Weeks Of Combined Treatment Research Articles

Modifying the gastric tumor microenvironment with tadalafil: A transcriptomic analysis of immune signatures from underserved patients of southern Arizona.

e16104 Background: Gastric adenocarcinoma (GAC) is the fifth most common cancer worldwide with significant morbidity and mortality. Recently, southern Arizona has seen a concerning surge in incidence of GAC due to ineffective H. pylori screening and treatment. Moreover, peri-operative chemotherapy treatment in stage IB-III GAC represents an area of unmet need for new targets. Our center serves a catchment area that is 40% Hispanic and sees a high volume of GAC patients, making this our research focus. Our preclinical work in Helicobacter infected mice showed a subset of myeloid derived suppressor cells (MDSCs) expressing Schlafen4 (SLFN4) concurrently with gastric metaplasia, a GAC precursor. SLFN4+ MDSCs exhibit robust transcriptional signatures associated with type I interferon(IFN-I) inducible genes, coupled with T cell suppressor function. Pharmacological inhibition via phosphodiesterase (PDE) 5,6 inhibitor sildenafil resulted in the suppression of SLFN4, reversal of T cell suppression, and mitigation of metaplasia. This is the first clinical study aimed to characterize SLFN12L, the human ortholog of mouse SLFN4, and to analyze the neoplastic and immune signatures in GAC before and after PDE5 inhibition with tadalafil. Methods: Using single-cell RNA sequencing, we examined tissues from GAC patients enrolled in a "Window of Opportunity" study (NCT05709574). The patients receive tadalafil (20mg) for 14 days, followed by combined tadalafil and FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) for 8 weeks. Gastric tissue and blood samples were collected i) before treatment, ii) after 14 days of tadalafil, and iii) after 8 weeks of combined treatment. We have enrolled 3 Hispanic patients to date with ongoing enrollment. Results: Tumors exhibited responses as per radiologic and pathologic criteria. In contrast to SLFN4, primarily expressed in myeloid cells, SLFN12L was found in most CD14+T lymphocytes and natural killer cells. A prominently activated and expanded myeloid population expressing SLFN12L was identified in the gastric mucosa of GAC patients. These cells exhibited transcriptional signatures associated with IFN-I signaling and immunosuppressive activities, diminishing after tadalafil treatment. Within GAC tissue, a notable increase in exhausted T cells and regulatory T cells was observed, decreasing after tadalafil. Post-tadalafil testing showed tissue PDE5/6 inhibition and higher plasma cGMP. Effector T cells exhibited an upward trend following tadalafil, suggesting a reduction in tumor immunosuppression. Conclusions: Preliminary data of this ongoing study show that tadalafil treatment combined with FLOT, has the potential to decrease SLFN12L+ MDSC, to attenuate their immunosuppression, and potentially inhibit tumor progression. The trial is active and further analysis will be presented in due course.

Effect of adding systematic desensitization to goal-directed paradigm on risk of falling in patients with stroke: a randomized controlled trial.

Improvement in rehabilitation outcomes for patients suffering from chronic stroke can be attained through systematic desensitization of their fear of falling, which in turn reduces the risk of falling. This study aimed to examine the effect of adding systematic desensitization to a goal-directed paradigm on functional performance, balance, risk of falling, and fear of falling among chronic ischemic stroke patients. Two equally sized groups, each comprising 40 stroke patients of both sexes, were randomly divided. For 8 weeks, Group A received three sessions per week of combined treatment consisting of systematic desensitization and a goal-directed paradigm, while Group B received only the goal-directed paradigm. The Timed Up and Go (TUG) test and Dynamic Gait Index (DGI) were used to assess function performance; the Berg Balance Scale (BBS) and the Biodex Fall Risk Index (FRI) were used to evaluate balance; and the 16-item Fall Efficacy Scale-International (FES-I) was used to evaluate fear of falling. At baseline and after the treatment, all measurements were obtained. Both groups (A and B) revealed a substantial increase in functional performance through a decrease in TUG scores and an increase in DGI. Additionally, there was a decrease in the risk of falling through an increase in the BBS scores and a decrease in the FRI. Furthermore, there was a decrease in the fear of falling, as measured using the FES-I, after treatment, with superior improvement in Group A with a p-value of <0.001. Systematic desensitization combined with a goal-directed paradigm has a superior effect on improving functional performance and reducing the risk of falling and the fear of falling in patients with stroke compared to a goal-directed paradigm alone.

DIPG-02. A NOVEL STRATEGY TO RADIOSENSITISE DIFFUSE MIDLINE GLIOMAS VIA DUAL-TARGETING OF GLUCOSE METABOLISM

Abstract Diffuse Midline Gliomas (DMG) is the leading cause of brain tumor-related death in children. Currently, radiation is the only treatment that offers transient benefit but almost all DMG relapse due to radioresistance. Compared to normal brain tissue, DMG are hypo-perfused with tumor cells being exposed to hypoxia, a low oxygen microenvironment serves as a potent barrier to effective radiotherapy. Biguanides are hypoglycemic agents that can reduce the oxygen consumption rate (OCR) in mitochondria, thereby sparing more oxygen and alleviating hypoxia. Our previous study has shown that metformin significantly improves the radiosensitivity of DMG and extends survival in a patient-derived xenograft (PDX) model. In comparison with metformin, phenformin demonstrated greater efficacies in anti-proliferation, OCR and hypoxia inhibition, and radiosensitization in a panel of DMG cultures. These effects were possibly induced by phenformin through inhibition of mitochondrial complex I in DMG cells. The anti-tumor effect of phenformin was further enhanced by combining a second drug dichloroacetate that simultaneously attenuated phenformin-induced acidification. Specifically, the combination treatment induced higher levels of reactive oxygen species and DNA damage, which subsequently resulted in a much stronger effect in cell-cycle and proliferation arrest, apoptosis, and hypoxia inhibition. Metabolically, the co-treatment simultaneously targeted multiple pathways, which significantly reduced ATP production and further triggered metabolic catastrophe. RNA sequencing demonstrated significant alterations induced by the combination in cell-cycle, DNA repair, unfolded protein response and alternative energetic pathways. Furthermore, the combination treatment significantly improved the radiosensitivity of DMG cells, evidenced by higher levels of DNA damage, apoptosis, and clonogenic inhibition. Our preliminary in vivo data demonstrated a possible reduction in tumor burden following 4 weeks of combination treatment, with no elevation of serum L-lactate level in phenformin-treated groups. This therapeutic efficacy is currently being validated in multiple orthotopic DMG models with optimized treatment schedules.

Serum cytokine change profile associated with HBsAg loss during combination therapy with PEG-IFN-α in NAs-suppressed chronic hepatitis B patients.

The aim of this study was to explore the profile of cytokine changes during the combination therapy with pegylated interferon alpha (PEG-IFN-α) and its relationship with HBsAg loss in nucleos(t)ide analogs (NAs)-suppressed chronic hepatitis B patients. Seventy-six patients with chronic hepatitis B with HBsAg less than 1,500 IU/ml and HBV DNA negative after receiving ≥ 1-year NAs therapy were enrolled. Eighteen patients continued to take NAs monotherapy (the NAs group), and 58 patients received combination therapy with NAs and PEG-IFN-α (the Add-on group). The levels of IFNG, IL1B, IL1RN, IL2, IL4, IL6, IL10, IL12A, IL17A, CCL2, CCL3, CCL5, CXCL8, CXCL10, TNF, and CSF2 in peripheral blood during treatment were detected. At week 48, 0.00% (0/18) in the NAs group and 25.86% (15/58) in the Add-on group achieved HBsAg loss. During 48 weeks of combined treatment, there was a transitory increase in the levels of ALT, IL1RN, IL2, and CCL2. Compared to the NAs group, CXCL8 and CXCL10 in the Add-on group remain higher after rising, yet CCL3 showed a continuously increasing trend. Mild and early increases in IL1B, CCL3, IL17A, IL2, IL4, IL6, and CXCL8 were associated with HBsAg loss or decrease >1 log, while sustained high levels of CCL5 and CXCL10 were associated with poor responses to Add-on therapy at week 48. The serum cytokine change profile is closely related to the response to the combination therapy with PEG-IFN-α and NAs, and may help to reveal the mechanism of functional cure and discover new immunological predictors and new therapeutic targets.

The dilemma of polypharmacy in psychosis: is it worth combining partial and full dopamine modulation?

Antipsychotic polypharmacy in psychotic disorders is widespread despite international guidelines favoring monotherapy. Previous evidence indicates the utility of low-dose partial dopamine agonist (PDAs) add-ons to mitigate antipsychotic-induced metabolic adverse effects or hyperprolactinemia. However, clinicians are often concerned about using PDAs combined with high-potency, full dopaminergic antagonists (FDAs) due to the risk of psychosis relapse. We, therefore, conducted a literature review to find studies investigating the effects of combined treatment with PDAs (i.e. aripiprazole, cariprazine and brexpiprazole) and FDAs having a strong D2 receptor binding affinity. Twenty studies examining the combination aripiprazole – high-potency FDAs were included, while no study was available on combinations with cariprazine or brexpiprazole. Studies reporting clinical improvement suggested that this may require a relatively long time (~11 weeks), while studies that found symptom worsening observed this happening in a shorter timeframe (~3 weeks). Patients with longer illness duration who received add-on aripiprazole on ongoing FDA monotherapy may be at greater risk for symptomatologic worsening. Especially in these cases, close clinical monitoring is therefore recommended during the first few weeks of combined treatment. These indications may be beneficial to psychiatrists who consider using this treatment strategy. Well-powered randomized clinical trials are needed to derive more solid clinical recommendations.

Effects of Combined Allogenic Adipose Stem Cells and Hyperbaric Oxygenation Treatment on Pathogenesis of Osteoarthritis in Knee Joint Induced by Monoiodoacetate.

The beneficial effects of HBO in inflammatory processes make it an attractive type of treatment for chronic arthritis. In addition, the effects of combination therapy based on adipose stem cells and HBO on OA progression have not been fully investigated. The current study explored the efficacy of intra-articular injection of allogeneic adipose-derived mesenchymal stem cells (ADMSCs) combined with hyperbaric oxygenation treatment (HBO) in a rat osteoarthritis (OA) model. The rat OA model was induced by intra-articular injection of monoiodoacetate (MIA) and 7 days after application of MIA rats were divided into five groups: healthy control (CTRL), osteoarthritis (OA), ADMSCs (ADS), the HBO+ADS21day and HBO+ADS28day groups. A single dose of 1 × 106 allogeneic ADMSCs suspended in sterile saline was injected into the knee joint alone or in combination with HBO treatment. Rats were sacrificed at 3 or 4 weeks after MIA injection. Treatment outcomes were evaluated by radiographic, morphological and histological analysis and by specific staining of articular cartilage. We also measured the level of inflammatory and pro/antioxidative markers. We confirmed that combined treatment of ADMSCs and HBO significantly improved the regeneration of cartilage in the knee joint. Rtg score of knee joint damage was significantly decreased in the HBO+ADS21day and HBO+ADS28day groups compared to the OA. However, the positive effect in the HBO+ADS28day group was greater than the HBO+ADS21day group. The articular cartilage was relatively normal in the HBO+ADS28day group, but moderate degeneration was observed in the HBO+ADS21day compared to the OA group. These findings are in line with the histopathological results. A significantly lower level of O2−. was observed in the HBO+ADS28day group but a higher NO level compared to the HBO+ADS21day group. Moreover, in the HBO+ADS28day group significantly higher concentrations of IL-10 were observed but there was no significant difference in proinflammatory cytokine in serum samples. These results indicate that a single intra-articular injection of allogeneic ADMSCs combined with HBO efficiently attenuated OA progression after 28 days with greater therapeutic effect compared to alone ADMSCs or after 3 weeks of combined treatment. Combined treatment might be an effective treatment for OA in humans.

Real-world study on HBsAg loss of combination therapy in HBeAg-negative chronic hepatitis B patients.

Combination therapy with pegylated interferon (PEG-IFN) and nucleos(t)ide analogues (NAs) can enhance hepatitis B surface antigen (HBsAg) clearance. However, the specific treatment strategy and the patients who would benefit the most are unclear. Therefore, we assessed the HBsAg loss rate of add-on PEG-IFN and explored the factors associated with HBsAg loss in chronic hepatitis B (CHB) patients. This was a real-world cohort study of adults with CHB. Hepatitis B e antigen (HBeAg)-negative NAs-treated patients with baseline HBsAg ≤1500 IU/ml and HBV DNA < the lower limit of detection, or 100 IU/ml, received 48 weeks of add-on PEG-IFN. The primary outcome of the study was the rate of HBsAg loss at 48 weeks of combination treatment. Using multivariable logistic regression analysis, we determined factors associated with HBsAg loss. HBsAg loss in 2579 patients (mean age: 41.2 years; 80.9% male) was 36.7% (947 patients) at 48 weeks. HBsAg loss was highest in patients from south-central and southwestern China (40.0%). Factors independently associated with HBsAg loss included: increasing age (odds ratio=0.961); being male (0.543); baseline HBsAg level (0.216); HBsAg decrease at 12 weeks (between 0.5 and 1.0 log10 IU/ml [2.405] and >1.0 log10 IU/ml [7.370]); alanine aminotransferase (ALT) increase at 12 weeks (1.365); haemoglobin (HGB) decrease at 12 weeks (1.558). There was no difference in the primary outcomes associated with the combination regimen. In conclusion, HBsAg loss by combination therapy was higher in patients from southern China than those from the north. An increased chance of HBsAg loss was associated with baseline characteristics and dynamic changes in clinical indicators.

P1055: CLINICAL AND GENETIC RESULTS OF THE PHASE IB/II TRIAL MPNSG-0212: RUXOLITINIB PLUS POMALIDOMIDE IN MYELOFIBROSIS WITH ANEMIA

Background: Ruxolitinib (RUX) alleviates disease-associated symptoms including splenomegaly in patients (pts) with myelofibrosis (MF). However, management of cytopenia remains challenging. Aims: As single-agent pomalidomide (POM) improved cytopenia in 14-29% of MF pts in our previous MPNSG-0109 trial, we sought to investigate the combination of RUX plus POM in MF pts with anemia (Hb <10 g/dL and/or RBC transfusion dependency [RBC-TD]). Methods: MPNSG-0212 is a multicenter, open-label, phase-Ib/II trial (NCT01644110) comprising 39 pts in cohort 1 (co1, recruited 2013-2017) and 52 pts in co2 (2017-2021). Co1 pts received RUX 10 mg BID plus POM 0.5 mg QD, while POM was intended to be increased in co2 to 1 and 2 mg QD after 3 and 6 28-day-cycles, respectively. Primary endpoint was response according to IWG-MRT and RBC-TI criteria at end of cycle 12 (EOC12). In addition, genomic landscape was characterized in all pts using targeted NGS of 269 candidate genes (Illumina NextSeq550). Results: Co1 and co2 pts had similar characteristics: median age was 71 years (range 49-86), median Hb level 8.6 g/dL (5.4-11.7), and median spleen size 17.5 cm (11.4-36); 30% were RBC-TD, 66% intermediate-2, and 25% high-risk according to DIPSS; mutations (muts) in JAK2, CALR, or MPL were identified in 57%, 23%, and 20%, respectively; 55% had ≥1 high-molecular risk (HMR) mut, with ASXL1 being the most common (41%), followed by SRSF2 (24%), EZH2 (10%) and IDH2 (9%). Of note, pts in co2 were more frequently pre-treated with RUX compared to co1 (44% vs 15%; p=.006). Median treatment time at data cut-off was 12 cycles in co1 (2-98) and co2 (3-46); 3 pts of co2 have not yet reached EOC12. In co1, 8/39 pts (21%) achieved response at EOC12: partial remission (PR, n=1), clinical improvement (CI, n=6), or RBC-TI (n=1); 18/39 pts (46%) were treated for >12 cycles due to response (n=8), clinical benefit (CB, n=5) defined as Hb increase ≥1 g/dL or >50% improvement of ≥1 quality of life (QoL) symptom according to MPN-SAF, or stable disease (SD, n=5). Median Hb level at EOC12 was 9.3 g/dL; 15/39 pts (38%) were on treatment for >30 cycles, and 3 pts remained on long-term treatment (cycle 76, 97, and 98). In 73% and 40% of pts in co2, POM dose was increased to 1 mg and 2 mg QD after cycle 3 and 6, respectively. 5/49 pts (10%) showed response at EOC12 (CI, n=3 and RBC-TI, n=2), while 14 additional pts (29%) had CB; median Hb level at EOC12 was 8.6 g/dL; 22/49 pts (45%) were treated for >12 cycles; 3 pts were still on treatment (cycle 21, 36, and 46). Targeted NGS did not reveal a distinct mutational pattern associated with treatment response. Median overall survival (OS) of co1 and co2 was 3.6 and 2.6 years, respectively (p=.66). Among all, CALR, but not JAK2 or MPL muts were associated with better OS (p=.04), whereas HMR muts were in trend prognostically adverse (p=.057). Pts with more than 3 muts had a worse median OS (1.2 vs 4 years, p=.002). Combination therapy was well tolerated in both cohorts. Most common grade 1/2 adverse events (AE) were dyspnea (28%) and fatigue (23%), while the most frequent grade 3 AE was worsening of anemia (32%) in the first weeks of combination treatment not limiting therapy. Summary/Conclusion: Treatment with RUX and POM was safe and feasible in our study of advanced MF with an adverse genetic profile. Almost half of co1 and co2 pts were treated >12 cycles due to clinical benefit of the combination therapy with a subset of 38% of pts in co1 receiving treatment for >30 cycles. Dose increase of POM in co2 did not result into better anemia response or improvement of OS. Authors FS and EJ contributed equally.

Durvalumab with cetuximab and radiotherapy for locally advanced squamous cell carcinoma of the head and neck: A phase 1/2 trial

Background and purposeTo report on the anti-tumor activity of a novel combination in high-risk locally advanced head and neck squamous cell carcinoma. Materials and methodsAt a fixed dose of 1500 mg every 28 days, anti PD-L1 Durvalumab was given concomitantly to Radiotherapy and Cetuximab starting from the first week of combined treatment, followed by adjuvant Durvalumab to a maximum of 6 months after completion of radiation. The primary endpoint of the study was 2-year progression-free survival (PFS). A safety run-in was planned. Due to regulatory issues which prevented from opening multiple centers, COVID-19 pandemic and withdrawal of Durvalumab from supporting company, the study was prematurely terminated in April 2021. ResultsBetween July 2019 and August 2020, 9 patients were enrolled in the study. All tumors had a PD-L1 Combined Positive Score > 1. Optimal drug exposure was observed, with mean relative dose intensity of 85.5% and 87.5% for Cetuximab and Durvalumab, respectively. No radiation breaks were necessary. A grade 4 mucositis lasting for 14 days corresponded to the only dose limiting toxicity we reported. At a median follow-up of 11.5 months (IQR 7.7–16.7) all surviving patients (6 out of 9) are disease-free, with 1 and 2-year PFS rates of 77.7% and 58.3%, respectively. A selective sparing of node levels in the elective volume was performed in all cases, yielding a cumulative mean dose of 37.6 Gy (SD 8.4). ConclusionAlbeit limited by the small sample size, our preliminary observation of anti-tumor activity and tolerability of Durvalumab in addition to Cetuximab and radiation may warrant further investigations.

Hepatic macrophage targeted siRNA lipid nanoparticles treat non-alcoholic steatohepatitis

HMGB1 is an inflammatory factor produced by macrophages after liver injury, which plays a key role in promoting NASH progression and further developing into liver fibrosis and cirrhosis. In this study, a mannose-modified HMGB1-siRNA loaded stable nucleic acid lipid particle delivery system (mLNP-siHMGB1) was constructed to target liver macrophages with mannose receptor mediation, thereby silencing HMGB1 protein expression and treating NASH. We also examined the effect of co-administration with docosahexaenoic acid (DHA), a kind of unsaturated fatty acid, on NASH. The results showed that mLNP-siHMGB1 could target macrophages through mannose receptors, effectively silence HMGB1 gene, reduce the release of HMGB1 protein in the liver, regulate liver macrophages to be an anti-inflammatory M2 phenotype, effectively reduce hepatic lobular inflammation and bullous steatosis in the liver, and restore the liver function of NASH model mice to a normal level. After 8 weeks of combined treatment with mLNP-siHMGB1 and DHA, the liver function of NASH model mice recovered rapidly and the hepatic steatosis returned to normal level. In view of inflammation, a key factor in the progression of NASH, we provided an actively targeted siRNA delivery system in this study, and clarified the important role of the delivery system in phenotypic regulation of liver macrophages in NASH. In addition, we also demonstrated the effectiveness of DHA co-administration in NASH treatment. This study provided a useful idea and scientific basis for the development of therapeutic strategies for NASH in the future.

High-Intensity, Low-Frequency Pulsed Electromagnetic Field as an Odd Treatment in a Patient with Mixed Foot Ulcer: A Case Report

Lower-extremity ulcers are associated with an increasing prevalence and significant economic and social costs. To date, there is no high-quality evidence related to an optimal treatment algorithm. A multimodal approach is needed particularly in patients with comorbidity and polytherapy. Herein, we report the case of a 94-year-old Caucasian female with comorbidity and polytherapy who was admitted to our observation for a history (1 year) of chronic painful malleolar mixed ulcer. After clinical evaluation, she was treated with a twice daily pain relief therapy and with a weekly diamagnetic therapy protocol plus a local treatment. During the clinical examination, we documented a statistically significant improvement in both pain (VAS score from 8 to 2 p &lt; 0.01) and foot ulcer (surface reduction from 6 cm × 4 cm to 2 cm × 2 cm, p &lt; 0.01) at the sixth week of combined treatment. The ulcer completely healed at the ninth week. This is the first study to document the effect of diamagnetic therapy as an add-on therapy in the management of wound healing. In conclusion, even if high-quality evidence is still lacking, diamagnetic therapy might represent an interesting option as an add-on treatment for ulcer.

Fenofibrate Mitigates Hypertriglyceridemia in Nonalcoholic Steatohepatitis Patients Treated With Cilofexor/Firsocostat

Patients with advanced fibrosis due to nonalcoholic steatohepatitis (NASH) are at high risk of morbidity and mortality. We previously found that a combination of the farnesoid X receptor agonist cilofexor (CILO) and the acetyl-CoA carboxylase inhibitor firsocostat (FIR) improved liver histology and biomarkers in NASH with advanced fibrosis but was associated with hypertriglyceridemia. We evaluated the safety and efficacy of icosapent ethyl (Vascepa) and fenofibrate to mitigate triglyceride elevations in patients with NASH treated with CILO and FIR. Patients with NASH with elevated triglycerides (≥150 and <500 mg/dL) were randomized to Vascepa 2 g twice daily (n= 33) or fenofibrate 145 mg daily (n= 33) for 2 weeks, followed by the addition of CILO 30 mg and FIR 20 mg daily for 6 weeks. Safety, lipids, and liver biochemistry were monitored. All treatments were well-tolerated; most treatment-emergent adverse events were Grade 1 to 2 severity, and there were no discontinuations due to adverse events. At baseline, median (interquartile range [IQR]) triglycerides were similar in the Vascepa and fenofibrate groups (median, 177 [IQR, 154-205] vs 190 [IQR, 144-258] mg/dL, respectively). Median changes from baseline in triglycerides for Vascepa vs fenofibrate after 2 weeks of pretreatment were-12 mg/dL (IQR,-33 to 7 mg/dL; P= .09) vs-32 mg/dL (IQR,-76 to 6 mg/dL; P= .012) and at 6 weeks were+41 mg/dL (IQR, 16-103 mg/dL; P < .001) vs-2 mg/dL (IQR,-42 to 54 mg/dL; P= .92). In patients with baseline triglycerides <250 mg/dL, fenofibrate was more effective vs Vascepa in mitigating triglyceride increases after 6 weeks of combination treatment (+6 vs+39 mg/dL); similar trends were observed in patients with baseline triglycerides ≥250 mg/d (-61 vs+99 mg/dL). In patients with NASH with hypertriglyceridemia treated with CILO and FIR, fenofibrate was safe and effectively mitigated increases in triglycerides associated with acetyl-CoA carboxylase inhibition. gov, Number: NCT02781584.

Myelin-associated glycoprotein combined with chitin conduit inhibits painful neuroma formation after sciatic nerve transection.

Studies have shown that myelin-associated glycoprotein (MAG) can inhibit axon regeneration after nerve injury. However, the effects of MAG on neuroma formation after peripheral nerve injury remain poorly understood. In this study, local injection of MAG combined with nerve cap made of chitin conduit was used to intervene with the formation of painful neuroma after sciatic nerve transfection in rats. After 8 weeks of combined treatment, the autotomy behaviors were reduced in rats subjected to sciatic nerve transfection, the mRNA expression of nerve growth factor, a pain marker, in the proximal nerve stump was decreased, the density of regenerated axons was decreased, the thickness of the myelin sheath was increased, and the ratio of unmyelinated to myelinated axons was reduced. Moereover, the percentage of collagen fiber area and the percentage of fibrosis marker alpha-smooth muscle actin positive staining area in the proximal nerve stump were decreased. The combined treatment exhibited superior effects in these measures to chitin conduit treatment alone. These findings suggest that MAG combined with chitin conduit synergistically inhibits the formation of painful neuroma after sciatic nerve transection and alleviates neuropathic pain. This study was approved by the Animal Ethics Committee of Peking University People's Hospital (approval No. 2019PHE027) on December 5, 2019.

Clinical features of Kasabach-Merritt syndrome: an analysis of 16 neonates

Objective To study the clinical features, treatment, and prognosis of neonates with Kasabach-Merritt syndrome (KMS), and to provide a reference for optimizing the diagnosis and treatment of this disease. Methods A retrospective analysis was performed for the clinical and follow-up data of 16 neonates with KMS who were admitted to the Anhui Children's Hospital, Anhui Medical University, from January 2016 to December 2020. Results Of the 16 neonates, there were 13 boys (81%) and 3 girls (19%), with an age of 1 hour to 10 days on admission. Among these neonates, 13 (81%) had cutaneous hemangioma (2 in the head and face, 5 in the trunk, and 6 in the extremities) and 3 (19%) had liver hemangioma. The main clinical manifestations of bleeding tendency and scattered petechiae and ecchymosis were observed in 10 neonates (62%). All the 16 neonates had varying degrees of thrombocytopenia and coagulation disorders. They all received glucocorticoid treatment after admission and 7 (44%) of them had response, among whom 4 experienced recurrence. Among the neonates with no response to glucocorticoid treatment, 3 received sirolimus treatment, among whom 1 had the tumor volume reduced by 58.8% after 4 weeks of treatment, with platelet count and coagulation function returning to normal, while 2 had no significant reduction in tumor volume or significant increase in platelet count and achieved a tumor volume reduced by (43.7±0.4)% after 4 weeks of combined treatment with bleomycin arterial embolization, with platelet count and coagulation function returning to normal. After 4 weeks of bleomycin arterial embolization alone for 4 neonates, tumor volume was reduced by (52.0±3.4)%, and platelet count and coagulation function returned to normal. Blunt and sharp dissection was performed for 2 neonates. The tumor was removed completely during surgery in the 2 neonates, with no infection or recurrence after surgery, and platelet count and coagulation function returned to normal. The postoperative pathological examination showed Kaposiform hemangioendothelioma in 1 out of the 2 neonates. Conclusions KMS has characteristic clinical manifestations, histopathological features, and laboratory examination results. The KMS neonates who are not sensitive to glucocorticoids can achieve a good curative effect through arterial embolization and sirolimus treatment.

The Combined Effect of Strength and Speed Training on Change of Direction Performance in Soccer Players

Soccer is an intermittent sport where high-intensity actions such as sprints, jumps, and change of direction (COD) can become determining factors of success. Strength and speed are essential physical qualities related to an athlete's COD ability. The influence of strength and speed training on COD performance has been examined in various sports. The purpose of this study was to determine the effect of a combined strength and speed training program on COD performance in high-performance junior soccer players. The study was a randomized crossover trial designed to determine whether there is a difference in the COD test performance after treatment of strength and speed training. Eighteen soccer players were recruited from the same team and randomly assigned to two experimental groups and a control group. The players were evaluated in four various tests, the Illinois Agility Test, 30 meters speed test, 30 meters speed with a change of direction Test and, the 5RM submaximal strength Test. Four 2(Test) x 3(groups) ANOVAs with Tukey posthoc test were performed to detect any statistically significant differences between and within the training groups. An alpha-level of &amp;lt;0.05 was considered to be statistically significant. This study did not find significant improvements in the performance of the studied qualities speed (linear and COD) and, nor an increase in the strength test's performance linked to the treatment used at the end of the six weeks of combined treatment of strength and speed. Strength plus speed training can be used to improve strength during the competitive season.

밸런스코어운동이 만성요통을 가진 중년여성의 체력, 척주변이 및 주관적 통증지수에 미치는 영향

The purpose of this study was 12 weeks of combined treatment of Balance Core Exercise using to women with chronic lower back pain symptoms to find about the effects on pain improvement.The subjects of this study were aged 40 to 60 years into middle age women 14 people with chronic back pain for more than 10 years in the exercise group (age 59.0±7.4) and seven persons each to a control group (age 53.1±8.5). The complex treatment of Balance Core Exercise were each performed three times a week. First, every one weeks to transform the body roller exercise 3 times to 12 weeks. And Yoga. Yoga exercise was Trikonasana; Adho Mukha Svanasana; Bhujangasana; Supta Padangusthasana1,2,3; Eka Padaanda Rajakapotasana. Body roller and Yoga exercise examined before and after for physical strength, flexibility and endurance. Cobb’s angle, rotation angle, tilt shoulders, pelvis horizontal degrees and observed the VAS. After 12 weeks was the Strength endurance change of the effective the time (T) and the interaction (T*G) showed a statistically significant (p>0.5) Change in the Cobb’s angle (°) was not significant. However, spinal rotation angle (mm) after exercise 3.15 mm was significantly decreased (p<.01). Shoulder slope post 3.57± 4.76 mm appeared in significant reduction in pre 5.07±3.40 mm in the exercise group (p<.05). VAS pain index was significant difference in the pre 6.32±1.0 to post 2.79±0.7 after exercise showed (p<.05). And also it showed significant interaction (T*G) effect (p<.01). Balance Core Exercise treatment has improved muscular endurance, spine rotation angle, tilt shoulders, improved statistically the VAS Index. It is determined as a solution to low back pain problem.

Combined Transplantation of Mesenchymal Stem Cells and Endothelial Colony-Forming Cells Accelerates Refractory Diabetic Foot Ulcer Healing.

Background This study is aimed at investigating the effect of combined transplantation of umbilical cord mesenchymal stem cells (UCMSCs) and umbilical cord blood-derived endothelial colony-forming cells (ECFCs) on diabetic foot ulcer healing and at providing a novel therapy for chronic diabetic foot ulcer. Methods We reported the treatment of refractory diabetic foot ulcers in twelve patients. Among them, five patients had two or more wounds; thus, one wound in the same patient was treated with cell injection, and other wounds were regarded as self-controls. The remaining seven patients had only one wound; therefore, the difference between the area of wound before and after treatment was estimated. The UCMSCs and ECFCs were injected into the wound along with topically applied hyaluronic acid (HA). Results In this report, we compared the healing rate of multiple separate wounds in the same foot of the same patient: one treated with cell injection combined with topically applied HA-based hydrogel and was later covered by the hydrocolloid dressings, while the self-control wounds were only treated with conventional therapy and covered by the hydrocolloid dressings. The wound underwent cell injection showed accelerated healing in comparison to control wound within the first week after treatment. In other diabetic patients with only one refractory wound, the healing rate after cell transplantation was significantly faster than that before injection. Two large wounds healed without needing skin grafts after combination therapy of cell injection and HA. After four weeks of combination treatment, wound closure was reached in six patients, and the wounds of the other six patients were significantly reduced in size. Conclusions Our study suggests that the combination of UCMSCs, ECFCs, and HA can safely synergize the accelerated healing of refractory diabetic foot ulcers.

Prospects of systemic enzyme therapy for treatment of male immune infertility

The study objective is to evaluate the effectiveness and safety of systemic enzyme therapy drugs (Wobenzym, Phlogenzym) and the natural complex of multi-component dietary supplement Spermstrong in the treatment of immune infertility.Materials and methods. Sixty-four men with immune infertility, high levels of antisperm antibodies (ASA) in ejaculate, serum and reproductive disorders were examined. All patients were divided into 2 groups. For 8 weeks, 32 patients in the group 1 received systemic enzyme therapy drugs in combination with a natural complex of multi-component dietary supplement Spermstrong (combined therapy), and 32 patients of the group 2 received only Spermstrong (monotherapy), and their comparative assessment was carried out. Immediate results of treatment were evaluated 4 weeks later and remote 8 weeks after treatment.Results. Increased ejaculate volume was observed in patients receiving combination therapy and Spermstrong only: by 19.0 and 10.0 %, respectively, after 4 weeks of treatment and by 42.9 and 15.0 % after 8 weeks. Mean sperm count increased only in patients receiving combination therapy (by 55.4 % after 8 weeks of treatment, p &lt;0.05). Sperm motility increased more after combination therapy (by 11.9 and 129.8 % after 4 and 8 weeks, respectively). Decrease in abnormal spermatozoa was slightly faster for combination treatment compared to Spermstrong monotherapy: after 4 weeks by 12.2 and 0.3 %, respectively, after 8 weeks by 24.8 and 6.5 %. The level of ASA IgG in the ejaculate decreased by 26.3 and 59.0 % after 4 and 8 weeks of combination treatment, and by 3.4 and 13.2 % after Spermstrong monotherapy. Serum level of ASA IgG/IgM significantly decreased only in patients receiving combination therapy (by 36.4 and 76.5 % after 4 and 8 weeks, respectively, p &lt;0.05). No adverse effects were observed in patients in both treatment groups.Conclusion. The results confirm that the use of combination therapy with Wobenzym, Phlogenzym and Spermstrong statistically significantly reduced ASA levels and increased the effectiveness of treatment.The authors declare no conflict of interest.All patients gave written informed consent to participate in the study.

Targeting CXCR4 potentiates anti-PD-1 efficacy modifying the tumor microenvironment and inhibiting neoplastic PD-1

BackgroundInefficient T-cell access to the tumor microenvironment (TME) is among the causes of tumor immune-resistance. Previous evidence demonstrated that targeting CXCR4 improves anti-PD-1/PD-L1 efficacy reshaping TME. To evaluate the role of newly developed CXCR4 antagonists (PCT/IB2011/000120/ EP2528936B1/US2013/0079292A1) in potentiating anti-PD-1 efficacy two syngeneic murine models, the MC38 colon cancer and the B16 melanoma-human CXCR4-transduced, were employed.MethodsMice were subcutaneously injected with MC38 (1 × 106) or B16-hCXCR4 (5 × 105). After two weeks, tumors bearing mice were intraperitoneally (ip) treated with murine anti-PD-1 [RMP1–14] (5 mg/kg, twice week for 2 weeks), Pep R (2 mg/kg, 5 days per week for 2 weeks), or both agents. The TME was evaluated through immunohistochemistry and flow-cytometry. In addition, the effects of the human-anti-PD-1 nivolumab and/or Peptide-R54 (Pep R54), were evaluated on human melanoma PES43 cells and xenografts treated.ResultsThe combined treatment, Pep R plus anti-PD-1, reduced the MC38 Relative Tumor Volume (RTV) by 2.67 fold (p = 0.038) while nor anti-PD-1, neither Pep R significantly impacted on tumor growth. Significant higher number of Granzyme B (GZMB) positive cells was detected in MC38 tumors from mice treated with the combined treatment (p = 0.016) while anti-PD-1 determined a modest but significant increase of tumor-infiltrating GZMB positive cells (p = 0.035). Also, a lower number of FoxP3 positive cells was detected (p = 0.022). In the B16-hCXCR4 tumors, two weeks of combined treatment reduced tumor volume by 2.27 fold while nor anti-PD-1 neither Pep R significantly impacted on tumor growth. A significant higher number of GRZB positive cells was observed in B16-hCXCR4 tumors treated with combined treatment (p = 0,0015) as compared to anti-PD-1 (p = 0.028). The combined treatment reduced CXCR4, CXCL12 and PD-L1 expression in MC38 tumors. In addition, flow cytometry on fresh B16-hCXCR4 tumors showed significantly higher Tregs number following anti-PD-1 partially reversed by the combined treatment Pep R and anti-PD-1. Combined treatment determined an increase of CD8/Tregs and CD8/MDSC ratio. To dissect the effect of anti-PD-1 and CXCR4 targeting on PD-1 expressed by human cancer cells, PES43 human melanoma xenograft model was employed. In vitro human anti-PD-1 nivolumab or pembrolizumab (10 μM) reduced PES43 cells growth while nivolumab (10 μM) inhibited pERK1/2, P38 MAPK, pAKT and p4EBP. PES43 xenograft mice were treated with Pep R54, a newly developed Pep R derivative (AcHN-Arg-Ala-[DCys-Arg- Nal(2′)-His-Pen]- COOH), plus nivolumab. After 3 weeks of combined treatment a significant reduction in tumor growth was shown (p = 0.038). PES43 lung disseminated tumor cells (DTC) were detected in fresh lung tissues as melanoma positive MCSP-APC+ cells. Although not statistically significant, DTC-PES43 cells were reduced in mice lungs treated with combined treatment while nivolumab or Pep R54 did not affect DTC number.ConclusionCombined treatment with the new developed CXCR4 antagonist, Pep R, plus anti-PD-1, reduced tumor-growth in two syngeneic murine models, anti-PD-1 sensitive and resistant, potentiating Granzyme and reducing Foxp3 cells infiltration. In addition, the human specific CXCR4 antagonist, Pep R54, cooperated with nivolumab in inhibiting the growth of the PD-1 expressing human PES43 melanoma xenograft. This evidence sheds light on PD-1 targeting mechanisms and paves the way for CXCR4/PD-1 targeting combination therapy.

Abstract 4759: Antitumor activity of eribulin after fulvestrant plus palbociclib treatments in the HR(+) human breast PDx model

Abstract Fulvestrant (FLV) and Palbociclib (Palb), which have an effect on degradation of estrogen receptor (ER) and inhibition of cyclin dependent kinases 4 and 6 (CDK4/6), respectively are used for treatments to postmenopausal breast cancer patients. However, there is not a clinical rationale to define a standard treatment regimen against breast cancer patients who are resistant to endocrine therapy plus Palb. Eribulin is a fully synthetic analog of the marine sponge natural product halichondrin B. Its clinical formulation is currently approved for advanced breast cancer (BC) and advanced liposarcoma in numerous countries. We examined the antitumor activity of eribulin after endocrine therapy (combination of FLV and Palb) compared with that of Capecitabine (Cape) in the luminal type breast cancer PDx model (OD-BRE-0438). OD-BRE-0438 is a patient derived xenograft (PDx) model developed from patient with luminal B breast cancer. Gene expression analysis by RNA-Seq showed that OD-BRE-0438 highly expressed ER and PR, but not ERBB2. OD-BRE-0438 tumor bearing mice were treated for 2 weeks of FLV (5mg/ head, Q7Dx2, sc) and Palb (10mg/kg, Q1Dx14, po), and treated mice were randomly divided using tumor volume around 350 mm3 as an index (day1). After that, mice were treated with eribulin (0.5 or 1 mg/kg, which are 1/4 MTD or 1/2 MTD in this model, Q7Dx2, iv) or Cape (125 or 250 mg/kg, which are 1/2 MTD or MTD in this model, Q1Dx14, po for 2 weeks). We measured tumor volume of each mouse after treatments (day 15) and analyzed the ratio of tumor volume at day 15 divided by that at day 1 (RTV: relative tumor volume). Treatments of FLV and Palb nearly completely inhibited in vivo growth of OD-BRE-0438 tumors, but didn’t cause tumor shrinkage. After two weeks of combination treatment with endocrine therapy, we started treatments with either eribulin or Cape, and compared the antitumor activity. Both drug showed strong antitumor activity with tumor shrinkage. In comparison of antitumor activity with either eribulin or Cape, that of eribulin was significantly greater than Cape. [eribulin 0.5mg/kg (RTV=0.42) vs Cape 125mg/kg (RTV=0.62, p=0.0068), eribulin 1.0mg/kg (RTV=0.32) vs Cape 250mg/kg (RTV=0.59, p=0.0008)]. Further investigation for mechanism of action of eribulin to show clear antitumor activity after treatments of FLV and Palb in the luminal type breast cancer PDx model are warranted. Citation Format: Makoto Asano, Takayuki Nakagawa, Taro Semba, Akira Yokoi, Junji Matsui, Yasuhiro Funahashi. Antitumor activity of eribulin after fulvestrant plus palbociclib treatments in the HR(+) human breast PDx model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4759.