However, there are no direct estimates of the amount and frequency of liquid water generation during these periods. Here we determine debris-flow size, frequency and associated water volumes in Istok crater, and show that debris flows occurred at Earth-like frequencies during high-obliquity periods in the last million years on Mars. Results further imply that local accumulations of snow/ice within gullies were much more voluminous than currently predicted; melting must have yielded centimetres of liquid water in catchments; and recent aqueous activity in some mid-latitude craters was much more frequent than previously anticipated.

Infrared spectroscopy and density functional theory investigation of calcite, chalk, and coccoliths--do we observe the mineral surface?

We have measured infrared spectra from several types of calcite: chalk, freshly cultured coccoliths produced by three species of algae, natural calcite (Iceland Spar), and two types of synthetic calcite. The most intense infrared band, the asymmetric carbonate stretch vibration, is clearly asymmetric for the coccoliths and the synthetic calcite prepared using the carbonation method. It can be very well fitted by two peaks: a narrow Lorenzian at lower frequency and a broader Gaussian at higher frequency. These two samples both have a high specific surface area. Density functional theory for bulk calcite and several calcite surface systems allows for assignment of the infrared bands. The two peaks that make up the asymmetric carbonate stretch band come from the bulk (narrow Lorenzian) and from a combination of two effects (broad Gaussian): the surface or near surface of calcite and line broadening from macroscopic dielectric effects. We detect water adsorbed on the high surface area synthetic calcite, which permits observation of the chemistry of thin liquid films on calcite using transmission infrared spectroscopy. The combination of infrared spectroscopy and density functional theory also allowed us to quantify the amount of polysaccharides associated with the coccoliths. The amount of polysaccharides left in chalk, demonstrated to be present in other work, is below the IR detection limit, which is 0.5% by mass.

MicroRNA-126 and epidermal growth factor-like domain 7-an angiogenic couple of importance in metastatic colorectal cancer. Results from the Nordic ACT trial.

BACKGROUND: This study investigated the clinical importance of linked angiogenetic biomarkers to chemotherapy, combined with the anti-vascular endothelial growth factor A (anti-VEGF-A), as a first-line treatment in patients with metastatic colorectal cancer (mCRC). METHODS: A total of 230 patients from a randomised phase III study were included. The primary microRNA-126 (pri-miRNA-126) A24G single-nucleotide polymorphism and the mature miRNA-126 were analysed by PCR using genomic DNA (full blood) and formalin-fixed paraffin-embedded tissue sections, respectively. The epidermal growth factor-like domain 7 (EGFL7) protein was visualised and quantified using immunohistochemistry. RESULTS: High tumour expression of miRNA-126 was significantly related to a longer progression-free survival. The independent prognostic value of miRNA-126 was confirmed using a Cox regression analysis (hazard ratio=0.49, 95% confidence interval=0.29-0.84, P=0.009). Although not significant, a relationship between EGFL7 expression and response rates is suggested, with EGFL7 expression at the invasive front being lower in responding patients than in the non-responders (P=0.063). CONCLUSION: The results validate the previous findings on the prognostic value of miRNA-126 in mCRC and may suggest a relationship between treatment efficacy and EGFL7 expression. As miRNA-126 may target VEGF-A as well as EGFL7, the results may provide predictive information in relation to next-generation anti-angiogenetics.

A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial.

BACKGROUND: The main objective was to study the effect on progression-free survival (PFS) of adding erlotinib to bevacizumab as maintenance treatment following chemotherapy and bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with untreated mCRC received doublet chemotherapy + bevacizumab during 18 weeks and those without tumor progression were eligible for randomization to bevacizumab + erlotinib (arm A) or bevacizumab alone (arm B), until progression or unacceptable toxic effect. RESULTS: Of the 249 patients enrolled, 80 started maintenance treatment in arm A and 79 in arm B. The rate of any grade 3/4 toxic effect was 53% in arm A and 13% in arm B. Median PFS was 5.7 months in arm A and 4.2 months in arm B (HR = 0.79; 95% confidence interval 0.55-1.12; P = 0.19). Overall survival (OS) from start of induction chemotherapy was 26.7 months in the randomized population, with no difference between the two arms. CONCLUSIONS: The addition of erlotinib to bevacizumab as maintenance treatment after first-line chemotherapy in mCRC did not improve PFS significantly. On-going clinical and translational studies focus on identifying subgroups of patients that may benefit from erlotinib in the maintenance setting. CLINICAL TRIALS NUMBER: NCT00598156.

Acupuncture compared with placebo acupuncture in radiotherapy-induced nausea--a randomized controlled study.

BACKGROUND: It is not known if verum (real) acupuncture is effective for nausea and vomiting (emesis) during radiotherapy. PATIENTS AND METHODS: We randomly treated 215 blinded cancer patients with verum: penetrating 'deqi' creating acupuncture (n = 109) or non-penetrating sham needles (n = 106) two to three times per week. The patients documented emesis daily during the radiotherapy period. Primary end point was the number of patients with at least one episode of nausea. RESULTS: In the verum and the sham acupuncture group, 70% and 62% experienced nausea at least once during the radiotherapy period (relative risk 1.1, 95% CI 0.9-1.4) for a mean number of 10.1 and 8.7 days. Twenty five percent and 28% vomited, and 42% and 37% used antiemetic drugs at least once, respectively. Ninety-five percent in the verum acupuncture group and 96% in the sham acupuncture group believed that the treatment had been effective against nausea. In both groups, 67% experienced positive effects on relaxation, mood, sleep or pain reduction and 89% wished to receive the treatment again. CONCLUSION: Acupuncture creating deqi is not more effective than sham in radiotherapy-induced nausea, but in this study, nearly all patients in both groups experienced that the treatment was effective for nausea.

Overexpression of podocalyxin-like protein is an independent factor of poor prognosis in colorectal cancer.

BACKGROUND: Podocalyxin-like 1 (PODXL) is a cell-adhesion glycoprotein and stem cell marker that has been associated with an aggressive tumour phenotype and poor prognosis in several forms of cancer. In this study, we investigated the prognostic impact of PODXL expression in colorectal cancer (CRC). METHODS: Using tissue microarrays and immunohistochemistry, PODXL expression was evaluated in 536 incident CRC cases from a prospective, population-based cohort study. Kaplan-Meier analysis and Cox proportional hazards modelling were used to assess the impact of PODXL expression on cancer-specific survival (CSS) and overall survival (OS). RESULTS: High PODXL expression was significantly associated with unfavourable clinicopathological characteristics, a shorter CSS (hazard ratio (HR)=1.98; 95% confidence interval (CI) 1.38-2.84, P<0.001) and 5-year OS (HR=1.85; 95% CI 1.29-2.64, P=0.001); the latter remaining significant in multivariate analysis (HR=1.52; 95% CI 1.03-2.25, P=0.036). In addition, in curatively resected stage III (T1-4, N1-2, M0) patients (n=122) with tumours with high PODXL expression, a significant benefit from adjuvant chemotherapy was demonstrated (p(interaction) =0.004 for CSS and 0.015 for 5-year OS in multivariate analysis). CONCLUSION: Podocalyxin-like 1 expression is an independent factor of poor prognosis in CRC. Our results also suggest that PODXL may be a useful marker to stratify patients for adjuvant chemotherapy.

Tracking single coccolith dissolution with picogram resolution and implications for CO2 sequestration and ocean acidification.

Coccoliths are micrometer scale shields made from 20 to 60 individual calcite (CaCO(3)) crystals that are produced by some species of algae. Currently, coccoliths serve as an important sink in the global carbon cycle, but decreasing ocean pH challenges their stability. Chalk deposits, the fossil remains of ancient algae, have remained remarkably unchanged by diagenesis, the process that converts sediment to rock. Even after 60 million years, the fossil coccolith crystals are still tiny (< 1 µm), compared with inorganically produced calcite, where one day old crystals can be 10 times larger, which raises the question if the biogenic nature of coccolith calcite gives it different properties than inorganic calcite? And if so, can these properties protect coccoliths in CO(2) challenged oceans? Here we describe a new method for tracking dissolution of individual specimens, at picogram (10(-12) g) resolution. The results show that the behavior of modern and fossil coccoliths is similar and both are more stable than inorganic calcite. Organic material associated with the biogenic calcite provides the explanation. However, ancient and modern coccoliths, that resist dissolution in Ca-free artificial seawater at pH > 8, all dissolve when pH is 7.8 or lower. Ocean pH is predicted to fall below 7.8 by the year 2100, in response to rising CO(2) levels. Our results imply that at these conditions the advantages offered by the biogenic nature of calcite will disappear putting coccoliths on algae and in the calcareous bottom sediments at risk.

Acute aortic dissection in a patient with extremely low body mass index due to anorexia nervosa.

We report a case of successful surgical repair of an acute aortic dissection (Stanford Type A) in a severely malnourished 39-year old patient with anorexia nervosa (body mass index [BMI] 11.3 kg/m2) and essential hypertension. The case is of interest since 1) acute aortic dissection in patients with anorexia nervosa has not previously been described; 2) hypertension is extremely rare in patients with eating disorders; and 3) successful aortic repair in a patient with so low BMI has not been reported before. We conclude that extremely low BMI due to anorexia nervosa is not an absolute contraindication for major aortic surgery.

The HIF-2α-driven pseudo-hypoxic phenotype in tumor aggressiveness, differentiation, and vascularization.

Cellular adaptation to diminished tissue oxygen tensions, hypoxia, is largely governed by the hypoxia inducible transcription factors, HIF-1 and HIF-2. Tumor hypoxia and high HIF protein levels are frequently associated with aggressive disease. In recent years, high tumor cell levels of HIF-2 and the oxygen sensitive subunit HIF-2α have been associated with unfavorable disease and shown to be highly expressed in tumor stem/initiating cells originating from neuroblastoma and glioma, respectively. In these cells, HIF-2 is active under nonhypoxic conditions as well, creating a pseudo-hypoxic phenotype with clear influence on tumor behavior. Neuroblastoma tumor initiating cells are immature with a neural crest-like phenotype and downregulation of HIF-2α in these cells results in neuronal sympathetic differentiation and the cells become phenotypically similar to the bulk of neuroblastoma cells found in clinical specimens. Knockdown of HIF-2α in neuroblastoma and glioma tumor stem/initiating cells leads to reduced levels of VEGF and poorly vascularized, highly necrotic tumors. As high HIF-2α expression further correlates with disseminated disease as demonstrated in neuroblastoma, glioma, and breast carcinoma, we propose that targeting HIF-2α and/or the pseudo-hypoxic phenotype induced by HIF-2 under normoxic conditions has great clinical potential.

Overview of two years of clinical experience of chest tomosynthesis at Sahlgrenska University Hospital.

Since December 2006, approximately 3800 clinical chest tomosynthesis examinations have been performed at our department at Sahlgrenska University Hospital. A subset of the examinations has been included in studies of the detectability of pulmonary nodules, using computed tomography (CT) as the gold standard. Visibility studies, in which chest tomosynthesis and CT have been compared side-by side, have been used to determine the depiction potential of chest tomosynthesis. Comparisons with conventional chest radiography have been made. In the clinical setting, chest tomosynthesis has mostly been used as an additional examination. The most frequent indication for chest tomosynthesis has been suspicion of a nodule or tumour. In visibility studies, tomosynthesis has depicted over 90 % of the nodules seen on the CT scan. The corresponding figure for chest radiography has been <30 %. In the detection studies, the lesion-level sensitivity has been approximately 60 % for tomosynthesis and 20 % for chest radiography. In one of the detection studies, an analysis of all false-positive nodules was performed. This analysis showed that all findings had morphological correlates on the CT examinations. The majority of the false-positive nodules were localised in the immediate subpleural region. In conclusion, chest tomosynthesis is an improved chest radiography method, which can be used to optimise the use of CT resources, thereby reducing the radiation dose to the patient population. However, there are some limitations with chest tomosynthesis. For example, patients undergoing tomosynthesis have to be able to stand still and hold their breath firmly for 10 s. Also, chest tomosynthesis has a limited depth resolution, which may explain why pathology in the subpleural region is more difficult to interpret and artefacts from medical devices may occur.

A phantom study of nodule size evaluation with chest tomosynthesis and computed tomography.

The aim of the present study was to investigate nodule size measurements with chest tomosynthesis (TS) and computed tomography (CT). A 26-mm thick phantom, composed of a Polylite block with embedded spheres of different materials and sizes (4-20 mm), was scanned by both CT and TS. Six observers without prior knowledge of the true diameters of the spheres independently measured the diameter of the spheres on the CT and TS images. Four observers were allowed to change the window settings and two of the observers used predetermined fixed viewing conditions. The mean relative errors for all observers and all measured spheres compared with the known diameter of the spheres were 1.4 % (standard deviation, SD: 5.4 %) on CT images and -1.1 % (SD: 5.0 %) on TS images. With regard to the four observers where the window settings were at the discretion of the observer, the mean relative errors were 1.4 % (SD: 6.4 %) on CT images and -1.7 % (SD: 5.7 %) on TS images. Regarding the two observers using identical viewing conditions the mean relative error was 1.5 % (SD: 2.8 %) on CT images and 0.2 % (SD: 2.6 %) on TS images. In conclusion, the study suggests that nodule size measurements on chest TS might be an alternative to measurements on CT.

Factors influencing return to work: a narrative study of women treated for breast cancer.

The purpose of this qualitative study was to identify factors contributing to a successful return to the labour market after treatment for breast cancer from the women's own perspective. The study is based on 16 narratives - open-ended, in-depth interviews - about women's experiences and thoughts from the period after breast cancer surgery when they focused on their return to work. The women were recruited from participants of a multicentre trial, which allowed comparisons across a range of adjuvant therapies. The narratives of women who worked full time at a cut-off point of 1 year after surgery are analysed separately from the narratives of women still sick-listed at that point of time. The findings show that while all the women strove to belong to the labour market, the study also reveals changes in women's perceptions of the value of employment. The quality of social support received from employers and coworkers differed between women who returned to work and those still sick-listed 1 year after breast cancer treatment. A need to design interventions focusing on the work arena of women treated for breast cancer is pointed out.

HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells.

High hypoxia-inducible factor-2alpha (HIF-2alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2alpha reduced VEGF expression and induced partial sympathetic neuronal differentiation when these TICs were grown in vitro under stem cell-promoting conditions. Xenograft tumors of HIF-2alpha-silenced cells were widely necrotic, poorly vascularized, and resembled the bulk of tumor cells in clinical neuroblastomas by expressing additional sympathetic neuronal markers, whereas control tumors were immature, well-vascularized, and stroma-rich. Thus, HIF-2alpha maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2alpha is an attractive target for neuroblastoma therapy.