[X-ray evaluation of pulp calcification in adult permanent teeth after pulpotomy].

OBJECTIVE: To compare the clinical effects of pulpotomy with two kinds of calcium silicate materials, and to evaluate the formation of dentin bridge and pulp calcification after pulpotomy of adult permanent teeth. METHODS: Patients who visited the General Department of Peking University School and Hospital of Stomatology from November 2017 to September 2019 and planned for pulpotomy on permanent premolars and molars with carious exposed pulp were selected. They were randomly divided into two groups. Bioceramic putty material iRoot BP (iRoot group, n=22) and mineral trioxide aggregate MTA (MTA group, n=21) were used as pulp capping agents, respectively. The patients were recalled after one year and two years. The clinical efficacy, dentin bridge index (DBI) and pulp calcification index (PCI) were recorded. Blinding method was used for the patients and evaluators. RESULTS: There was no significant difference in gender, mean age, dentition and tooth position between the two groups (P>0.05). Seven cases were lost during the first year (4 cases in iRoot group and 3 cases in MTA group). In the iRoot group, 1 case had transient sensitivity at the time of 1-year follow-up. The cure rate of the two groups was 100% at the time of 2-year follow-up. The proportion of dentin bridge formation was 38.9% one year after operation, 55.6% two years after operation. The proportion of partial or even complete disappearance of root canal image was 5.6% before operation, 38.9% and 55.6% one and two years after operation, respectively. The difference was statistically significant by rank sum test (P < 0.05). There was no significant difference in dentin bridge formation and pulp calcification between the two groups (P < 0.05). DBI and PCI after operation was as the same as those before operation (44.4% cases of DBI and 25% cases of PCI) or gradually increased (55.6% cases of DBI and 75% cases of PCI). Spearman's nonparametric correlation analysis showed that age was positively correlated with preoperative pulp calcification index (PCI0, P < 0.05), but not with the dentin bridge index (DBI1, DBI2), pulp calcification index (PCI1, PCI2) and the degree of change (DBI2 vs. DBI1, PCI1 vs. PCI0, PCI2 vs. PCI0) 1-year and 2-year after operation (P>0.05). CONCLUSION: According to this study, good clinical effects were obtained within 2-year after pulpotomy of adult permanent teeth with MTA and iRoot. In some cases, the root canal system had a tendency of calcification aggravation, and there was no statistical difference in the development of this trend between the two groups.

[Evaluation of bioceramic putty repairmen iRoot and mineral trioxide aggregate in mature permanent teeth pulpotomy].

OBJECTIVE: To evaluate the clinical characteristics and effectiveness of pulpotomy in mature permanent teeth with bioceramic putty repairmen iRoot and mineral trioxide aggregate (MTA). METHODS: Pulpotomy was performed on mature permanent premolars and molars with carious exposures at the Department of General Dentistry of Peking University School and Hospital of Stomatology, from November 2017 to September 2019. The patients were randomly divided into 2 groups, Group iRoot (n=22) and Group MTA (n=21). In Group iRoot, bioceramic putty repairmen iRoot was used as pulp capping agent, while in Group MTA, mineral trioxide aggregate was used as pulp capping agent. All the patients had signed informed consent forms. The clinical efficacy was evaluated by clinical examinations (temperature and electrical activity test) and imaging examinations 3, 6, and 12 months after surgery. Blinding was used for the patients and evaluators, but due to the obvious differences in the properties of the two pulp capping agents, the blinding method was not used for the treatment provider (the attending physician). RESULTS: There was no significant difference in gender, average age, dentition and tooth position distribution between the two groups (P>0.05). In the study, 7 cases were lost to follow-up 12 months after operation (4 cases in Group iRoot, and 3 cases in Group MTA). One case in each of the two groups had transient sensitivity at the end of the 3-month follow-up, and the pulp vitality was normal at the end of the 6-month follow-up. One case in Group iRoot showed sensitivity at the end of the 12-month follow-up. The success rates of the two groups at the end of 12-month follow-up were 100%, and the cure rates were 94.4% (Group iRoot) and 100% (Group MTA), respectively, and the difference was not statistically significant (P>0.05). No cases in Group iRoot had obvious crown discoloration, while 3 cases in Group MTA had. CONCLUSION: The clinical characteristics and effectiveness of pulpotomy in mature permanent teeth with bioceramic putty repairmen iRoot were similar with MTA. Bioceramic putty repairmen iRoot is an acceptable material when used in pulpotomy of mature permanent teeth. Because it is not easy to cause tooth discoloration after treatment and is convenient to operate, bioceramic putty repairmen iRoot has a better clinical application prospect.

Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group.

BACKGROUND: The bevacizumab-Avastin® adjuVANT (AVANT) study did not meet its primary end point of improving disease-free survival (DFS) with the addition of bevacizumab to oxaliplatin-based chemotherapy in stage III colon cancer (CC). We report here the long-term survival results (S-AVANT). PATIENTS AND METHODS: Patients with curatively resected stage III CC were randomly assigned to FOLFOX4, FOLFOX4-bevacizumab, or XELOX-bevacizumab. RESULTS: A total of 2867 patients were randomized: FOLFOX4: n = 955, FOLFOX4-bevacizumab: n = 960, XELOX-bevacizumab: n = 952. With a median of 6.73 years follow-up (interquartile range 5.51-10.54), 672 patients died, of whom 198 (20.7%), 250 (26.0%), and 224 (23.5%) were in the FOLFOX4, FOLFOX4-bevacizumab, and XELOX-bevacizumab arms, respectively. The 10-year overall survival (OS) rates were 74.6%, 67.2%, and 69.9%, (P = 0.003) and 5-year disease-free survival (DFS) rates were 73.2%, 68.5%, and 71.0% (P = 0.174), respectively. OS and DFS hazard ratios were 1.29 [95% confidence interval (CI) 1.07-1.55; P = 0.008] and 1.16 (95% CI 0.99-1.37; P = 0.063) for FOLFOX4-bevacizumab versus FOLFOX4 and 1.15 (95% CI 0.95-1.39; P = 0.147) and 1.1 (95% CI 0.93-1.29; P = 0.269) for XELOX-bevacizumab versus FOLFOX4, respectively. CC-related deaths (n = 542) occurred in 157 (79.3%) patients receiving FOLFOX4, 205 (82.0%) receiving FOLFOX4-bevacizumab, and 180 (80.4%) receiving XELOX-bevacizumab (P = 0.764), while non-CC-related deaths occurred in 41 (20.7%), 45 (18.0%), and 44 (19.6%) patients, respectively. Cardiovascular-related and sudden deaths during treatment or follow-up were reported in 13 (6.6%), 17 (6.8%), and 14 (6.3%) patients, in the FOLFOX4, FOLFOX4-bevacizuamb, and XELOX-bevacizumab arms, respectively (P = 0.789). Treatment arm, sex, age, histological differentiation, performance status, T/ N stages, and localization of primary tumor were independent prognostic factors of OS in stage III. CONCLUSIONS: S-AVANT confirms the initial AVANT report. No benefit of the bevacizumab addition to FOLFOX4 adjuvant therapy in patients with stage III CC was observed in terms of DFS with a negative effect in OS, without increase in non-CC related deaths. CLINICAL TRIAL IDENTIFICATION: NCT00112918.

Time to second kidney transplantation in young adults after failed pediatric kidney transplant.

BACKGROUND: Under the current kidney allocation system, pediatric candidates listed prior to age 18 receive priority for high-quality deceased donor organs. This has resulted in a decline in living donor transplantation in pediatrics, despite superior outcomes of living donor transplantation. Due to a young age at transplantation, most pediatric kidney transplant recipients require re-transplantation. The effects of a previously failed deceased donor vs a previously failed living donor on re-transplant candidates are unknown. METHODS: Using the United Network for Organ Sharing database, we examined 2772 re-transplant recipients aged 18-30 years at time of relisting for second KT from 2000 to 2018 with history of prior pediatric KT (age ≤ 18 years). RESULTS: PFLDKT recipients compared to those with PFDDKT had shorter median waiting times and dialysis time regardless of their second donor type (14.0 vs 20.3 months, and 19.1 vs 34.5 months, respectively). PFLDKT recipients had higher re-transplant rates (adjusted HR 1.17, 95% CI 1.09-1.27, and adjusted HR 1.05, 95% CI 0.95-1.15 when calculating from time of relisting and time of returning to dialysis, respectively). PFDDKT recipients were more likely to have higher median PRA levels (90% vs 73%). CONCLUSIONS: Re-transplant candidates who received a previous deceased donor as a child had a higher level of sensitization, longer waiting time, and dialysis exposure compared to those with PFLDKT. Among primary pediatric kidney transplant candidates, consideration should be considered for living donor transplantation, despite the priority for deceased donor organs, to avoid increased sensitization and longer waiting times for with re-transplantation.

Entropy production and fluctuation theorems on complex networks.

Entropy production (EP) is a fundamental quantity useful for understanding irreversible process. In stochastic thermodynamics, EP is more evident in probability density functions of trajectories of a particle in the state space. Here, inspired by a previous result that complex networks can serve as state spaces, we consider a data packet transport problem on complex networks. EP is generated owing to the complexity of pathways as the packet travels back and forth between two nodes along the same pathway. The total EPs are exactly enumerated along all possible shortest paths between every pair of nodes, and the functional form of the EP distribution is proposed based on our numerical results. We confirm that the EP distribution satisfies the detailed and integral fluctuation theorems. Our results should be pedagogically helpful for understanding trajectory-dependent EP in stochastic processes and exploring nonequilibrium fluctuations associated with the entanglement of dividing and merging among the shortest pathways in complex networks.

Mixed phenotype acute leukaemia with t(9,22), BCR-ABL1: A case report.

INTRODUCTION: Mixed phenotype acute leukaemia (MPAL) is a rare entity of acute leukaemia. CASE REPORT: Here we report a case of a 39-year-old lady, with an incidental finding of hyperleukocytosis (white blood cells count: 139.2 x 109/L). Her peripheral blood film revealed 36% of blasts and a bone marrow aspiration showed 53% of blasts. Immunophenotyping showed a population of blasts exhibiting positivity of two lineages, myeloid lineage and B-lymphoid lineage with strong positivity of CD34 and terminal deoxynucleotidyl transferase (Tdt). A conventional karyotyping revealed the presence of Philadelphia chromosome. She was diagnosed with MPAL with t(9,22), BCR ABL1, which carried a poor prognosis. She was treated with acute lymphoblastic leukaemia (ALL) chemotherapy protocol coupled with a tyrosine kinase inhibitor and was planned for an allogeneic stem cells transplant. CONCLUSION: This MPAL case was diagnosed incidentally in an asymptomatic patient during medical check-up. We highlight this rare case report to raise the awareness about this rare disease. Understanding the pathogenesis of the disease with the underlying genes responsible for triggering the disease, uniform protocols for diagnosis and targeted treatment will help for proper management of these patients.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic oesophageal cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of oesophageal cancer was published in 2016, and covered the management and treatment of local/locoregional disease, limited disease, locally advanced disease and the management of advanced/metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic oesophageal cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic oesophageal cancer representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic gastric cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of gastric cancer (GC) was published in 2016, and covered the management and treatment of local, locoregional, locally advanced and metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and The Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic GC in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic GC representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

Wound-healing effect of adipose stem cell-derived extracellular matrix sheet on full-thickness skin defect rat model: Histological and immunohistochemical study.

The potential use of extracellular matrix (ECM) as a source of wound dressing material has recently received much attention. The ECM is an intricate network of various combinations of elastin, collagens, laminin, fibronectin, and proteoglycans that play a key role in stimulating cell proliferation and differentiation. We evaluated the efficacy of an ECM sheet derived from human adipose tissue as a wound dressing material to enhance healing. We prepared a novel porous ECM sheet dressing scaffold from human adipose tissue. in vitro analysis of the ECM sheets showed efficient decellularisation; absence of immunostimulatory components; and the presence of a wide number of angiogenic and bioactive factors, including collagen, elastin, and proteoglycans. To evaluate in vivo efficacy, full-thickness excisional wounds were created on the dorsal skin of a rat, and the ECM sheets; secondary healing foam wound dressing, Healoderm; or a conventional dressing were applied to each wound site. Photographs were taken every other day, and the degree of reepithelialisation of the wounds was determined. Application of an ECM sheet dressing enhanced the macroscopic wound-healing rate on days 4, 7, and 10 compared with that in the control group. Microscopic analysis indicated that the reepithelialisation rate of the wound was higher in the ECM group compared with that in the control group; the reepithelialisation rate was better than that of the secondary healing foam wound dressing. Moreover, a denser and more organised granulation tissue was formed in the ECM sheet group compared with that in the secondary healing foam wound dressing and control groups. The ECM sheet also showed the highest microvessel density compared with the secondary healing foam wound dressing and control groups. Based on these data, we suggest that a bioactive ECM sheet dressing derived from human adipose can provide therapeutic proteins for wound healing.

Electroporation of Brain Endothelial Cells on Chip toward Permeabilizing the Blood-Brain Barrier.

The blood-brain barrier, mainly composed of brain microvascular endothelial cells, poses an obstacle to drug delivery to the brain. Controlled permeabilization of the constituent brain endothelial cells can result in overcoming this barrier and increasing transcellular transport across it. Electroporation is a biophysical phenomenon that has shown potential in permeabilizing and overcoming this barrier. In this study we developed a microengineered in vitro model to characterize the permeabilization of adhered brain endothelial cells to large molecules in response to applied pulsed electric fields. We found the distribution of affected cells by reversible and irreversible electroporation, and quantified the uptaken amount of naturally impermeable molecules into the cells as a result of applied pulse magnitude and number of pulses. We achieved 81 ± 1.7% (N = 6) electroporated cells with 17 ± 8% (N = 5) cell death using an electric-field magnitude of ∼580 V/cm and 10 pulses. Our results provide the proper range for applied electric-field intensity and number of pulses for safe permeabilization without significantly compromising cell viability. Our results demonstrate that it is possible to permeabilize the endothelial cells of the BBB in a controlled manner, therefore lending to the feasibility of using pulsed electric fields to increase drug transport across the BBB through the transcellular pathway.

A phase Ib study of selumetinib (AZD6244, ARRY-142886) in combination with sorafenib in advanced hepatocellular carcinoma (HCC).

BACKGROUND: Treatment with sorafenib, although associated with inhibition of tumour growth and angiogenesis in in vivo studies, leads to up-regulation of pERK. The addition of MEK inhibition could potentially abrogate this effect and potentiate anti-tumour activity. This phase I study investigated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and biomarker correlates of selumetinib combined with sorafenib in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients with Child-Pugh (CP) score ≤7 were treated with 400 mg twice daily of sorafenib with escalating doses of selumetinib in a 3 + 3 study design. The dose-limiting toxicity (DLT) evaluation period was 28 days. PK of selumetinib was determined. Angiogenic effect was evaluated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Twenty-seven patients of Asian ethnicity were enrolled. The MTD was selumetinib 75 mg daily with sorafenib 400 mg twice daily. DLT included grade 3 transaminitis, diarrhoea and fatigue. Most common treatment-related adverse events at MTD (all grades) were diarrhoea (85%), rash (59%), hypertension (44%), fatigue (30%), anorexia (22%) and hand-foot syndrome (22%). Four patients (15%) had PR and 13 (48%) had SD. PR or SD was observed for ≥6 months in seven patients. The median overall survival was 14.4 months. Selumetinib exposures in combination with sorafenib were comparable to other monotherapy studies. A reduction in permeability-surface area product noted in DCE-MRI with treatment correlated with worse survival outcomes. CONCLUSION: The MTD of selumetinib was 75 mg daily when combined with sorafenib 400 mg twice a day in CP ≤7 HCC. Acceptable adverse events and encouraging anti-tumour activity warrant further evaluation. DCE-MRI findings deserve prospective evaluation. CLINICALTRIALSGOV IDENTIFIER: NCT01029418.

An outbreak of multiple norovirus strains on a cruise ship in China, 2014.

AIMS: To determine the cause of an outbreak of acute gastroenteritis that occurred on a cruise ship sailing along the Yangzi River from Chongqing to Nanjing, China. METHODS AND RESULTS: Noroviruses were identified by reverse transcription-PCR (RT-PCR) in rectal swabs from 34 of 54 subjects tested (63·0%). Sequencing and genotyping showed that noroviruses of up to seven different genotypes circulated in this outbreak: noroviruses GI.1, GI.2, GI.3, GI.4, GI.8, GI.9 and an uncommon strain GII.17. Common genotypes were not identified in this event. None of the food or water samples were tested positive for noroviruses. CONCLUSIONS: We suspected that it was a point-source infection due to contaminated water or food harvested from contaminated water, taking account of the co-existence of diverse norovirus genotypes. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, we presented the molecular investigation of a norovirus outbreak on a cruise in China. We revealed that the outbreak was caused by several different norovirus genotypes and analysed the possible source of infection as well, thus facilitating the evaluation of epidemiological issues regarding noroviruses in this area.

Triamcinolone acetonide nanoparticles incorporated in thermoreversible gels for age-related macular degeneration.

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the US affecting millions yearly. It is characterized by intraocular neovascularization, inflammation and retinal damage which can be ameliorated through intraocular injections of glucocorticoids. However, the complications that arise from repetitive injections as well as the difficulty posed by targeting the posterior segment of the eye make this interesting territory for the development of novel drug delivery systems (DDS). In the present study, we described the development of a DDS composed of triamcinolone acetonide-encapsulated PEGylated PLGA nanoparticles (NP) incorporated into PLGA-PEG-PLGA thermoreversible gel and its use against VEGF expression characteristic of AMD. We found that the NP with mean size of 208 ± 1.0 nm showed uniform size distribution and exhibited sustained release of the drug. We also demonstrated that the polymer can be injected as a solution and transition to a gel phase based on the biological temperature of the eye. Additionally, the proposed DDS was non-cytotoxic to ARPE-19 cells and significantly reduced VEGF expression by 43.5 ± 3.9% as compared to a 1.53 ± 11.1% reduction with triamcinolone. These results suggest the proposed DDS will contribute to the development of novel therapeutic strategies for AMD.

Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study.

BACKGROUND: Existing evidence suggests that proinflammatory cytokines play an intermediary role in postchemotherapy cognitive impairment. This is one of the largest multicentered, cohort studies conducted in Singapore to evaluate the prevalence and proinflammatory biomarkers associated with cognitive impairment in breast cancer patients. PATIENTS AND METHODS: Chemotherapy-receiving breast cancer patients (stages I-III) were recruited. Proinflammatory plasma cytokines concentrations [interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, interferon-γ and tumor necrosis factor-α] were evaluated at 3 time points (before chemotherapy, 6 and 12 weeks after chemotherapy initiation). The FACT-Cog (version 3) was utilized to evaluate patients' self-perceived cognitive disturbances and a computerized neuropsychological assessment (Headminder) was administered to evaluate patients' memory, attention, response speed and processing speed. Changes of cognition throughout chemotherapy treatment were compared against the baseline. Linear mixed-effects models were applied to test the relationships of clinical variables and cytokine concentrations on self-perceived cognitive disturbances and each objective cognitive domain. RESULTS: Ninety-nine patients were included (age 50.5 ± 8.4 years; 81.8% Chinese; mean duration of education = 10.8 ± 3.3 years). Higher plasma IL-1ß was associated with poorer response speed performance (estimate: -0.78; 95% confidence interval (CI) -1.34 to -0.03; P = 0.023), and a higher concentration of IL-4 was associated with better response speed performance (P = 0.022). Higher concentrations of IL-1ß and IL-6 were associated with more severe self-perceived cognitive disturbances (P = 0.018 and 0.001, respectively). Patients with higher concentrations of IL-4 also reported less severe cognitive disturbances (P = 0.022). CONCLUSIONS: While elevated concentrations of IL-6 and IL-1ß were observed in patients with poorer response speed performance and perceived cognitive disturbances, IL-4 may be protective against chemotherapy-associated cognitive impairment. This study is important because cytokines would potentially be mechanistic mediators of chemotherapy-associated cognitive changes.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer (GC), published in late 2022 and the updated ESMO Gastric Cancer Living Guideline published in July 2023, were adapted in August 2023, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with GC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with GC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), coordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with GC across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

Phase I PIANO trial-PIPAC-oxaliplatin and systemic nivolumab combination for gastric cancer peritoneal metastases: clinical and translational outcomes.

INTRODUCTION: Pressurized intraperitoneal aerosol chemotherapy-oxaliplatin (PIPAC-OX) induces direct DNA damage and immunogenic cell death in patients with gastric cancer peritoneal metastases (GCPM). Combining PIPAC-OX with immune checkpoint inhibition remains untested. We conducted a phase I first-in-human trial evaluating the safety and efficacy of PIPAC-OX combined with systemic nivolumab (NCT03172416). METHODS: Patients with GCPM who experienced disease progression on at least first-line systemic therapy were recruited across three centers in Singapore and Belgium. Patients received PIPAC-OX at 90 mg/m2 every 6 weeks and i.v. nivolumab 240 mg every 2 weeks. Translational studies were carried out on GCPM samples acquired during PIPAC-OX procedures. RESULTS: In total, 18 patients with GCPM were prospectively recruited. The PIPAC-OX and nivolumab combination was well tolerated with manageable treatment-related adverse events, although one patient suffered from grade 4 vomiting. At second and third PIPAC-OX, respectively, the median decrease in peritoneal cancer index (PCI) was -5 (interquartile range: -12 to +1) and -7 (interquartile range: -6 to -20) and peritoneal regression grade 1 or 2 was observed in 66.7% (6/9) and 100% (3/3). Translational analyses of 43 GCPM samples revealed enrichment of immune/stromal infiltration and inflammatory signatures in peritoneal tumors after PIPAC-OX and nivolumab. M2 macrophages were reduced in treated peritoneal tumor samples while memory CD4+, CD8+ central memory and naive CD8+ T-cells were increased. CONCLUSIONS: The first-in-human trial combining PIPAC-OX and nivolumab demonstrated safety and tolerability, coupled with enhanced T-cell infiltration within peritoneal tumors. This trial sets the stage for future combinations of systemic immunotherapy with locoregional intraperitoneal treatments.

PIPAC nebulizer: How to test the new devices in the market, expert recommendations.

Pressurized intraperitoneal aerosol chemotherapy, named PIPAC, is now used in many centers around the world and as an intraperitoneal drug delivery system for treatment of peritoneal carcinomatosis. Recently, many of us have encountered problems during PIPAC procedures due to changes in material and production features of the original PIPAC nebulizer. Concomitantly, new PIPAC nebulizers proposed by other manufacturers are being launched on the market; which claim that they are the same as the original device in delivering PIPAC. However, these new devices are all different in terms of materials, technical characteristics and costs. We have considered that, to maintain the acquired results of PIPAC, we must ensure that the new systems are equivalent. The characteristics deemed essential by the expert group are as follows: 1: The nebulizer must be able to create droplets through an injector pressure between 10 and 20 bars, 2: The mean droplet size must be 3 micrometers, with 95% of the droplets between 0 and 10 micrometers, 3: The diffusion angle must be 70 degrees, which is the minimum.

Association of common genetic variants with breast cancer risk and clinicopathological characteristics in a Chinese population.

Genome-wide association studies (GWAS) have identified various genetic susceptibility loci for breast cancer based mainly on European-ancestry populations. Differing linkage disequilibrium patterns exist between European and Asian populations, and thus GWAS-identified single nucleotide polymorphisms (SNPs) in one population may not be of significance in another population. In order to explore the role of breast cancer susceptibility variants in a Chinese population of Southern Chinese descent, we analyzed 22 SNPs for 1,191 breast cancer cases and 1,534 female controls. Associations between the SNPs and clinicopathological features were also investigated. In addition, we evaluated the combined effects of associated SNPs by constructing risk models. Eight SNPs were associated with an elevated breast cancer risk. Rs2046210/6q25.1 increased breast cancer risk via an additive model [per-allele odds ratio (OR) = 1.43, 95 % confidence interval (CI) = 1.26-1.62], and was associated with estrogen receptor (ER)-positive (per-allele OR = 1.39, 95 % CI = 1.20-1.61) and ER-negative (per-allele OR = 1.55, 95 % CI = 1.28-1.89) disease. Rs2046210 was also associated with stage 1, stage 2, and stage 3 disease, with per-allele ORs of 1.38 (1.14-1.68), 1.48 (1.25-1.74), and 1.58 (1.28-1.94), respectively. Four SNPs mapped to 10q26.13/FGFR2 were associated with increased breast cancer risk via an additive model with per-allelic risks (95 % CI) of 1.26 (1.12-1.43) at rs1219648, 1.22 (1.07-1.38) at rs2981582, 1.21 (1.07-1.36) at rs2981579, and 1.18 (1.04-1.35) at rs11200014. Variants of rs7696175/TLR1, TLR6, rs13281615/8q24, and rs16886165/MAP3K1 were also associated with increased breast cancer risk, with per-allele ORs (95 % CI) of 1.16 (1.00-1.34), 1.15 (1.02-1.29), and 1.15 (1.01-1.29), respectively. Five SNPs associated with breast cancer risk predominantly among ER-positive tumors (rs2981582/FGFR2, rs4415084/MRPS30, rs1219648/FGFR2, rs2981579/FGFR2, and rs11200014/FGFR2). Among our Chinese population, the risk of developing breast cancer increased by 90 % for those with a combination of 6 or more risk alleles, compared to patients with ≤3 risk alleles.