Oxaliplatin use in pressurized intraperitoneal aerosol chemotherapy (PIPAC) is safe and effective: A multicenter study

IntroductionPressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new drug delivery method used in patients with peritoneal cancer (PC) of primary or secondary origin. Intraperitoneal use of oxaliplatin raises concerns about toxicity, especially abdominal pain. The objective of this study was to assess the tolerance of PIPAC with oxaliplatin (PIPAC-Ox) in a large cohort of patients and to identify the risk factors for high grade toxicity, discontinuation of treatment and impaired survival.Material and methodsThis retrospective cohort study included all consecutive patients treated with PIPAC-Ox (92 mg/m²) in five centers specialized in the treatment of PC. The procedure was repeated every 6 weeks. Outcomes of interest were Common Terminology Criteria for Adverse Events (CTCAE), symptoms and survival (Kaplan-Meier). Univariate risk factors were included in a multinominal regression model to control for bias.ResultsOverall, 251 PIPAC-Ox treatments were performed in 101 patients (45 female) having unresectable PC of various origins: 66 colorectal, 15 gastric, 5 ovarian, 3 mesothelioma, 2 pseudomyxoma, 10 other malignancies (biliary, pancreatic, endocrine) respectively. The median PCI was 19 (IQR: 10–28). Postoperative abdominal pain was present in 23 patients. Out of the 9 patients with grade 3 abdominal pain, only 3 needed a change of PIPAC drug. CTCAE 4.0 toxicity grade 4 or higher was encountered in 16(15.9%) patients. The patients had a mean of 2.5 procedures/patient (SD = 1.5). 50 subjects presented with symptom improvement.ConclusionsOxaliplatin-based PIPAC appears to be a safe treatment that offers good symptom control and promising survival for patients with advanced peritoneal disease.     

A retrospective analysis comparing set up errors from standard versus customised headrests for head and neck radiotherapy

IntroductionIn response to advice from The National Institute for Health and Care Excellence ⁽¹⁾ to reduce hospital visits during COVID-19, standard headrests were introduced for head and neck radiotherapy within Northern Centre for Cancer Care (NCCC). The standard headrest requires one mould room appointment compared to 3 appointments with customised headrests.MethodsTwo groups of 10 patients treated between December 2019 and June 2020 were retrospectively analysed by 1 observer. Groups were stratified according to age, sex and tumour site. One group had customised headrest and the other had standard headrest. Five hundred and forty seven cone beam computed tomography images were reviewed. A 6 Degree of Freedom match was performed then chin, shoulder and spine position were assessed using dosimetrist drawn structures. Structures out of the tolerance were recorded. A chi-squared test was used for statistical analysis.ResultsThe out of tolerance chin position count recorded was 21 for customised headrest and 36 for standard headrest, p-value 0.046. The shoulder position count was 13 for customised headrest and 77 for standard headrest p-value <0.001. The spine position count was 3 for CHR and 21 for standard headrest, p-value <0.001. This means the headrests compared are not equivalent in terms of set up reproducibility. Overall the standard headrest group had 10 set-up re-scans and no set up re-scans were recorded in the customised headrest group.ConclusionFewer hospital visits with SHR reduce patient exposure to COVID-19. However, CHR provided a more reliable level of immobilisation in this study.Implications for practiceThe radiotherapy service will be reviewed in line with these findings.     

Cellular targets of regulatory B cell-mediated suppression

Regulatory B cells (Bregs) are defined by their ability to restrain inflammatory responses both in vivo and in vitro. Interleukin 10 (IL-10) production by Bregs is thought to be central to their ability to regulate inflammation, largely due to IL-10s’ ability to suppress pro-inflammatory cytokine production by effector lymphocytes and to maintain the differentiation of regulatory T cells (Tregs). However, with an increase in available published data, it has become evident that Bregs utilize a number of suppressive mechanisms in order to alter the activation of a variety of different lymphocytes. Here, we summarize the multiplicity of cellular targets of Breg-mediated suppression and describe the mechanisms employed by Bregs to suppress chronic inflammatory responses.     

Immunosuppressive potency of mechanistic target of rapamycin inhibitors in solid-organ transplantation

Mammalian target of rapamycin, also known as mechanistic target of rapamycin (mTOR) is a protein kinase that belongs to the PI3K/AKT/mTOR signaling pathway, which is involved in several fundamental cellular functions such as cell growth, proliferation, and survival. This protein and its associated pathway have been implicated in cancer development and the regulation of immune responses, including the rejection response generated following allograft transplantation. Inhibitors of mTOR (mTORi) such as rapamycin and its derivative everolimus are potent immunosuppressive drugs that both maintain similar rates of efficacy and could optimize the renal function and diminish the side effects compared with calcineurin inhibitors. These drugs are used in solid-organ transplantationtoinduceimmunosuppression while also promoting the expansion of CD4+CD25+FOXP3+ regulatory T-cells that could favor a scenery of immunological tolerance. In this review, we describe the mechanisms by which inhibitors of mTOR induce suppression by regulation of these pathways at different levels of the immune response. In addition, we particularly emphasize about the main methods that are used to assess the potency of immunosuppressive drugs, highlighting the studies carried out about immunosuppressive potency of inhibitors of mTOR.     

2015—2019年全国外照射个人剂量监测能力考核结果分析与总结

目的规范个人剂量监测技术服务机构的个人剂量监测工作,提高监测能力和水平。方法汇总2015—2019年全国外照射个人剂量监测能力考核的结果,并对考核中出现的问题进行总结与分析。结果截至2019年,来自全国30个省、自治区或直辖市的个人剂量监测技术服务机构参加了全国外照射个人剂量监测能力考核,涉及的机构有疾控中心、职防院(所)、科研院所、大专院校、核工业、医疗机构及民营技术机构等。参加考核的机构数从202家增加到382家。考核结果除2017年的合格率略低,其他4年的合格率均高于90%。优秀率随着年份的增加而增加。结论2015—2019年全国外照射个人剂量监测技术服务机构测量能力满足个人剂量监测需求,能出具符合标准的检测报告,但尚有一些机构未能合格,相关机构应仔细分析查找不合格的原因,规范实验室的质量控制手段,提高测量水平和数据分析能力。     

ROS清除剂在细菌抗生素耐受中的作用研究进展

活性氧簇(ROS)是生物在有氧环境中进行能量代谢时产生的一类分子的总称，ROS不仅在动物、植物以及细菌的生理过程中发挥着重要的作用，也在研究抗生素杀菌和细菌耐药性的产生上有着重要的功能，添加ROS清除剂有助于我们更好的研究ROS在细菌对抗菌剂耐受中的作用。本文主要通过对常见的ROS清除剂过氧化氢酶、硫脲、联吡啶、DMSO、褪黑素和其他较为常见的清除剂等化合物在抗生素杀菌过程中的作用机制、ROS清除剂添加对细菌耐受性的影响及其他生理作用进行综述，旨在对这些常见的ROS清除剂的不同功能和缺点进行一个更广泛和深入的了解，以便我们在选用相关ROS清除剂时对其作用机理有较为清楚的了解从而选取合适的ROS清除剂。     

Immune checkpoints and the regulation of tolerogenicity in dendritic cells: Implications for autoimmunity and immunotherapy

The immune system is responsible for defending the host from a large variety of potential pathogens, while simultaneously avoiding immune reactivity towards self-components. Self-tolerance has to be tightly maintained throughout several central and peripheral processes; immune checkpoints are imperative for regulating the immunity/tolerance balance. Dendritic cells (DCs) are specialized cells that capture antigens, and either activate or inhibit antigen-specific T cells. Therefore, they play a key role at inducing and maintaining immune tolerance. DCs that suppress the immune response have been called tolerogenic dendritic cells (tolDCs). Given their potential as a therapy to prevent transplant rejection and autoimmune damage, several strategies are under development to generate tolDCs, in order to avoid activation and expansion of self-reactive T cells. In this article, we summarize the current knowledge relative to the main features of tolDCs, their mechanisms of action and their therapeutic use for autoimmune diseases. Based on the literature reviewed, autologous antigen-specific tolDCs might constitute a promising strategy to suppress autoreactive T cells and reduce detrimental inflammatory processes.     

Dexamethasone turns tumor antigen-presenting cells into tolerogenic dendritic cells with T cell inhibitory functions

BackgroundDendritic cells (DCs) are usually immunogenic, but they are also capable of inducing tolerance under anti-inflammatory conditions. Immunotherapy based on autologous DCs loaded with an allogeneic melanoma cell lysate (TRIMEL/DCs) induces immunological responses and increases melanoma patient survival. Glucocorticoids can suppress DC maturation and function, leading to a DC-mediated inhibition of T cell responses.MethodsThe effect of dexamethasone, a glucocorticoid extensively used in cancer therapies, on TRIMEL/DCs phenotype and immunogenicity was examined.ResultsDexamethasone induced a semi-mature phenotype on TRIMEL/DC with low maturation surface marker expressions, decreased pro-inflammatory cytokine induction (IL-1β and IL-12) and increased release of regulatory cytokines (IL-10 and TGF-β). Dexamethasone-treated TRIMEL/DCs inhibited allogeneic CD4⁺ T cell proliferation and cytokine release (IFNγ, TNF-α and IL-17). Co-culturing melanoma-specific memory tumor-infiltrating lymphocytes with dexamethasone-treated TRIMEL/DC inhibited proliferation and effector T cell activities, including cytokine secretion and anti-melanoma cytotoxicity.ConclusionsThese findings suggest that dexamethasone repressed melanoma cell lysate-mediated DC maturation, generating a potent tolerogenic-like DC phenotype that inhibited melanoma-specific effector T cell activities. These results suggest that dexamethasone-induced immunosuppression may interfere with the clinical efficacy of DC-based melanoma vaccines, and must be taken into account for optimal design of cellular therapy against cancer.     

Immune tolerance induction using a factor VIII/von Willebrand factor concentrate (BIOSTATE®), with or without immunosuppression,in Australian paediatric severe haemophilia A patients with high titre inhibitors: A multicentre,retrospective study

Introduction

It has been postulated that factor VIII (FVIII) products containing von Willebrand factor (VWF) may improve immune tolerance induction (ITI) success rate in patients with haemophilia A and poor prognostic factors.

Materials and methods

We conducted a retrospective cohort analysis of a FVIII/VWF concentrate (BIOSTATE®) for ITI in paediatric patients with severe haemophilia A (SHA) and inhibitors, from January 2003 to December 2011 at 3 paediatric-only Haemophilia Treatment Centres in Australia. Response to ITI was assessed at or before 33 months and at completion of ITI. Fifteen male patients with SHA were included in the analysis.

Results

BIOSTATE was used for primary ITI in 8 patients (2 years, range 1.1–11.5 years) and for salvage ITI in 7 patients (9.9 years, range 1.1–15.4). At the end of the observation period there were 11 patients who achieved a complete response with BIOSTATE after a median duration of 21 months (range 5–85 months); a partial response was achieved in 2 patients in whom ITI is ongoing. Therefore, the overall response rate was 86.6%. Two patients were deemed treatment failures: one due to non-compliance after 18 months of ITI and another in whom a partial response had not been achieved after 22 months of ITI.

Conclusion

BIOSTATE was well-tolerated and effective when used for primary or salvage ITI in this cohort of paediatric patients with SHA and a high-level inhibitor.     

单中心327例次腹膜透析相关性腹膜炎致病菌及药敏结果分析

目的 探讨持续性非卧床腹膜透析(continuous ambulatory peritoneal dialysis,CAPD)相关性腹膜炎的致病菌及其耐药性.方法 回顾性分析2008年1月至2013年5月在我中心就诊的180例327例次CAPD相关性腹膜炎的致病菌及其耐药性.结果 202例次培养阳性,培养阳性率为61.77％.革兰阳性球菌154例次,其中金黄色葡萄球菌及凝固酶阴性葡萄球菌123例次,占病原微生物培养阳性的60.89％;革兰阴性杆菌38例次,其中大肠埃希菌11例次,占病原微生物培养阳性的5.45％;真菌10例次,其中假丝酵母菌7例次,占病原微生物培养阳性的3.47％.革兰阳性球菌对万古霉素耐药率最低,为3.25％,其次为莫西沙星,为5.19％,对利福平、庆大霉素、左氧氟沙星耐药率分别为12.99％、35.71％、45.45％,对青霉素的耐药率最高,达84.42％.革兰阴性菌对哌拉西林/他唑巴坦耐药率最低,为10.53％,其次为头孢他啶,为23.68％,对左氧氟沙星、头孢匹美、庆大霉素耐药率分别为26.32％、28.21％、36.84％,对氨苄西林/舒巴坦的耐药率最高,达50.00％.重复感染54例,共114例次,72例次培养阳性,阳性率为63.16％,其中革兰阳性球菌63例次,占87.50％,革兰阴性杆菌9例次,占12.50％,革兰阳性球菌以金黄色葡萄球菌为主,革兰阴性杆菌以大肠埃希菌为主.结论 本中心CAPD相关性腹膜炎致病菌以革兰阳性球菌为多,接触污染是导致腹膜炎的主要原因.革兰阳性球菌对青霉素耐药率最高,革兰阴性杆菌对氨苄西林/舒巴坦耐药率最高.