Application of aSi-kVCBCT for Volume Assessment and Dose Estimation: An Offline Adaptive Study for Prostate Radiotherapy

Objective: The purpose of this study is to develop a method to estimate the dose using amorphous silicon detectorpanel cone beam computed tomography (aSi-kVCBCT) for the OARs and targets in prostate radiotherapy and to comparewith the actual planned dose. Methods: The aSi-kVCBCT is used widely in radiotherapy to verify the patient positionbefore treatment. The advancement in aSi-kVCBCT combined with adaptive software allows us to verify the dosedistribution in daily acquired CBCT images. CBCT images from 10 patients undergoing radical prostate radiotherapywere included in this study. Patients received total dose of 65Gy in 25 fractions using volumetric modulated arc therapy(VMAT). aSi-kVCBCT scans were acquired before daily treatment and exported to smart adapt software for imageadaptation. The planning CT is adapted to daily aSi-kVCBCT images in terms of HU mapping. The primary VMATplans were copied on to the adapted planning CT images and dose was calculated using Anisotropic Analytic Algorithm(AAA). The DVH is then used to evaluate the volume changes of organs at risk (OAR), the actual dose received byOARs, CTV and PTV during a single fraction. Results: The normalized volume of the bladder and rectum rangedfrom 0.70–1.66 and 0.70–1.16 respectively. The cumulative mean Sorensen–Dice coefficient values of bladder andrectum were 0.89±0.04 and 0.79±0.06 respectively. The maximum dose differences for CTV and PTV were 2.5% and-4.7% and minimum were 0.1% and 0.1% respectively. Conclusion: The adapted planning CT obtained from dailyimaging using aSi-kVCBCT and SmartAdapt® can be used as an effective tool to estimate the volume changes anddose difference in prostate radiotherapy.     

低剂量电离辐射诱导EL-4细胞适应性反应中DNA-PKcs基因的作用研究

[目的]探讨低剂量电离辐射诱导EL-4细胞适应性反应中DNA-PKcs基因的作用。[方法]EL-4细胞应用渥曼青霉素处理后接受低剂量0.075Gy预先照射,再分别进行较高攻击剂量照射（1.0,1.5和2.0Gy）,RT-PCR和免疫荧光法检测DNA-PKcsmRNA及蛋白表达。同时应用流式细胞术检测细胞凋亡和周期进程变化。[结果]应用渥曼青霉素能够阻断DNA-PKcs基因在mRNA及蛋白水平的表达。应用渥曼青霉素后直接接受攻击剂量照射和应用渥曼青霉素后先接受低剂量0.075Gy预先照射后再接受攻击剂量照射,均能诱导EL-4细胞发生适应性反应。[结论]DNA-PKcs基因在低剂量电离辐射诱导EL-4细胞发生适应性反应中可能不起决定性作用。     

A Phase II Study to Determine the Safety and Efficacy of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase (IDO) Enzyme INCB024360 in Patients with Myelodysplastic Syndromes

Background

INCB024360 is an oral inhibitor of the enzyme indoleamine 2,3-dioxygenase (IDO), which catalyzes the degradation of tryptophan to kynurenine. Preclinical data suggest that IDO1 inhibition by INCB024360 will increase T cell proliferation, and decrease T regulatory cells and myeloid derived suppressor cells suppressive activity. We conducted a phase II study to explore activity and pharmacodynamics of INCB024360 in patients with myelodysplastic syndromes.

乳癌根治术后静脉自控镇痛曲马多的最佳负荷剂量

 目的　寻求乳癌根治术后静脉自控镇痛曲马多的最佳负荷剂量。方法　 80例ASAⅠ～Ⅱ级女性乳癌病人 ,每组 2 0例 ,随机分为Ⅰ～Ⅳ组。各组分别在手术结束前 30min ,静脉注射曲马多负荷剂量1.2 5mg/kg、2 .5mg/kg、3.75mg/kg、5mg/kg。观察各组患者在PACU中疼痛、恶心、呕吐、镇静的发生情况。结果　在PACU中 ,为达到基础VAS评分≤ 3,Ⅰ组使用曲马多高达 8.8± 2 .91ml;95 % (19/ 2 0 )得使用PCA。Ⅲ组有 1例患者 (37min)、Ⅳ组有 2例患者 (39min、6 2min)发生苏醒延迟。Ⅲ组和Ⅳ组患者 2级镇静发生率分别为 30 %和 35 % (P <0 .0 5 )。结论　曲马多用于乳癌根治术后自控镇痛效果满意 ,手术结束前 30min 2 .5mg/kg曲马多的静脉负荷剂量具有与 3.75mg/kg和 5mg/kg等同的镇痛效果 ,同时并发症较轻     

Adaptive Radiotherapy for Carcinoma of the Urinary Bladder: Long-term Outcomes With Dose Escalation

AimsTo report long-term outcomes with dose-escalated, image-guided adaptive radiotherapy (ART) for bladder preservation in muscle-invasive bladder cancer (MIBC).Materials and methodsAll MIBC patients receiving bladder-preserving ART at our institute from 2009 to 2018 were analysed. For ART, three anisotropic planning target volumes (PTV) were concentrically grown around the simulation bladder volume. A library of intensity-modulated radiotherapy plans was created for each patient. A total dose of 64 Gy in 32 fractions to the entire bladder and 55 Gy to pelvic nodes was planned, with 68 Gy to the tumour bed (2 Gy equivalent dose = 68.7 Gy, α/β = 10) as simultaneous integrated boost for solitary tumours. The most appropriate PTV encompassing the bladder (‘plan-of-the-day’) was chosen daily using on-board megavoltage imaging. Neoadjuvant and concurrent chemotherapy was prescribed for medically fit patients.ResultsOf a total of 106 patients, most had T2 (68%) or T3 (19%) disease. Ninety-two patients (87%) completed 64 Gy to the whole bladder. Sixty-three patients (59%) received 68 Gy as tumour bed boost. Seventy-six per cent received concurrent weekly chemotherapy. At a median follow-up of 26 months, 3-year locoregional control, disease-free survival and overall survival were 74.3, 62.9 and 67.7%, respectively. Eighty-two per cent of patients retained disease-free bladder. Radiation Therapy Oncology Group grade III/IV acute genitourinary and gastrointestinal toxicities were 7.5% and 0%, respectively, and late genitourinary/gastrointestinal toxicities were 6.5% and 3.8%, respectively. Overall survival, disease-free survival, locoregional control and grade III/IV genitourinary/gastrointestinal toxicities did not differ significantly with dose escalation.ConclusionPlan-of-the-day ART is clinically safe and effective for bladder preservation and can be implemented in routine clinical practice. A high bladder preservation rate is achievable without compromising on survival or toxicities. Dose escalation does not seem to affect outcomes.     

Doubling Down on the PI3K-AKT-mTOR Pathway Enhances the Antitumor Efficacy of PARP Inhibitor in Triple Negative Breast Cancer Model beyond BRCA-ness

Phosphoinositide 3-kinase (PI3K) pathway, in addition to its pro-proliferative and antiapoptotic effects on tumor cells, contributes to DNA damage repair (DDR). We hypothesized that GDC-0980, a dual PI3K-mammalian target of rapamycin (mTOR) inhibitor, would induce an efficient antitumor effect in BRCA-competent triple negative breast cancer (TNBC) model when combined with ABT888 and carboplatin. Mechanism-based in vitro studies demonstrated that GDC-0980 treatment alone or in combination led to DNA damage (increased pγH2AX^S139; Western blot, immunofluorescence), gain in poly ADP-ribose (PAR), and a subsequent sensitization of BRCA-competent TNBC cells to ABT888 plus carboplatin with a time-dependent 1) decrease in proliferation signals (pAKT^T308/^S473, pP70S6K^T421/S424, pS6RP^S235/236), PAR/poly(ADP-ribose) polymerase (PARP) ratios, PAR/pγH2AX ratios, live/dead cell ratios, cell cycle progression, and three-dimensional clonogenic growths and 2) increase in apoptosis markers (cleaved caspases 3 and 9, a pro-apoptotic BH3-only of Bcl-2 family (BIM), cleaved PARP, annexin V). The combination was effective in vitro in BRCA-wild-type PIK3CA-H1047R-mutated BT20 and PTEN-null HCC70 cells. The combination blocked the growth of established xenograft tumors by 80% to 90% with a concomitant decrease in tumor Ki67, CD31, phosphorylated vascular endothelial growth factor receptor, pS6RP^S235/236, and p4EBP1^T37/46 as well as an increase in cleaved caspase 3 immunohistochemistry (IHC) levels. Interestingly, a combination with GDC-0941, a pan-PI3K inhibitor, failed to block the tumor growth in MDA-MB231. Results demonstrate that the dual inhibition of PI3K and mTOR regulates DDR. In a BRCA-competent model, GDC-0980 enhanced the antitumor activity of ABT888 plus carboplatin by inhibiting both tumor cell proliferation and tumor-induced angiogenesis along with an increase in the tumor cell apoptosis. This is the first mechanism-based study to demonstrate the integral role of the PI3K-AKT-mTOR pathway in DDR-mediated antitumor action of PARP inhibitor in TNBC.     

调强放疗中剂量验证方法的探究

[目的]探究调强放疗计划的剂量验证方法.[方法]利用Varian Clinal CX 4994号医用电子直线加速器出束的6MV能量X射线,对通过Eclipse 8.6治疗计划系统设计的调强放疗计划,采用PTW二维电离室矩阵进行平面剂量验证,采用Gamma分析.[结果]86.1％(292/339)的调强放疗计划绝对剂量通过率≥90.0％.[结论]使用二维电离室矩阵,进行调强放疗患者的个体化剂量验证,简单可靠,完善了调强放疗剂量验证体系.     

Evaluation of Self-Reported Progression and Correlation of Imatinib Dose to Survival in Patients with Metastatic Gastrointestinal Stromal Tumors: An Open Cohort Study

Objectives

Self-reported progression was evaluated as a predictor of survival in patients with metastatic gastrointestinal stromal tumor (GIST).

Methods

This is a follow-up of an open cohort study of Life Raft Group (LRG) members with a diagnosis of KIT-positive metastatic GIST receiving imatinib from May 2000–December 2007 reporting their subjective response to therapy by completion of an internet-based questionnaire. Subjects received ≥?1 year of imatinib and reported an initial positive response. Members reporting stable disease or progression were excluded. Self-reported progression-free survival (srPFS) was compared with overall survival (OS) and analyzed by starting and last reported dose.

Results

One hundred sixty-nine subjects reported a mean starting dose of 527.8±177.9 mg/d at a mean age of 53.8±11.6 years at initial diagnosis. Of those reporting progression, 66% died versus 11% of those not reporting progression (P?<?0.0001). When analyzed by last reported dose, a median srPFS benefit of 27.3 months was observed for the >400 mg/d group (P?=?0.0017). Sixty-two percent of subjects who initiated therapy at >400 mg/d reported a dose reduction. When analyzed by last reported dose, a significant benefit in OS (P?=?0.0229) and srPFS (P?=?0.0069) was observed for subjects taking 600 over 400 mg/d.

Conclusions

srPFS strongly correlated with OS. Significant advantages were observed when last reported dose was considered, as was higher daily dose. These observations suggest that careful escalation to intermediate daily doses should be investigated further for its potential to reduce the incidence and severity of adverse events, but also as a strategy against developing secondary resistance to imatinib.     

An Inter-observer Study to Determine Radiotherapy Planning Target Volumes for Recurrent Gynaecological Cancer Comparing Magnetic Resonance Imaging Only With Computed Tomography-Magnetic Resonance Imaging

AimsTarget delineation uncertainty is arguably the largest source of geometric uncertainty in radiotherapy. Several factors can affect it, including the imaging modality used for delineation. It is accounted for by applying safety margins to the target to produce a planning target volume (PTV), to which treatments are designed. To determine the margin, the delineation uncertainty is measured as the delineation error, and then a margin recipe used. However, there is no published evidence of such analysis for recurrent gynaecological cancers (RGC). The aims of this study were first to quantify the delineation uncertainty for RGC gross tumour volumes (GTVs) and to calculate the associated PTV margins and then to quantify the difference in GTV, delineation uncertainty and PTV margin, between a computed tomography-magnetic resonance imaging (CT-MRI) and MRI workflow.Materials and methodsSeven clinicians delineated the GTV for 20 RGC tumours on co-registered CT and MRI datasets (CT-MRI) and on MRI alone. The delineation error, the standard deviation of distances from each clinician's outline to a reference, was measured and the required PTV margin determined. Differences between using CT-MRI and MRI alone were assessed.ResultsThe overall delineation error and the resulting margin were 3.1 mm and 8.5 mm, respectively, for CT-MRI, reducing to 2.5 mm and 7.1 mm, respectively, for MRI alone. Delineation errors and therefore the theoretical margins, varied widely between patients. MRI tumour volumes were on average 15% smaller than CT-MRI tumour volumes.DiscussionThis study is the first to quantify delineation error for RGC tumours and to calculate the corresponding PTV margin. The determined margins were larger than those reported in the literature for similar patients, bringing into question both current margins and margin calculation methods. The wide variation in delineation error between these patients suggests that applying a single population-based margin may result in PTVs that are suboptimal for many. Finally, the reduced tumour volumes and safety margins suggest that patients with RGC may benefit from an MRI-only treatment workflow.