Biomarker and pharmacodynamic activity of the transforming growth factor-beta (TGFß) inhibitor SAR439459 as monotherapy and in combination with cemiplimab in a phase I clinical study in patients with advanced solid tumors.

SAR439459, a 'second-generation' human anti-transforming growth factor-beta (TGFß) monoclonal antibody, inhibits all TGFß isoforms and improves the antitumor activity of anti-programmed cell death protein-1 therapeutics. This study reports the pharmacodynamics (PD) and biomarker results from phase I/Ib first-in-human study of SAR439459 ± cemiplimab in patients with advanced solid tumors (NCT03192345). In dose-escalation phase (Part 1), SAR439459 was administered intravenously at increasing doses either every 2 weeks (Q2W) or every 3 weeks (Q3W) with cemiplimab IV at 3 mg/kg Q2W or 350 mg Q3W, respectively, in patients with advanced solid tumors. In dose-expansion phase (Part 2), patients with melanoma received SAR439459 IV Q3W at preliminary recommended phase II dose (pRP2D) of 22.5/7.5 mg/kg or at 22.5 mg/kg with cemiplimab 350 mg IV Q3W. Tumor biopsy and peripheral blood samples were collected for exploratory biomarker analyses to assess target engagement and PD, and results were correlated with patients' clinical parameters. SAR439459 ± cemiplimab showed decreased plasma and tissue TGFß, downregulation of TGFß-pathway activation signature, modulation of peripheral natural killer (NK) and T cell expansion, proliferation, and increased secretion of CXCL10. Conversion of tumor tissue samples from 'immune-excluded' to 'immune-infiltrated' phenotype in a representative patient with melanoma SAR439459 22.5 mg/kg with cemiplimab was observed. In paired tumor and plasma, active and total TGFß1 was more consistently elevated followed by TGFß2, whereas TGFß3 was only measurable (lower limit of quantitation ≥2.68 pg/mg) in tumors. SAR439459 ± cemiplimab showed expected peripheral PD effects and TGFß alteration. However, further studies are needed to identify biomarkers of response.

AMEERA-1 phase 1/2 study of amcenestrant, SAR439859, in postmenopausal women with ER-positive/HER2-negative advanced breast cancer.

AMEERA-1 is a Phase 1/2 open-label single-arm study evaluating once-daily (QD) amcenestrant, an orally bioavailable selective estrogen receptor (ER) degrader, in postmenopausal women with ER+/HER2- advanced breast cancer (NCT03284957), who were mostly heavily pretreated (including targeted therapies and fulvestrant). In the dose escalation phase (Part A: n = 16), patients received amcenestrant 20-600 mg QD. Based on absence of dose-limiting toxicities, paired functional 18F-fluoroestradiol positron emission tomography, and pharmacokinetics, 400 mg QD was selected as recommended Phase 2 dose (RP2D) for the dose expansion phase (Part B: n = 49). No Grade ≥3 treatment-related adverse events or clinically significant cardiac/eye toxicities were reported. The Part B primary endpoint, confirmed objective response rate (ORR) was 3/45 at the interim analysis and 5/46 (10.9%) at the final analysis. The overall clinical benefit rate (CBR) was 13/46 (28.3%). CBRs among patients with baseline wild-type and mutated ESR1 were 9/26 (34.6%) and 4/19 (21.1%), respectively. Paired tumor biopsy and cell-free DNA analyses revealed ER inhibition and degradation, and a reduction in detectable ESR1 mutations, including Y537S. In conclusion, amcenestrant at RP2D of 400 mg QD for monotherapy is well-tolerated with no dose-limiting toxicities, and demonstrates preliminary antitumor activity irrespective of baseline ESR1 mutation status.

An experimental model of anti-PD-1 resistance exhibits activation of TGFß and Notch pathways and is sensitive to local mRNA immunotherapy.

Immune checkpoint blockade elicits durable anti-cancer responses in the clinic, however a large proportion of patients do not benefit from treatment. Several mechanisms of innate and acquired resistance to checkpoint blockade have been defined and include mutations of MHC I and IFNγ signaling pathways. However, such mutations occur in a low frequency of patients and additional mechanisms have yet to be elucidated. In an effort to better understand acquired resistance to checkpoint blockade, we generated a mouse tumor model exhibiting in vivo resistance to anti-PD-1 antibody treatment. MC38 tumors acquired resistance to PD-1 blockade following serial in vivo passaging. Lack of sensitivity to PD-1 blockade was not attributed to dysregulation of PD-L1 or ß2M expression, as both were expressed at similar levels in parental and resistant cells. Similarly, IFNγ signaling and antigen processing and presentation pathways were functional in both parental and resistant cell lines. Unbiased gene expression analysis was used to further characterize potential resistance mechanisms. RNA-sequencing revealed substantial differences in global gene expression, with tumors resistant to anti-PD-1 displaying a marked reduction in expression of immune-related genes relative to parental MC38 tumors. Indeed, resistant tumors exhibited reduced immune infiltration across multiple cell types, including T and NK cells. Pathway analysis revealed activation of TGFß and Notch signaling in anti-PD-1 resistant tumors, and activation of these pathways was associated with poorer survival in human cancer patients. While pharmacological inhibition of TGFß and Notch in combination with PD-1 blockade decelerated tumor growth, a local mRNA-based immunotherapy potently induced regression of resistant tumors, resulting in complete tumor remission, and resensitized tumors to treatment with anti-PD-1. Overall, this study describes a novel anti-PD-1 resistant mouse tumor model and underscores the role of two well-defined signaling pathways in response to immune checkpoint blockade. Furthermore, our data highlights the potential of intratumoral mRNA therapy in overcoming acquired resistance to PD-1 blockade.

SAR439859, a Novel Selective Estrogen Receptor Degrader (SERD), Demonstrates Effective and Broad Antitumor Activity in Wild-Type and Mutant ER-Positive Breast Cancer Models.

Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERD), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here, we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models, including MCF7-ESR1 wild-type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those who have resistance to endocrine therapy with both wild-type and mutant ER.

Favorable short-term oncologic outcomes following laparoscopic surgery for small T4 colon cancer: a multicenter comparative study.

BACKGROUND: Laparoscopic surgery for T4 colon cancer may be safe in selected patients. We hypothesized that small tumor size might preoperatively predict a good laparoscopic surgery outcome. Herein, we compared the clinicopathologic and oncologic outcomes of laparoscopic and open surgery in small T4 colon cancer. METHODS: In a retrospective multicenter study, we reviewed the data of 449 patients, including 117 patients with tumors ≤ 4.0 cm who underwent surgery for T4 colon cancer between January 2014 and December 2017. We compared the clinicopathologic and 3-year oncologic outcomes between the laparoscopic and open groups. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards model. A p < 0.05 was considered statistically significant. RESULTS: Blood loss, length of hospital stay, and postoperative morbidity were lower in the laparoscopic group than in the open group (median [range], 50 [0-700] vs. 100 [0-4000] mL, p < 0.001; 8 vs. 10 days, p < 0.001; and 18.0 vs. 29.5%, p = 0.005, respectively). There were no intergroup differences in 3-year overall survival or disease-free survival (86.6 vs. 83.2%, p = 0.180, and 71.7 vs. 75.1%, p = 0.720, respectively). Among patients with tumor size ≤ 4.0 cm, blood loss was significantly lower in the laparoscopic group than in the open group (median [range], 50 [0-530] vs. 50 [0-1000] mL, p = 0.003). Despite no statistical difference observed in the 3-year overall survival rate (83.3 vs. 78.7%, p = 0.538), the laparoscopic group had a significantly higher 3-year disease-free survival rate (79.2 vs. 53.2%, p = 0.012). CONCLUSIONS: Laparoscopic surgery showed similar outcomes to open surgery in T4 colon cancer patients and may have favorable short-term oncologic outcomes in patients with tumors ≤ 4.0 cm.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy With Mitomycin C Used for Colorectal Peritoneal Carcinomatosis.

PURPOSE: This study aimed to assess the evaluation of clinical outcomes and consequences of complications after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the peritoneal carcinomatosis (PC) from colorectal cancer. METHODS: A total 26 patients underwent CRS and HIPEC for PC from colorectal cancer between March 2009 and April 2018. All the patients underwent CRS with the purpose of complete or near-complete cytoreduction. Intraoperative HIPEC was performed simultaneously after the CRS. Mitomycin C was used as chemotherapeutic agent for HIPEC. RESULTS: Median disease-free survival was 27.8 months (range, 13.4-42.2 months). Median overall survival was 56.0 months (range, 28.6-83.5 months). The mean peritoneal cancer index (PCI) was 8.73 ± 5.54. The distributions thereof were as follows: PCI <10, 69.23%; PCI 10-19, 23.08%; and PCI ≥20, 7.69%. The completeness of cytoreduction was 96.2% of patients showed CC-0, with 3.8% achieved CC-1. The mean operation time was 8.5 hours, and the mean postoperative hospital stay was 21.6 days. The overall rate of early postoperative complications was 88.5%; the rate of late complications was 34.6%. In the early period, most complications were grades I-II complications (65.4%), compared to grades III-V (23.1%). All late complications, occurring in 7.7% of patients, were grades III-V. There was no treatment-related mortality. CONCLUSION: Although the complication rate was approximately 88%, but the rate of severe complication rate was low. In selective patients with peritoneal recurrence, more aggressive strategies for management, such as CRS with HIPEC, were able to be considered under the acceptable general condition and life-expectancy.

Effect of membrane insertion for tricuspid regurgitation using immersed-boundary lattice Boltzmann method.

BACKGROUND: Tricuspid regurgitation is treated by valve repair or replacement. However, these methods have limitations, and alternative treatment methods are therefore required. OBJECTIVES: In this study, a new method of tricuspid valve treatment using artificial membrane insertion is analyzed. We performed tricuspid valve simulations using an artificial membrane inserted into the right ventricle (RV) or right atrium (RA). METHODS: We use the lattice Boltzmann method with the immersed boundary condition to model the structural motion of the valve leaflet. The effect of membrane insertion is analyzed in terms of the stress, force, and impulse on the valve leaflet, along with the velocity, pressure, jet volume, and Reynolds stress in the flow field. RESULTS: While the use of either membrane (RA or RV) leads to improved valve closure relative to the use of no membrane, the RV membrane is more effective than the RA membrane in achieving improved valve closure. In addition, a larger membrane area with a shorter distance between the leaflet and membrane increases membrane efficacy. CONCLUSION: Our results suggest that membrane insertion can form an effective new method for the treatment of tricuspid regurgitation.

Computational analysis of airflow dynamics for predicting collapsible sites in the upper airways: machine learning approach.

Obstructive sleep apnea (OSA) is a common sleep breathing disorder. With the use of computational fluid dynamics (CFD), this study provides a quantitative standard for accurate diagnosis and effective surgery based on the investigation of the relationship between airway geometry and aerodynamic characteristics. Based on computed tomography data from patients having normal geometry, 4 major geometric parameters were selected and a total of 160 idealized cases were modeled and simulated. We created a predictive model using Gaussian process regression (GPR) through a data set obtained through numerical method. The results demonstrated that the mean accuracy of the overall GPR model was ~72% with respect to the CFD results for the realistic upper airway model. A support vector machine model was also used to identify the degree of OSA symptoms in patients as normal-mild and moderate and severe. We achieved an accuracy of 82.5% with the training data set and an accuracy of 80% with the test data set.NEW & NOTEWORTHY There have been many studies on the analysis of obstructive sleep apnea (OSA) through computational fluid dynamics and finite element analysis. However, these methods are not useful for practical medical applications because they have limited information for OSA symptom. This study employs the machine learning algorithm to predict flow characteristics quickly and to determine the symptoms of the patient's OSA. The overall Gaussian process regression model's mean accuracy was ~72%, and the accuracy for the classification of OSA was >80%.

TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma.

In tumours that harbour wild-type p53, p53 protein function is frequently disabled by the mouse double minute 2 protein (MDM2, or HDM2 in humans). Multiple HDM2 antagonists are currently in clinical development. Preclinical data indicate that TP53 mutations are a possible mechanism of acquired resistance to HDM2 inhibition; however, this resistance mechanism has not been reported in patients. Utilizing liquid biopsies, here we demonstrate that TP53 mutations appear in circulating cell-free DNA obtained from patients with de-differentiated liposarcoma being treated with an inhibitor of the HDM2-p53 interaction (SAR405838). TP53 mutation burden increases over time and correlates with change in tumour size, likely representing selection of TP53 mutant clones resistant to HDM2 inhibition. These results provide the first clinical demonstration of the emergence of TP53 mutations in response to an HDM2 antagonist and have significant implications for the clinical development of this class of molecules.

Jamming and unjamming transition of oil-in-water emulsions under continuous temperature change.

To analyze the jamming and unjamming transition of oil-in-water emulsions under continuous temperature change, we simulated an emulsion system whose critical volume fraction was 0.3, which was validated with experimental results under oscillatory shear stress. In addition, we calculated the elastic modulus using the phase lag between strain and stress. Through heating and cooling, the emulsion experienced unjamming and jamming. A phenomenon-which is when the elastic modulus does not reach the expected value at the isothermal system-occurred when the emulsion system was cooled. We determined that this phenomenon was caused by the frequency being faster than the relaxation of the deformed droplets. We justified the relation between the frequency and relaxation by simulating the frequency dependency of the difference between the elastic modulus when cooled and the expected value at the same temperature.

[A case of Bell's palsy associated with peginterferon Alfa-2a and ribavirin therapy for chronic hepatitis C virus infection].

Pegylated interferon alfa-2a (PEG-IFN) and ribavirin combination therapy is the first line treatment for chronic HCV infection. There are four reports of Bell's palsy associated with interferon-alpha (IFN-alpha) and ribavirin therapy. We report here a case of Bell's palsy that occurred in a patient with chronic HCV infection during combination PEG-IFN and ribavirin therapy. The patient was 49-year-old man with chronic hepatitis C for 2 years. The liver biopsy showed grade 1 and stage 1. Therapy with PEG-IFN (Pegasys) 180 microgram/week and ribavirin 1200 mg/day was initiated. After 3 weeks of treatment, the patient showed a loss of muscular tone on the left side of his face. A diagnosis of Bell's palsy was made, and the PEG-IFN and ribavirin therapy was stopped. Prednisolone 45 mg/d was given and then tapered for 8 weeks. His palsy improved over 6 weeks.

Expression of cysteine proteinase of Clonorchis sinensis and its use in serodiagnosis of clonorchiasis.

A gene encoding cysteine proteinase from Clonorchis sinensis has been cloned and expressed in Escherichia coli. The cysteine proteinase cDNA fragment was amplified by reverse transcription-polymerase chain reaction using degenerate oligonucleotide primers derived from conserved active site of cysteine proteinases. The 5' and 3' regions of the gene were amplified using rapid amplification of cDNA ends. The cloned gene has an open reading frame of 696 bp and deduced amino acid sequence of 232. Sequence analysis and alignment showed significant homologies with the eukaryotic cysteine proteinases and conservation of the Cys, His, and Asp residues that form the catalytic triad. Analysis of the expressed protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that the molecular weight of the protein was approximately 28.5 kDa. Proteolytic activity of the expressed protein was inhibited by cysteine proteinase inhibitors such as L-trans-epoxysuccinyl-leucylamide-(4-guanidino)-butane, iodoacetic acid, and leupeptin. The expressed protein showed biochemical properties similar to those of cysteine proteinases of other parasites. The expressed protein strongly reacted with the sera from patients with clonorchiasis but not with the sera from patients with paragonimiasis, fascioliasis, cysticercosis, and sparganosis, or with sera from normal human controls. These results suggest that the expressed protein may be valuable as a specific diagnostic material for the immunodiagnosis of clonorchiasis.

Purification and characterization of a 7-kDa protein from Clonorchis sinensis adult worms.

A 7-kDa protein was purified from extracts of adult Clonorchis sinensis by a combination of ammonium sulfate precipitation, anion exchange chromatography, cation exchange chromatography, gel-filtration chromatography, and reversed-phase FPLC. The 7-kDa protein exists in the excretory-secretory products of adult C. sinensis, but not in extracts of adult Paragonimus westermani. Also, the 7-kDa protein reacted with the sera of patients with clonorchiasis but not with paragonimiasis or normal human sera. To observe the localization of the 7-kDa protein in the tissue of adult C. sinensis, an immunogold labeling method was followed using anti-7-kDa antibody. The gold particles were observed in the basal layer below the tegumental syncytium, in the interstitial matrix of the parenchyma, and in the content of the uterus. The 7-kDa cDNA was obtained through reverse transcription-polymerase chain reaction using a primer designed from N-terminal sequence analysis. Rapid amplification of cDNA ends (5'-RACE) was used to obtain the complete protein coding sequence. The sequence encodes a 90-amino acid polypeptide. The deduced amino acid sequence of the 7-kDa protein revealed no homology with proteins of different organisms reported so far. These results suggest that the 7-kDa protein is a fluid antigen and may be valuable as a tool for the immunodiagnosis of clonorchiasis.

Therapeutic Trial Of Praziquantal (Embay 8440; Biltricide(R)) On The Dermal And Cerebral Human Cysticercosis.

A total of 28 adult cases who were confirmed cysticercosis with or without cerebral involvements were treated with praziquantel at the daily dose of 3 x 25 mg/kg for 3 to 7 consecutive days and was evaluated for tolerance and therapeutic effects in the trials clinically performed.The assessment of drug efficacy of praziquantel in the dermal cysticercosis was made by comparing the numbers of cysticercus nodules and histopathological findings of the biopsied parasites by means of light, scanning and transmission electron microscope. In the cerebral cysticercosis, the assessment was considered by the frequency of the episodes of convulsive seizure before and after treatment with praziquantel and by the findings of the disapearance or decreased densities of the lesions in C.T. scan in comparison with those of before and after treatment. The results were as follows: 1. The cysticerci in the subcutaneous tissues began to disappear within one month of drug administration of 3 x 25 mg/kg praziquantel over 3 to 7 days. Within 3 to 6 months most of the cysticerci had disappeared, although in some case a small number of cysticercus nodules remained even one year after treatment. 2. Histological observation of the cysticerci biopsied at different times during the course of treatment revealed that morphological changes were already taking place within two weeks after the treatment. At the early stage of the treatment, small vacuoles were scattered along the basement layer in the tegumental syncytium of the scolex and neck regions. In the scanning electron microscopic observation, marked surface changes were present in the neck region with many bleb-like structures formed by the bursting of the large vacuoles in the tegumental syncytium. In the specimens biopsied at 2 or 5 weeks after treatment, the degenerations and necrosis of the tegumental syncytium were seen in all parts of cysticercus. 3. In 12 cases of cerebral cysticercosis treated with praziquantel at the daily dose of 3 x 35 mg/kg for 3 or 4 consecutive days, there were no ceasing of the convulsive seizures during the 6 months follow-up. Among them 9 cases were given again the same doses of the drug for 4 or 7 days. In 7 of 9 cases, no more convulsive seizure was experienced over one or two years after the second time. At the same treatment the lesions of the brain C.T. scan disappeared, decreasd in size or calcified after treatment. In other 3 cerebral cysticercosis cases, complete cure was also obtained after the oral medication of praziquantel at the daily dose of 3 x 25 mg/kg for 7 consecutive days. 4. In the treatment of cerebral cysticercosis with praziquantel, it was found that the concomitant oral medication of dexamethasone during the course of treatment was effective for preventing and minimizing the side-effects.