Radiotherapy for breast cancer reduces disease recurrence and breast cancer mortality. However, it has also been associated with increased second cancer risks in exposed sites.
We evaluated long-term ...second cancer risks among 182 057 5-year survivors of locoregional invasive breast cancer diagnosed between 1973 and 2000 and reported to US NCI-SEER Program cancer registries. Multivariate Poisson regression was used to estimate the relative risk (RR) and excess cases of second cancer in women who had surgery and radiotherapy, compared with those who had surgery alone. Second cancer sites were grouped according to doses received from typical tangential breast fields.
By the end of 2005 (median follow-up=13.0 years), 15 498 second solid cancers had occurred, including 6491 contralateral breast cancers. The RRs for radiotherapy were 1.45 (95% confidence interval (CI)=1.33-1.58) for high-dose second cancer sites (1+ Gy: lung, oesophagus, pleura, bone and soft tissue) and 1.09 (1.04-1.15) for contralateral breast cancer ( approximately 1 Gy). These risks decreased with increasing age and year of treatment. There was no evidence of elevated risks for sites receiving medium (0.5-0.99 Gy, RR=0.89 (0.74-1.06)) or low doses (<0.5 Gy, RR=1.01 (0.95-1.07)). The estimated excess cases of cancer in women treated with radiotherapy were as follows: 176 (95% CI=69-284) contralateral breast cancers or 5% (2-8%) of the total in all 1+year survivors, and 292 (222-362) other solid cancers or 6% (4-7%) of the total.
Most second solid cancers in breast cancer survivors are not related to radiotherapy.
The topoisomerase I (Top 1) poison irinotecan is an important component of the modern treatment of colorectal cancer. By stabilising Top 1-DNA complexes, irinotecan generates Top 1-linked DNA ...single-strand breaks that can evolve into double-strand breaks and ultimately cause cell death. However, cancer cells may overcome cell killing by releasing the stalled topoisomerase from DNA termini, thereby reducing the efficacy of Top 1 poisons in clinics. Thus, understanding the DNA repair mechanisms involved in the repair of Top 1-mediated DNA damage provides a useful tool to identify potential biomarkers that predict response to this class of chemotherapy. Furthermore, targeting these pathways could enhance the therapeutic benefits of Top 1 poisons. In this review, we describe the cellular mechanisms and consequences of targeting Top 1 activity in cells. We summarise preclinical data and discuss the potential clinical utility of small-molecule inhibitors of the key proteins.
The European Organisation for Research and Treatment of Cancer (EORTC) health-related quality of life questionnaire for anal cancer (QLQ-ANL27) supplements the EORTC cancer generic measure (QLQ-C30) ...to measure concerns specific to people with anal cancer treated with chemoradiotherapy. This study tested the psychometric properties and acceptability of the QLQ-ANL27.
People with anal cancer were recruited from 15 countries to complete the QLQ-C30 and QLQ-ANL27 and provide feedback on the QLQ-ANL27. Item responses, scale structure (multitrait scaling, factor analysis), reliability (internal consistency and reproducibility) and sensitivity (known group comparisons and responsiveness to change) of the QLQ-ANL27 were evaluated.
Data from 382 people were included in the analyses. The EORTC QLQ-ANL27 was acceptable, comprehensive, and easy to complete, taking an average 8 minutes to complete. Psychometric analyses supported the EORTC QLQ-ANL27 items and reliability (Cronbach's α ranging from 0.71-0.93 and test-retest coefficients above 0.7) and validity of the scales (particularly nonstoma bowel symptoms and pain/discomfort). Most scales distinguished people according to treatment phase and performance status. Bowel (nonstoma), pain/discomfort, and vaginal symptoms were sensitive to deteriorations over time. The stoma-related scales remained untested because of low numbers of people with a stoma. Revisions to the scoring and question ordering of the sexual items were proposed.
The QLQ-ANL27 has good psychometric properties and is available in 16 languages for people treated with chemoradiotherapy for anal cancer. It is used in clinical trials and has a potential role in clinical practice.
Only limited data exist on the effect of neutron irradiation on the brittle to ductile transition (BDT) in tungsten. This work investigates the increase in brittle to ductile transition temperature ...(BDTT) following neutron irradiation to 1.67 displacements per atom, using four-point bend tests over a range of temperatures (623–1173 K) and strain rates (3.5 × 10−7 - 2.5 × 10−5 s−1). The BDTT was found to increase by 500 K after irradiation. The activation energy for the BDT was determined using Arrhenius analysis of the four-point bend tests. Nanoindentation strain-rate jump tests were used to characterise the activation volume for dislocation motion. These were quantified as 1.05 eV and 4.6 b3 respectively, very close to values found for unirradiated tungsten. This suggests that kink-pair formation is the controlling mechanism for the BDT before and after irradiation. This work also carries out a unique verification of inventory-code-modelling (via FISPACT-II) of transmutation of tungsten to rhenium and osmium under neutron irradiation using two independent techniques (X-ray and gamma-ray spectroscopy). These results show that modelling can correctly predict this transmutation, provided that an accurate neutron spectrum is used. This is a critical result given the widespread use of inventory codes such as FISPACT-II, and the associated nuclear data libraries, for modelling transmutation of tungsten.
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Although elevated risks of pancreatic cancer have been observed in long-term survivors of Hodgkin lymphoma (HL), no prior study has assessed the risk of second pancreatic cancer in relation to ...radiation dose and specific chemotherapeutic agents.
We conducted an international case–control study within a cohort of 19 882 HL survivors diagnosed from 1953 to 2003 including 36 cases and 70 matched controls.
Median ages at HL and pancreatic cancer diagnoses were 47 and 60.5 years, respectively; median time to pancreatic cancer was 19 years. Pancreatic cancer risk increased with increasing radiation dose to the pancreatic tumor location (Ptrend = 0.005) and increasing number of alkylating agent (AA)-containing cycles of chemotherapy (Ptrend = 0.008). The odds ratio (OR) for patients treated with both subdiaphragmatic radiation (≥10 Gy) and ≥6 AA-containing chemotherapy cycles (13 cases, 6 controls) compared with patients with neither treatment was 17.9 (95% confidence interval 3.5–158). The joint effect of these two treatments was significantly greater than additive (P = 0.041) and nonsignificantly greater than multiplicative (P = 0.29). Especially high risks were observed among patients receiving ≥8400 mg/m2 of procarbazine with nitrogen mustard or ≥3900 mg/m2 of cyclophosphamide.
Our study demonstrates for the first time that both radiotherapy and chemotherapy substantially increase pancreatic cancer risks among HL survivors treated in the past. These findings extend the range of nonhematologic cancers associated with chemotherapy and add to the evidence that the combination of radiotherapy and chemotherapy can lead to especially large risks.
Manufacturing has been the key factor limiting rollout of vaccination during the COVID‐19 pandemic, requiring rapid development and large‐scale implementation of novel manufacturing technologies. ...ChAdOx1 nCoV‐19 (AZD1222, Vaxzevria) is an efficacious vaccine against SARS‐CoV‐2, based upon an adenovirus vector. We describe the development of a process for the production of this vaccine and others based upon the same platform, including novel features to facilitate very large‐scale production. We discuss the process economics and the “distributed manufacturing” approach we have taken to provide the vaccine at globally‐relevant scale and with international security of supply. Together, these approaches have enabled the largest viral vector manufacturing campaign to date, providing a substantial proportion of global COVID‐19 vaccine supply at low cost.
Well over a billion doses of the ChAdOx1 nCoV‐19 vaccine developed by The University of Oxford and AstraZeneca have been produced and distributed at low cost. This represents a substantial proportion of global COVID‐19 vaccine supply to date, especially in low‐ and middle‐income countries. The authors report on the development of the manufacturing process for the vaccine, and the process economics and distributed manufacturing approach involving bulk vaccine (drug substance) production on five continents.
We present results from a new incoherent-beam fast radio burst (FRB) search on the Canadian Hydrogen Intensity Mapping Experiment (CHIME) Pathfinder. Its large instantaneous field of view (FoV) and ...relative thermal insensitivity allow us to probe the ultra-bright tail of the FRB distribution, and to test a recent claim that this distribution's slope, , is quite small. A 256-input incoherent beamformer was deployed on the CHIME Pathfinder for this purpose. If the FRB distribution were described by a single power law with = 0.7, we would expect an FRB detection every few days, making this the fastest survey on the sky at present. We collected 1268 hr of data, amounting to one of the largest exposures of any FRB survey, with over 2.4 × 105 deg2 hr. Having seen no bursts, we have constrained the rate of extremely bright events to <13 sky−1 day−1 above for τ between 1.3 and 100 ms, at 400-800 MHz. The non-detection also allows us to rule out 0.9 with 95% confidence, after marginalizing over uncertainties in the GBT rate at 700-900 MHz, though we show that for a cosmological population and a large dynamic range in flux density, is brightness dependent. Since FRBs now extend to large enough distances that non-Euclidean effects are significant, there is still expected to be a dearth of faint events and relative excess of bright events. Nevertheless we have constrained the allowed number of ultra-intense FRBs. While this does not have significant implications for deeper, large-FoV surveys like full CHIME and APERTIF, it does have important consequences for other wide-field, small dish experiments.
Background. A recombinant canarypox vector expressing human immunodeficiency virus type 1 (HIV-1) Gag, Pro, and membrane-linked gp120 (vCP1521), combined with a bivalent gp120 protein boost (AIDSVAX ...B/E), provided modest protection against HIV-1 infection in a community-based population in Thailand (RV144 trial). No protection was observed in Thai injection drug users who received AIDSVAX B/E alone (Vax003 trial). We compared the neutralizing antibody response in these 2 trials. Methods. Neutralization was assessed with tier 1 and tier 2 strains of virus in TZM-bl and A3R5 cells. Results. Neutralization of several tier 1 viruses was detected in both RV144 and Vax003. Peak titers were higher in Vax003 and waned rapidly in both trials. The response in RV144 was targeted in part to V3 of gp120.vCP1521 priming plus 2 boosts with gp120 protein was superior to 2 gp120 protein inoculations alone, confirming a priming effect for vCP1521. Sporadic weak neutralization of tier 2 viruses was detected only in Vax003 and A3R5 cells. Conclusion. The results suggest either that weak neutralizing antibody responses can be partially protective against HIV-1 in low-risk heterosexual populations or that the modest efficacy seen in RV144 was mediated by other immune responses, either alone or in combination with neutralizing antibodies.
Two components of cortical circuits could mediate contour integration in primary visual cortex (V1): intrinsic horizontal connections and feedback from higher cortical areas. To distinguish between ...these, we combined functional mapping with a new technique for labeling axons, a recombinant adenovirus bearing the gene for green fluorescent protein (GFP), to determine the extent, density, and orientation specificity of V1 intrinsic connections and V2 to V1 feedback. Both connections cover portions of V1 representing regions of visual space up to eight times larger than receptive fields as classically defined, though the intrinsic connections are an order of magnitude denser than the feedback. Whereas the intrinsic connections link similarly oriented domains in V1, V2 to V1 feedback displays no such specificity. These findings suggest that V1 intrinsic horizontal connections provide a more likely substrate for contour integration.
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