Tumor Response Predicts Survival Time of Nivolumab Monotherapy for Advanced Gastric Cancer: A Subgroup Analysis of the DELIVER Trial (JACCRO GC-08).

BACKGROUND: This prospective observational study evaluated the real-world effectiveness of nivolumab monotherapy in previously treated advanced gastric cancer (GC). A preplanned 2-year final analysis was performed to confirm survival and tumor behavior with nivolumab monotherapy. PATIENTS AND METHODS: The primary endpoint was overall survival (OS). The data regarding tumor size were prospectively collected and evaluated using the RECIST criteria. Exploratory analyses were performed for survival according to the tumor response and depth of response (DpR) in patients with measurable lesions who were receiving nivolumab monotherapy as third- or later-line therapy. RESULTS: In 487 patients, the median OS and progression-free survival (PFS) were 5.8 (95% CI 5.3-6.9) months and 1.8 (95% CI 1.7-2.0) months, respectively. The response rate (RR) was 14.5% in 282 patients with measurable lesions. In 234 patients treated with third- or later-line, the DpR was found to be associated with PFS and OS in the Spearman analysis (r = 0.55 and 0.44, respectively) as well as using a discrete variable. When the DpR was divided into 5 groups (-20%≥DpR; -20%

Factors Affecting the Second Complete Atypical Femoral Fracture after the First Atypical Fracture.

OBJECTIVES: Atypical femoral fracture (AFF) is an atypical low-energy subtrochanteric and diaphyseal femoral fracture. Even if bone fusion is achieved in patients with AFF, the risk of AFF in the contralateral femur must be considered. This study aimed to investigate the factors affecting complete AFF in the contralateral femur and conservatively treated incomplete AFF. SUBJECT AND METHODS: Radiographs of 111 femurs in 104 AFF cases were examined, and the femurs were classified as follows: 85 contralateral femurs with complete AFF; 18 contralateral femurs with incomplete AFF; 8 femurs with incomplete AFF without surgical treatment. Various patients' clinical data were collected, and we investigated the factors affecting the second complete AFF. RESULTS: Complete fractures occurred in 10 (9.7%) of 103 femurs without incomplete AFF at the first visit and in 3 (37.5%) of 8 femurs with incomplete AFF. The Kaplan-Meier curve revealed that lateral cortical bone thickening and thigh pain were associated with significantly poorer prognoses (p = 0.026 and p = 0.013, respectively). Multivariate analyses revealed that eldecalcitol usage after AFF onset (p = 0.0094) and previous use of bisphosphonate or denosumab (p = 0.0126) were protective factors for second complete AFF and that the presence of thigh pain (p = 0.0134) was a risk factor for second complete AFF. CONCLUSIONS: Eldecalcitol administration after bone union of first AFF may prevent AFF recurrence. In addition, painful incomplete AFF has a high risk of developing a complete fracture.

Correlation of multiple endpoints in the first-line chemotherapy of advanced gastric cancer: Pooled analysis of individual patient data from Japanese Phase III trials.

BACKGROUND: Individual-level surrogates are important for management in patients treated for advanced gastric cancer (AGC). This study aimed to comprehensively investigate the correlation of multiple clinical endpoints in the first-line chemotherapy of AGC. METHODS: Individual patient data (IPD) were collected from four Japanese Phase III trials comparing S-1-based first-line chemotherapies (SPIRITS, START, GC0301/TOP-002, and G-SOX trials). Patients without Response Evaluation Criteria in Solid Tumors (RECIST)-based radiological assessments were excluded. Spearman's rank correlation coefficient was tested for correlation among overall survival (OS), progression-free survival (PFS), and postprogression survival (PPS). OS, PFS, and PPS were compared between responders (best response: complete response or partial response) and nonresponders (best response: stable disease or progressive disease). RESULTS: The study included a total of 1492 patients. Eighty percent of the patients (n = 1190) received subsequent chemotherapies after the failure of each trial's treatment protocol. PFS moderately correlated with OS (Spearman correlation coefficient = 0.66, p < 0.005), whereas the correlation between PPS and OS was strong (Spearman correlation coefficient = 0.87, p < 0.005). Responders had significantly longer OS (median, 17.7 vs. 9.1 months, p < 0.005), PFS (median, 6.9 vs. 2.8 months, p < 0.005), and PPS (median, 10.5 vs. 6.0 months, p < 0.005) than nonresponders. CONCLUSIONS: Our results reacknowledged the mild surrogacy of PFS and importance of postprogression treatments in patients with AGC receiving first-line chemotherapy. Consistent longer survival outcomes in better RECIST categories suggested that tumor response might be a useful individual-level surrogate.

Characteristics and Treatment Strategies for Basicervical and Transcervical Shear Fractures of the Femoral Neck.

This study aimed to define basicervical and transcervical shear fractures using area classification and to determine the optimal osteosynthesis implants for them. The clinical outcomes of 1042 proximal femur fractures were investigated. A model of the proximal femur of a healthy adult was created from computed tomography images, and basicervical and transcervical shear fractures were established in the model. Osteosynthesis models were created using a short femoral nail with a single lag screw or two lag screws and a long femoral nail with a single lag screw or two lag screws. The minimum principal strains of the fracture surfaces were compared when the maximum loads during walking were applied to these models using finite element analysis software. Basicervical fractures accounted for 0.96% of all proximal femur fractures, 67% of which were treated with osteosynthesis; the failure rate was 0%. Transcervical shear fractures accounted for 9.6% of all proximal femur fractures, 24% of which were treated with osteosynthesis; the failure rate was 13%. Finite element analysis showed that transcervical shear fracture has high instability. To perform osteosynthesis, multiple screw insertions into the femoral head and careful postoperative management are required; joint replacement should be considered to achieve early mobility.

Relationship between the Arthroscopic Findings and Pathology of Greater Trochanteric Pain Syndrome.

In recent publications on greater trochanteric pain syndrome (GTPS), the pathology receiving the most attention has been gluteus medius muscle tendinous injury, and surgical techniques such as gluteus medius tendon repair and their outcomes for GTPS have been reported. In our department-related facilities, arthroscopic surgeries are routinely performed for the patients with recalcitrant GTPS. A total of 51 patients were diagnosed with GTPS. Surgical treatment was carried out 22 patients (24 joints; 4 males and 18 females; mean age at surgery of 52.0 years). Arthroscopic findings confirmed bursitis in all 24 joints. In all cases, debridement of the greater trochanter bursa provided rapid relief of greater trochanter pain. The Numerical Rating Scale showed significant improvement, from the preoperative mean of 7.8 (range, 6-10) to the postoperative day 7 mean of 1.6 (range, 0-3). The modified Harris Hip Score was significantly improved from the preoperative mean of 65.5 (range, 52.5-78.3) to the final follow-up (average 2.9 months) mean of 96.0 (range, 85.2-100). Fascial damage of the gluteus medius muscle was observed in 21 joints while only 2 patients had a gluteus medius tendinous injury. Greater trochanteric bursitis and fascia or muscle-fiber injury of the gluteus medius muscle are the most common pathologies in patients with lateral hip pain.

Addition of docetaxel to S-1 results in significantly superior 5-year survival outcomes in Stage III gastric cancer: a final report of the JACCRO GC-07 study.

PURPOSE: A phase III trial comparing S-1 and docetaxel with S-1 alone as postoperative chemotherapy for pathologically Stage III gastric cancer was conducted and clarified the superiority of the doublet in terms of 3-year relapse-free survival as the primary endpoint (67.7% versus 57.4%, hazard ratio [HR] 0.715, 95% confidence interval [CI] 0.587-0.871; p = 0.0008). This final report analyzed 5-year survival outcomes along with the incidence and pattern of late recurrences. PATIENTS AND METHODS: Patients with histologically confirmed Stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive adjuvant chemotherapy with either S-1 plus docetaxel or S-1 alone. The same 912 patients who were evaluated for 3-year survival outcomes in the previous report were analyzed. RESULTS: Five-year overall survival rate of the S-1 plus docetaxel group (67.91%) was significantly superior to that in the S-1 group (60.27%; HR 0.752, 95% CI 0.613-0.922; p = 0.0059). The incidence of late recurrence at > 3 years after randomization was similar in both groups (7.3% versus 7.2%). Peritoneal dissemination was the most common pattern of late recurrence. Addition of docetaxel significantly suppressed relapse through the lymphatic (6.8% [95% CI 4.52-9.17] versus 15% [95% CI 11.76-18.30]; p < 0.0001) and hematogenous (10.2% [95% CI 7.37-12.94] versus 15.7% [95% CI 12.36-19.01]; p < 0.0137) pathways throughout the 5 years of follow-up. CONCLUSION: The survival benefit of postoperative chemotherapy with S-1 and docetaxel in terms of 5-year overall survival rate was confirmed for patients with pathologically Stage III gastric cancer, although late recurrences were not prevented.

The BEETS (JACCRO CC-18) trial: an observational and translational study of BRAF-mutated metastatic colorectal cancer.

For BRAF V600E-mutated metastatic colorectal cancer (mCRC), the BEACON phase 3 trial showed survival benefit of triplet therapy with cetuximab (anti-EGFR antibody), encorafenib (BRAF inhibitor) and binimetinib (MEK inhibitor) as well as doublet therapy with cetuximab and encorafenib over irinotecan-based chemotherapy plus anti-EGFR antibody. Both regimens are standards of care in Japan, but definite biomarkers for predicting efficacy and selecting treatment remain lacking. The mechanisms underlying resistance to these regimens also warrant urgent exploration to further evolve treatment. This prospective observational/translational study evaluated real-word clinical outcomes with cetuximab and encorafenib with or without binimetinib for BRAF-mutated mCRC patients and investigated biomarkers for response and resistance by collecting blood samples before and after treatment. Clinical Trial Registration: UMIN000045530 (https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000051983).

The BEETS trial is a study that looks at how well two combinations of targeted therapies (cetuximab + encorafenib with or without binimetinib) work and how safe they are for patients with advanced colorectal cancer that has a mutation (change) in the BRAF gene. In this trial, patients participate voluntarily instead of being assigned to one of the two therapy groups. When a patient has BRAF-mutated advanced colorectal cancer, it means that the cancer cells in their body have changes in a gene called BRAF. This gene normally produces a protein called BRAF, which is involved in the growth of cells. However, when there is a mutation in this gene, it can cause the production of an overactive BRAF protein, leading to fast and excessive cell growth and division. For patients with BRAF-mutated advanced colorectal cancer, combinations of targeted therapies have been found to be effective as a second- or third-line treatment, based on the results of a phase 3 clinical trial. The main goal of the BEETS trial is to evaluate how well these treatments work and how safe they are when used in real-world clinical practice. Additionally, the study will use laboratory tests (liquid biopsy) to explore new biomarkers that can help predict how well a treatment will work and assist in selecting the most suitable treatment plans. We hope that the findings of this study will contribute to improving the overall management of this specific type of cancer.

Use of a laryngeal tube for sialolithotomy in a pediatric patient with left vocal cord paralysis: a case report.

BACKGROUND: The laryngeal tube (LT), a closed esophageal supraglottic device comprising pharyngeal and esophageal cuffs, is used for emergency airway management. However, it is not often used in intraoperative airway management. CASE PRESENTATION: A 9-year-old boy was scheduled for a sialolithotomy for sialolithiasis. He had a history of surgery for tetralogy of Fallot and had undergone vocal cord fusion for postoperative left-sided vocal cord paralysis. Following a strong request by the mother to avoid tracheal intubation to reduce the risk of bilateral vocal cord paralysis, management without intubation was initially considered in the preoperative anesthesia plan. Airway management was planned using an LT in case of ventilation failure due to positional abnormalities. Although some leakage was observed during intraoral surgery, it was quickly resolved by adjusting the position of the LT outside the sterile surgical field. CONCLUSIONS: The LT may be a viable option in cases where tracheal intubation is not preferred.

Human epidermal growth factor 2 overexpressed alpha-fetoprotein-producing-gastric cancer.

PURPOSE: This study aimed to elucidate the clinicopathological characteristics of α-fetoprotein (AFP)-producing gastric carcinoma (AFP-GC) with human epidermal growth factor receptor (HER)2 overexpression to extend the treatment strategy for AFP-GC. METHODS: We analyzed 41 patients with AFP-GC who underwent surgical resection or chemotherapy from 1989 to 2019, and who had over 20ng/mL of serum AFP or positive immunohistochemical AFP expression. HER2 expression status was investigated by immunohistochemistry (IHC) for all patients and by fluorescence in situ hybridization (FISH) for cases with an IHC score of 2+. AFP-GC with an IHC score of 3 + or 2 + and FISH positivity was defined as HER2 overexpressed AFP-GC. The correlation between HER2 status and clinicopathological characteristics and prognosis in AFP-GC was analyzed. RESULTS: HER2 overexpression was detected in 17.1% of AFP-GC patients. The prognosis of the patients with HER2 overexpressed AFP-GC was not significantly different compared to HER2 non-overexpressed AFP-GC. HER2 overexpressed AFP-GC consisted of heterogeneous histology with a higher proportion of mixed-type tumors (p = 0.002). The clinical outcome of AFP-GC with mixed-type of histology tended to be better than other intestinal or diffuse types (p = 0.05). CONCLUSION: HER2 overexpressed AFP-GC consisted of a mixed type of histology, which showed a better prognosis. The results presented that HER2 status in AFP-GC is one of the molecular candidates to improve the prognosis.

Evaluation of the Hemoglobin Concentration in Drainage Fluid After Surgery by Absorbance Spectrophotometry Using an Optical Sensor.

Background: A drain is often placed in the abdominal cavity for postoperative monitoring and early detection of complications such as rebleeding and pancreatic or bile leaks. Since determining the color of the drainage fluid is subjective, an objective method of judging color is needed. Methods: The hemoglobin concentration of the drainage fluid after gastrointestinal surgery was measured using the Hemato Check Module, a newly developed instrument capable of absorbance analysis with an optical sensor. The correlation between the results and those measured by an existing blood count measuring device (XN3000) was investigated. Results: A total of 215 specimens were analyzed in 43 patients. For the correlation analysis, there was a strong positive correlation with a correlation coefficient of 0.884 (P < 0.001). The Hemato Check Module showed a clear proportional error compared to the XN3000. Conclusion: The Hemato Check Module was a convenient and accurate instrument for measuring hemoglobin concentration in waste fluid to determine the presence of blood.

Characteristic growth of chemical gardens from mixtures of two salts.

Chemical gardens formed from two metal salts (MCl2 or MSO4) have been investigated to understand the effects of mixing on the growth of precipitate tubes. The growth of tubes can be classified into three types, i.e., collaborative, inhibited, and individual growth, depending on the combination of the two metal salts. Characteristic features of tube growth are discussed in relation to the flow near the tip of the tube controlled by osmotic pressure and the solubility product, Ksp, for M(OH)2. The present study can be interpreted as an inanimate model system of symbiosis among different species, such as mixed cropping systems and survival among different kinds of microbial cells.

A Multicenter, Phase II Trial of Schedule Modification for Nab-Paclitaxel in Combination with Ramucirumab for Patients with Previously Treated Advanced Gastric or Gastroesophageal Junction Cancer: The B-RAX Trial (JACCRO GC-09).

BACKGROUND: This study investigated whether schedule modification of bi-weekly nanoparticle albumin-bound paclitaxel (nab-PTX) plus ramucirumab (RAM) is efficacious against gastric cancer (GC) or gastroesophageal junction cancer (GJC). PATIENTS AND METHODS: Patients with unresectable GC or GJC who were previously treated with fluoropyrimidine-containing regimens received nab-PTX (100 mg/m2) on days 1, 8, and 15 and RAM (8 mg/kg) on days 1 and 15 of a 28-day cycle. Based on the incidence of severe adverse events (AEs) during the first cycle, patients were modified to bi-weekly therapy from the second cycle. The primary endpoint was progression-free survival (PFS) in the bi-weekly therapy population. Based on the hypothesis that bi-weekly nab-PTX plus RAM would improve PFS from 4.5 to 7.0 months, 40 patients were required for power of 0.8 with a one-sided α of 0.05. RESULTS: Of the 81 patients enrolled, 47 patients (58%) were assigned to bi-weekly therapy. Patient characteristics were Eastern Cooperative Oncology Group performance status of 1 (19%) and diffuse type (45%). Median PFS was 4.7 months (95% confidence interval [CI] 3.7-5.6 months) and overall response rate was 25% (95% CI 11-39%). Severe AEs of grade 3 or worse were mainly neutropenia (83%) and hypertension (23%). EQ-5D scores were maintained during the treatment. In patients who continued standard-schedule therapy, median PFS was 2.7 months (95% CI 1.8-4.0 months). CONCLUSIONS: The primary endpoint for PFS was statistically not met, but modification of nab-PTX plus RAM to a bi-weekly schedule might be a feasible treatment option as second-line treatment for advanced GC/GJC patients, especially elderly patients, with severe AEs during the first cycle.

Soluble programmed cell death ligand 1 predicts prognosis for gastric cancer patients treated with nivolumab: Blood-based biomarker analysis for the DELIVER trial.

BACKGROUND: The clinical value of soluble forms of programmed cell death-1 (sPD-1), PD ligand 1 (sPD-L1) and cytotoxic T lymphocyte-associated protein-4 (sCTLA-4) for gastric cancer (GC) patients treated with nivolumab monotherapy has remained unknown. METHODS: Blood samples collected before nivolumab treatment from 439 GC patients enrolled in the DELIVER (Japan Clinical Cancer Research Organisation GC-08) trial were analysed for sPD-1, sPD-L1 and sCTLA-4. Corresponding baseline clinical data were also retrieved. RESULTS: Higher plasma levels of sPD-1 (hazard ratio [HR] = 1.27, p = 0.020), sPD-L1 (HR = 1.86, p < 0.001) and sCTLA-4 (HR = 1.33, p = 0.008) were significantly associated with shorter overall survival (OS), whereas only higher sPD-L1 levels was significantly associated with shorter progression-free survival (HR = 1.30, p = 0.008). The sPD-L1 concentration was significantly associated with the Glasgow prognostic score (GPS) (p < 0.001), but both sPD-L1 (HR = 1.67, p < 0.001) and GPS (HR = 1.39, p = 0.009 for GPS 0 versus 1; HR = 1.95, p < 0.001 for GPS 0 versus 2) were independently associated with OS. Patients with a GPS of 0 and low sPD-L1 thus showed the longest OS (median, 12.0 months) and those with a GPS of 2 and high sPD-L1 showed the shortest OS (median, 3.1 months), yielding a HR of 3.69 (p < 0.001). CONCLUSION: Baseline sPD-L1 levels have the potential to predict survival for advanced GC patients treated with nivolumab, with the prognostic accuracy of sPD-L1 being improved by its combination with GPS.

In vivo transomic analyses of glucose-responsive metabolism in skeletal muscle reveal core differences between the healthy and obese states.

Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and leptin-deficient obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

Methylome data derived from maternal-zygotic DNA methyltransferase 3aa-/- zebrafish.

Genomic DNA methylation is an epigenetic marker mediated by DNA methyltransferases (Dnmts); in vertebrates, it comprises of a maintenance DNA methyltransferase, Dnmt1, and two de novo DNA methyltransferases (Dnmt3a and Dnmt3b). In zebrafish, there are two homologs of the mammalian Dnmt3a: Dnmt3aa and Dnmt3ab. A knockout (KO) mutant of zebrafish dnmt3aa was generated using the CRISPR/Cas9 genome-editing system as a new model for DNA methylation research. Since zebrafish dnmt3aa KO mutants were viable and fertile, a maternal-zygotic dnmt3aa deficient mutant (MZdnmt3aa) was generated. We performed whole-genome bisulfite sequencing (WGBS) to reveal the DNA methylation profile using this mutant and identified genomic regions with altered CpG methylation as differentially methylated regions (DMRs) in this mutant compared to those in the wild-type fish. We provided novel raw and processed datasets using the MZdnmt3aa KO mutant, and the raw data of WGBS are available through the Gene Expression Omnibus (GEO), accession number GSE178690.

Epigenetic-structural changes in X chromosomes promote Xic pairing during early differentiation of mouse embryonic stem cells.

X chromosome inactivation center (Xic) pairing occurs during the differentiation of embryonic stem (ES) cells from female mouse embryos, and is related to X chromosome inactivation, the circadian clock, intra-nucleus architecture, and metabolism. However, the mechanisms underlying the identification and approach of X chromosome pairs in the crowded nucleus are unclear. To elucidate the driving force of Xic pairing, we developed a coarse-grained molecular dynamics model of intranuclear chromosomes in ES cells and in cells 2 days after the onset of differentiation (2-day cells) by considering intrachromosomal epigenetic-structural feature-dependent mechanics. The analysis of the experimental data showed that X-chromosomes exhibit the rearrangement of their distributions of open/closed chromatin regions on their surfaces during cell differentiation. By simulating models where the excluded volume effects of closed chromatin regions are stronger than those of open chromatin regions, such rearrangement of open/closed chromatin regions on X-chromosome surfaces promoted the mutual approach of the Xic pair. These findings suggested that local intrachromosomal epigenetic features may contribute to the regulation of cell species-dependent differences in intranuclear architecture.

Objective Methods of 5-Aminolevulinic Acid-Based Endoscopic Photodynamic Diagnosis Using Artificial Intelligence for Identification of Gastric Tumors.

Positive diagnoses of gastric tumors from photodynamic diagnosis (PDD) images after the administration of 5-aminolevulinic acid are subjectively identified by expert endoscopists. Objective methods of tumor identification are needed to reduce potential misidentifications. We developed two methods to identify gastric tumors from PDD images. Method one was applied to segmented regions in the PDD endoscopic image to determine the region in LAB color space to be attributed to tumors using a multi-layer neural network. Method two aimed to diagnose tumors and determine regions in the PDD endoscopic image attributed to tumors using the convoluted neural network method. The efficiencies of diagnosing tumors were 77.8% (7/9) and 93.3% (14/15) for method one and method two, respectively. The efficiencies of determining tumor region defined as the ratio of the area were 35.7% (0.0-78.0) and 48.5% (3.0-89.1) for method one and method two, respectively. False-positive rates defined as the ratio of the area were 0.3% (0.0-2.0) and 3.8% (0.0-17.4) for method one and method two, respectively. Objective methods of determining tumor region in 5-aminolevulinic acid-based endoscopic PDD were developed by identifying regions in LAB color space attributed to tumors or by applying a method of convoluted neural network.