Selective-laser-melting (SLM) is a powder-bed fusion additive-manufacturing process that has the potential to deliver three-dimensional complex parts with mechanical properties comparable or superior ...to parts produced via traditional manufacturing using cast and wrought alloys. Concerns for metallic parts built via SLM are the process-induced residual stresses, and anisotropic mechanical properties. This paper investigates the effect of residual stresses on the fatigue crack growth rate of SLM Ti6Al4V in as-built and stress-relieved conditions. Neutron diffraction and the contour method are employed to measure residual stresses in compact-tension samples. Neutron diffraction results are in good agreement with the contour method. It was found that tensile stresses are present at the notch root and the free edge areas, and compressive stress is seen in the middle of the sample. The tensile stresses in the as-built condition resulted in a higher fatigue crack growth rate. After stress relieving by heat treatment, the tensile residual stress diminished by around 90%, resulting in decreased crack growth rate. The build direction was seen to affect the crack growth rate, although the trend was different between the as-built and stress-relieved conditions.
To reduce the Hickman line-associated morbidity of continuous infusion 5-fluorouracil combined with epirubicin and cisplatin (ECF) and to investigate the need for infusional regimens, we conducted a ...retrospective study in patients with advanced gastro-oesophageal adenocarcinoma. Thirty-six patients, with histologically proven irresectable gastro-oesophageal adenocarcinoma were given: 60 mg/m 2 cisplatin on day 1, 35 mg/m 2 doxorubicin on day 1 and 500 mg/m 2 5-fluorouracil on days 1 and 8 (NIACF) every 3-weeks. A median of 3 cycles was administered. The principal toxicity was myelosuppression with grade III/IV neutropenia in 47% of cycles. Neutropenic fever occurred in 5% of the cycles; non-haematological toxicity was mild and there were no treatment-related deaths. Administered dose intensity was 96.1% for doxorubicin, 93.6% for cisplatin and 90.5% for 5-fluorouracil. There were 16 partial responses and 1 complete response (overall response rate 47%, 95% confidence interval CI 31-63%); 8 patients had stable disease. Median progression-free and overall survival rates were 5 months (95% CI 4-6) and 8 months (95% CI 6-10), respectively. NIACF is a well-tolerated regimen in advanced gastro-oesophageal adenocarcinoma that precludes the need for central venous access, with activity similar to that observed with ECF.
Both gemcitabine (GEM) and fluoropyrimidines are valuable treatment for advanced pancreatic cancer. This open-label study was designed to compare the overall survival (OS) of patients randomly ...assigned to GEM alone or GEM plus capecitabine (GEM-CAP).
Patients with previously untreated histologically or cytologically proven locally advanced or metastatic carcinoma of the pancreas with a performance status <or= 2 were recruited. Patients were randomly assigned to GEM or GEM-CAP. The primary outcome measure was survival. Meta-analysis of published studies was also conducted.
Between May 2002 and January 2005, 533 patients were randomly assigned to GEM (n = 266) and GEM-CAP (n = 267) arms. GEM-CAP significantly improved objective response rate (19.1% v 12.4%; P = .034) and progression-free survival (hazard ratio HR, 0.78; 95% CI, 0.66 to 0.93; P = .004) and was associated with a trend toward improved OS (HR, 0.86; 95% CI, 0.72 to 1.02; P = .08) compared with GEM alone. This trend for OS benefit for GEM-CAP was consistent across different prognostic subgroups according to baseline stratification factors (stage and performance status) and remained after adjusting for these stratification factors (P = .077). Moreover, the meta-analysis of two additional studies involving 935 patients showed a significant survival benefit in favor of GEM-CAP (HR, 0.86; 95% CI, 0.75 to 0.98; P = .02) with no intertrial heterogeneity.
On the basis of our trial and the meta-analysis, GEM-CAP should be considered as one of the standard first-line options in locally advanced and metastatic pancreatic cancer.
Abstract
18F-fluorodeoxyglucose PET-CT may guide treatment decisions in patients with oesophageal adenocarcinoma (OAC). This study evaluated the added value of maximum standardised uptake value ...(SUVmax) to a novel DNA-damage immune response (DDIR) assay to improve pathological response prediction. The diagnostic accuracy of PET response and the prognostic significance of PET metrics for recurrence-free survival (RFS) and overall survival (OS) were assessed. This was a retrospective, single-centre study of OAC patients treated with neo-adjuvant chemotherapy from 2003 to 2014. SUVmax was recorded from baseline and repeat PET-CT after completion of pre-operative chemotherapy. Logistic regression models tested the additional predictive value of PET metrics combined with the DDIR assay for pathological response. Cox regression models tested the prognostic significance of PET metrics for RFS and OS. In total, 113 patients were included; 25 (22.1%) were DDIR positive and 88 (77.9%) were DDIR negative. 69 (61.1%) were PET responders (SUVmax reduction of 35%) and 44 (38.9%) were PET non-responders. After adding PET metrics to DDIR status, post-chemotherapy SUVmax (hazard ratio (HR) 0.75, p = 0.02), SUVmax change (HR 1.04, p = 0.003) and an optimum SUVmax reduction of 46.5% (HR 4.36, p = 0.021) showed additional value for predicting pathological response. The optimised SUVmax threshold was independently significant for RFS (HR 0.47, 95% CI 0.26–0.85, p = 0.012) and OS (HR 0.51, 95% CI 0.26–0.99, p = 0.047). This study demonstrated the additional value of PET metrics, when combined with a novel DDIR assay, to predict pathological response in OAC patients treated with neo-adjuvant chemotherapy. Furthermore, an optimised SUVmax reduction threshold for pathological response was calculated and was independently significant for RFS and OS.
Pharmacological studies suggest that dopamine release from lateral olivocochlear efferent neurons suppresses spontaneous and sound-evoked activity in cochlear nerve fibers and helps control ...noise-induced excitotoxicity; however, the literature on cochlear expression and localization of dopamine receptors is contradictory. To better characterize cochlear dopaminergic signaling, we studied receptor localization using immunohistochemistry or reverse transcriptase PCR and assessed histopathology, cochlear responses and olivocochlear function in mice with targeted deletion of each of the five receptor subtypes. In normal ears, D1, D2, and D5 receptors were detected in microdissected immature (postnatal days 10-13) spiral ganglion cells and outer hair cells but not inner hair cells. D4 was detected in spiral ganglion cells only. In whole cochlea samples from adults, transcripts for D1, D2, D4, and D5 were present, whereas D3 mRNA was never detected. D1 and D2 immunolabeling was localized to cochlear nerve fibers, near the first nodes of Ranvier (D2) and in the inner spiral bundle region (D1 and D2) where presynaptic olivocochlear terminals are found. No other receptor labeling was consistent. Cochlear function was normal in D3, D4, and D5 knock-outs. D1 and D2 knock-outs showed slight, but significant enhancement and suppression, respectively, of cochlear responses, both in the neural output auditory brainstem response (ABR) wave 1 and in outer hair cell function distortion product otoacoustic emissions (DPOAEs). Vulnerability to acoustic injury was significantly increased in D2, D4 and D5 lines: D1 could not be tested, and no differences were seen in D3 mutants, consistent with a lack of receptor expression. The increased vulnerability in D2 knock-outs was seen in DPOAEs, suggesting a role for dopamine in the outer hair cell area. In D4 and D5 knock-outs, the increased noise vulnerability was seen only in ABRs, consistent with a role for dopaminergic signaling in minimizing neural damage.
Summary Background We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or ...metastatic pancreatic cancer. Methods TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m2 , 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m2 orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2–4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138. Findings The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4–12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months 95% CI 7·1–8·8 vs 6·9 months 6·4–7·6; hazard ratio HR 1·19, 98·25% CI 0·97–1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months 95% CI 7·3–9·7, HR 1·05, 98·25% CI 0·85–1·29, p=0·64; overall log-rank of χ22df =4·3; p=0·11). The commonest grade 3–4 toxic effects were neutropenia (68 19% patients in the chemotherapy group, 58 17% patients in the sequential chemoimmunotherapy group, and 79 22% patients in the concurrent chemoimmunotherapy group; fatigue (27 8% in the chemotherapy group, 35 10% in the sequential chemoimmunotherapy group, and 44 12% in the concurrent chemoimmunotherapy group); and pain (34 9% patients in the chemotherapy group, 39 11% in the sequential chemoimmunotherapy group, and 41 12% in the concurrent chemoimmunotherapy group). Interpretation Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy. Funding Cancer Research UK and KAEL-GemVax.
TP300, a recently developed synthetic camptothecin analogue, is a highly selective topoisomerase I inhibitor. A phase I study showed good safety and tolerability. As camptothecins have proven active ...in oesophago-gastric adenocarcinomas, in this phase II study we assessed the efficacy and safety of TP300 in patients with gastric or gastro-oesophageal junction (GOJ) adenocarcinomas.
Eligible patients had metastatic or locally advanced gastric or Siewert Types II or III GOJ inoperable adenocarcinoma. Patients were chemotherapy naïve unless this had been administered in the perioperative setting. TP300 was administered as a 1-h intravenous infusion every 3 weeks (a cycle) for up to 6 cycles at a starting dose of 8 mg/m
with intra-patient escalation to 10 mg/m
from cycle 2 in the absence of dose-limiting toxicity. Tumour responses (RECIST 1.1) were assessed every 6 weeks. Toxicity was recorded by NCI-CTCAE version 3.0. Using a modified two-stage Simon design (Stage I and II), a total of 43 patients were to be included providing there were 3 of 18 patients with objective response in Stage I of the study.
In Stage I of the study 20 patients (14 males, 6 females), median age 67 years (range 40 - 82), performance status ECOG 0/1, with GC 14 or GOJ carcinoma 6 were enrolled. Of the 16 evaluable patients, 11 received the planned dose increase to 10 mg/m
at cycle 2, 2 decreased to 6 mg/m
, and 3 continued on 8 mg/m
. There were no objective responses after 2 cycles of treatment. Twelve patients had stable disease for 1 - 5 months and 4 had progressive disease. Median progression free survival (PFS) was 4.1 months (CI 1.6 - 4.9), median time to progression (TTP) was 2.9 months (CI 1.4 - 4.2). Grade 3/4 toxicities (worst grade all cycles) included 7 patients (35 %) with neutropenia, 4 patients (20 %) with anaemia, 2 patients (10 %) with thrombocytopenia, and 3 patients (15 %) with fatigue. This study was terminated at the end of Stage I due to a lack of the required (3/18) responders.
This study of TP300 showed good drug tolerability but it failed to demonstrate sufficient efficacy as measured by radiological response.
EU-CTR 2009-012097-12 2009-09-03.
In pre-clinical models, the only two chemotherapy drugs which have been demonstrated to directly reduce the number of myeloid-derived suppressor cells (MDSCs) are gemcitabine and 5-fluorouracil. Here ...we analyze the dynamics of MDSCs, phenotyped as Lin-DR-CD11b+, in patients with advanced pancreatic cancer receiving the combination of gemcitabine and capecitabine, a 5-FU pro-drug. We found no evidence that gemcitabine and capecitabine directly reduce MDSC% in patients. Gemcitabine and capecitabine reduced MDSCs in 42 % of patients (
n
= 19) and MDSC% fell in only 3/9 patients with above-median baseline MDSCs. In 5/8 patients with minimal tumour volume change on treatment, the MDSC% went up: increases in MDSC% in these patients appeared to correlate with sustained cancer-related inflammatory cytokine upregulation. In a separate cohort of 21 patients treated with gemcitabine and capecitabine together with concurrently administered GV1001 vaccine with adjuvant GM-CSF, the MDSC% fell in 18/21 patients and there was a significant difference in the trajectory of MDSCs between those receiving GV1001 and GM-CSF in combination with chemotherapy and those receiving chemotherapy alone. Thus, there was no evidence that the addition of low-dose adjuvant GM-CSF increased Lin-DR-CD11b+ MDSC in patients receiving combination chemoimmunotherapy. 9/21 patients developed an immune response to GV1001 and the MDSCs fell in 8 of these 9 patients, 6 of whom had above-median pre-vaccination MDSC levels. A high pre-vaccination MDSC% does not preclude the development of immunity to a tumour-associated antigen.
Sonic Kayaks are low-cost open-source systems for gathering fine-scale environmental data. The system is designed to be simple to fit on to standard kayaks or canoes, and full instructions have been ...made available for anyone wishing to build their own. The previous version included temperature sensors and a hydrophone for recording underwater sound. Here we outline the design and integration of two new sensors, for underwater turbidity and above water air particulate pollution. All sensors record continually, and the GPS location, time and date are also stored for every data point, allowing fine-scale environmental data mapping. The data being collected by the sensors is sonified (turned into sound) in real-time, allowing the paddler to hear the data as they are collecting it, making it possible to locate and follow interesting occurrences. We present proof-of principle data for the first time for all the sensors, demonstrating how the system can be used for environmental mapping, and discuss potential future applications and adaptations. We believe the Sonic Kayak system offers particular promise for citizen science and environmental activism, and allows professional researchers to gather data that was previously difficult or impossible to obtain.
Adrenocortical sarcomatoid carcinoma (ASC) is an extremely rare variant of adrenocortical carcinoma (ACC). Its relative rarity and its characteristic histological pattern of both epithelioid and ...sarcomatoid components may pose diagnostic challenges which influence treatment. Here, we report a case of ASC in a 58 year-old man presenting with increasing abdominal pain and associated abdominal bloating with a large right adrenal mass detected by computed tomographic scan (CT). To our knowledge, only eleven prior cases of ASC have been reported in the literature. Here, we discuss the clinical, radiological and histopathological findings in our case, review the literature on ASCs and offer opinion on best management.
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