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.

Partial exogastrulation due to apical-basal polarity of F-actin distribution disruption in sea urchin embryo by omeprazole.

Gastrulation is a universal process in the morphogenesis of many animal embryos. Although morphological and molecular events in gastrulation have been well studied, the mechanical driving forces and underlying regulatory mechanisms are not fully understood. Here, we investigated the gastrulation of embryos of a sea urchin, Hemicentrotus pulcherrimus, which involves the invagination of a single-layered vegetal plate into the blastocoel. We observed that omeprazole, a proton pump inhibitor capable of perturbing the left-right asymmetry of sea urchin embryo, induced "partial exogastrulation" where the secondary invagination proceeds outward. During early gastrulation, intracellular apical-basal polarity of F-actin distribution in vegetal half was higher than those in animal half, while omeprazole treatment disturbed the apical-basal polarity of F-actin distribution in vegetal half. Furthermore, gastrulation stopped and even partial exogastrulation did not occur when F-actin polymerization or degradation in whole embryo was partially inhibited via RhoA or YAP1 knockout. A mathematical model of the early gastrulation reproduced the shapes of both normal and exogastrulating embryos using cell-dependent cytoskeletal features based on F-actin. Additionally, such cell position-dependent intracellular F-actin distributions might be regulated by intracellular pH distributions. Therefore, apical-basal polarity of F-actin distribution disrupted by omeprazole may induce the partial exogastrulation via anomalous secondary invagination.

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.

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.

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.

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.

Three-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 plus docetaxel versus S-1 alone in stage III gastric cancer: JACCRO GC-07.

PURPOSE: The second planned interim analysis (median follow-up 12.5 months) in a phase III trial of postoperative adjuvant chemotherapy for stage III gastric cancer revealed significant improvement in relapse-free survival (RFS) for S-1 plus docetaxel over S-1 alone. Although enrollment was terminated on the recommendation of the independent data and safety monitoring committee, we continued follow-up and herein report on 3-year RFS, the primary endpoint. 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. In the S-1 plus docetaxel group, S-1 was given orally for 2 weeks followed by 1 week of rest for seven courses, and docetaxel was given intravenously on day 1 of the second to seventh courses. The combination therapy was followed by S-1 monotherapy for up to 1 year. RESULTS: The 3-year RFS rate of the S-1 plus docetaxel group was 67.7%. This was significantly superior to that of 57.4% in the S-1 group (hazard ratio [HR] 0.715, 95% CI 0.587-0.871, P = 0.0008). This translated into a significant benefit in the 3-year overall survival (OS) rate in the S-1 plus docetaxel group (77.7% versus 71.2%, HR 0.742, 95% CI 0.596-0.925, P = 0.0076). CONCLUSION: On 3-year follow-up data, postoperative adjuvant therapy with S-1 plus docetaxel was confirmed to improve both RFS and OS and can be recommended as a standard of care for patients with stage III gastric cancer treated by D2 dissection.

Real-world effectiveness of nivolumab in advanced gastric cancer: the DELIVER trial (JACCRO GC-08).

BACKGROUND: There is no large real-world data regarding efficacy and safety of immunotherapy in gastric cancer (GC). Although some tumors can grow rapidly after immunotherapy, the patient proportions and survival outcomes are unclear in GC. METHODS: A multicenter, prospective observational study was performed to evaluate clinical outcomes including survival time, safety, and tumor behavior of nivolumab treatment for patients with advanced GC. Primary endpoint was overall survival (OS), and secondary endpoints included response rate (RR), disease control rate (DCR), progression-free survival (PFS), tumor growth rate (TGR) at first evaluation, and safety. RESULTS: Of 501 enrolled patients, 487 were evaluable (median age 70 years, 71% male, performance status 0/1/2 [42%/44%/14%], 21% HER2-pos, 42% patients with ascites). Median OS was 5.82 months (95% CI 5.29-7.00) with a 1-year survival rate of 30% and median PFS of 1.84 months (95% CI 1.71-1.97). The DCR was 39.4% and the RR was 14.2% (95% CI 10.3-18.8) in 282 patients with measurable lesions. In 219 patients evaluable for TGR, 20.5% were identified as hyperprogressive disease (HPD). OS from the first evaluation of patients with HPD was shorter compared with non-HPD (HR 1.77, 95% CI 1.25-2.51, P = 0.001), but it was not worse than that of patients with progression and non-HPD (HR 1.05, 95% CI 0.72-1.53, P = 0.8). A multivariate analysis revealed the presence of peritoneal metastasis was a prognostic factor for OS and PFS. CONCLUSIONS: Our real-world data demonstrated the comparable survival time to a previous clinical trial and revealed the frequency and prognosis of patients with HPD in advanced GC treated with nivolumab.

Characteristic imaging findings of tendinosis of the direct head of rectus femoris and their interpretation.

BACKGROUND: Tendinosis at the origin of the direct head of rectus femoris causing anterior hip pain is termed AIISpinitis, but no study has investigated its imaging findings. The aim of the present study was to determine the characteristic imaging findings of AIISpinitis and clarify their pathological significance. METHODS: We reviewed the preoperative imaging findings of 62 hips in 58 patients who had undergone endoscopy with a diagnosis of AIISpinitis. The origin of the direct head of rectus femoris was evaluated by ultrasound (US) and magnetic resonance imaging (MRI), and the positive rate of abnormal findings and their agreement with endoscopy regarding injury of the direct head of rectus femoris were measured. Signal changes in the fat pad around the anterior inferior iliac spine (AIIS fat pad) in MRI were compared with the pathological findings of that harvested endoscopically. RESULTS: Hypoechoic regions in US (53/62, 85%) and signal change in MRI (55/62, 89%) were observed with high frequency and corresponded with injury of the direct head of rectus femoris observed by endoscopy (58/62, 94%) (kappa coefficient, 0.43 [moderate agreement], 0.69 [good agreement] respectively). Hypoechoic regions had high sensitivity (85%) and specificity (86%) for AIISpinitis. Regarding the AIIS fat pad, punctate and completely hypo-intense change relative to normal fat corresponded to fibrosis and scar formation, respectively (weighted kappa coefficient, 0.51 [moderate agreement]). CONCLUSIONS: Hypoechoic regions on US which had high sensitivity and specificity; and signal change at the origin of the direct head of rectus femoris and hypo-intensity of the AIIS fat pad on MRI were characteristic findings of tendinosis of the direct head of rectus femoris. These findings correspond pathologically to injury of the direct head of rectus femoris and fibrosis or scar formation in the AIIS fat pad, respectively.

Phase 2 study of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type metastatic colorectal cancer: JACCRO CC-08.

BACKGROUND: Regorafenib or trifluridine/tipiracil as third-line treatment have limited efficacy in metastatic colorectal cancer (mCRC). METHODS: This Phase 2 trial evaluated the efficacy and safety of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type mCRC patients who achieved clinical benefit with first-line cetuximab-containing therapy. The primary endpoint was 3-month progression-free survival (PFS) rate. A sample size was calculated; 30 patients with a 3-month PFS rate of 45% deemed promising and 15% unacceptable. Patients with greater and less than the cut-off value of cetuximab-free intervals (CFIs) were classified into the long and short CFI groups, respectively, in subgroup analyses. RESULTS: Among 34 eligible patients who received treatment at least once, 3-month PFS rate was 44.1% (95% confidence interval, 27.4-60.8%). The median PFS and overall survival (OS) were 2.4 and 8.2 months, respectively. The response and disease control rates were 2.9 and 55.9%, respectively. PFS and OS were significantly longer in the long- than in the short CFI group. CONCLUSIONS: Irinotecan plus cetuximab rechallenge as third-line treatment for KRAS wild-type mCRC was safe and had promising activity, especially in those with a long CFI, warranting further investigation in a Phase 3 randomised trial. CLINICAL TRIAL REGISTRATION: UMIN000010638.

Reconstruction of global regulatory network from signaling to cellular functions using phosphoproteomic data.

Cellular signaling regulates various cellular functions via protein phosphorylation. Phosphoproteomic data potentially include information for a global regulatory network from signaling to cellular functions, but a procedure to reconstruct this network using such data has yet to be established. In this paper, we provide a procedure to reconstruct a global regulatory network from signaling to cellular functions from phosphoproteomic data by integrating prior knowledge of cellular functions and inference of the kinase-substrate relationships (KSRs). We used phosphoproteomic data from insulin-stimulated Fao hepatoma cells and identified protein phosphorylation regulated by insulin specifically over-represented in cellular functions in the KEGG database. We inferred kinases for protein phosphorylation by KSRs, and connected the kinases in the insulin signaling layer to the phosphorylated proteins in the cellular functions, revealing that the insulin signal is selectively transmitted via the Pi3k-Akt and Erk signaling pathways to cellular adhesions and RNA maturation, respectively. Thus, we provide a method to reconstruct global regulatory network from signaling to cellular functions based on phosphoproteomic data.

NMDAR-Mediated Ca2+ Increase Shows Robust Information Transfer in Dendritic Spines.

A dendritic spine is a small structure on the dendrites of a neuron that processes input timing information from other neurons. Tens of thousands of spines are present on a neuron. Why are spines so small and many? We addressed this issue by using the stochastic simulation model of N-methyl-D-aspartate receptor (NMDAR)-mediated Ca2+ increase. NMDAR-mediated Ca2+ increase codes the input timing information between prespiking and postspiking. We examined how much the input timing information is encoded by Ca2+ increase against presynaptic fluctuation. We found that the input timing information encoded in the cell volume (103µm3) largely decreases against the presynaptic fluctuation, whereas that in the spine volume (10-1µm3) slightly decreases. Therefore, the input timing information encoded in the spine volume is more robust against presynaptic fluctuation than that in the cell volume. We further examined the mechanism of the robust information transfer in the spine volume. We demonstrated that the condition for the robustness is that the stochastic NMDAR-mediated Ca2+ increase (intrinsic noise) becomes much larger than the presynaptic fluctuation (extrinsic noise). When the presynaptic fluctuation is large, the condition is satisfied in the spine volume but not in the cell volume. Moreover, we compared the input timing information encoded in many small spines with that encoded in a single large spine. We found that the input timing information encoded in many small spines are larger than that in a single large spine when presynaptic fluctuation is large because of their robustness. Thus, robustness is a functional reason why dendritic spines are so small and many.

Impact of vitamin C on teriparatide treatment in the improvement of bone mineral density, strength, and quality in vitamin C-deficient rats.

Age-related decreases in serum levels of vitamin C (VC) may negatively affect the efficacy of anti-osteoporotic pharmacotherapy. The purpose of this study was to evaluate the effects of VC and teriparatide (TPTD) on bone mineral density (BMD), strength, and quality in VC-deficient osteogenic disorder Shionogi (ODS) rats. Six-month-old female ODS rats were divided into an untreated ODS control group, a VC group, a TPTD group, and a VC + TPTD group, based on the administration of VC and TPTD (n = 10 each). VC was given as 2.0 mg/ml supplemented water. TPTD was administered subcutaneously once a week at 30 µg/kg body weight. After 12 weeks of treatment, BMDs of the femur and lumbar spine, bone strengths of the femoral diaphysis and metaphysis, and cancellous bone quality of proximal tibiae as estimated by Fourier transform infrared spectroscopy (FTIR) were compared between groups. Compared to the ODS control group, the VC group showed significantly higher total femoral BMD, but the TPTD group showed significantly higher femoral and lumbar spinal BMD, maximum load of femoral metaphysis, and hydroxyapatite (HA) crystallinity by FTIR (p < 0.05). In addition to the increases shown in the TPTD group, the VC + TPTD group also showed significantly higher stiffness of the femoral diaphysis and breaking energy of the femoral metaphysis compared to the ODS control group (p < 0.05). These results indicated that TPTD alone increased cancellous/cortical BMD and cancellous bone strength with improvement of HA crystallinity in ODS rats, but addition of VC supplementation further improved cortical bone strength.

DELIVER (JACCRO GC-08) trial: discover novel host-related immune-biomarkers for nivolumab in advanced gastric cancer.

Aim: Nivolumab has survival benefit in patients with previously treated advanced gastric cancer; however, about 60% of the patients did not respond to nivolumab, raising the necessity of its predictive biomarkers. Gut microbiome has been shown to be associated with efficacy of anti-PD-1 antibody in various types of cancers, but little is known about gastric cancer. Design: This is an observational/translational study to evaluate clinical outcomes of nivolumab and to discover novel immune-related biomarkers (gut microbiome, genetic polymorphism, gene expression and metabolome in plasma) in gastric cancer, using fecal and blood samples at two points before and after treatment. Candidate factors will be explored in first 200 patients and then validated in last 300 patients. Trial registration: UMIN000030850.

[A Case of Advanced Gastric Cancer with Bone Marrow Metastasis Treated with Low-Dose Combination Chemotherapy Containing S-1 and Docetaxel].

A 77-year-old woman was admitted to our hospital with complaints of lumbago. Based on MRI, bone marrow biopsy, and upper endoscopy, she was diagnosed as having advanced gastric cancer accompanied by bone marrow metastasis and multiple bone metastases. She underwent combination chemotherapycontaining S-1 and docetaxel(TXT). However, during the first course of chemotherapy, she developed Grade 4 neutropenia and sepsis, and her ADL worsened. The anticancer agent doses were reduced drasticallyto 40% of the initial dose from the next course of chemotherapy. She was able to continue treatment without developing severe adverse events, and the disease did not progress for 11 months. However, during the 6 course of chemotherapy, she developed Grade 4 neutropenia and sepsis again, and it became difficult to continue treatment. Subsequent S-1 monotherapywas not efficacious, and she died 17 months after diagnosis. From the view of persistence and efficacy, we believe that low-dose combination chemotherapycontaining S-1 and TXT maybe a suitable regimen for advanced gastric cancer with bone marrow metastasis.

System identification of signaling dependent gene expression with different time-scale data.

Cells decode information of signaling activation at a scale of tens of minutes by downstream gene expression with a scale of hours to days, leading to cell fate decisions such as cell differentiation. However, no system identification method with such different time scales exists. Here we used compressed sensing technology and developed a system identification method using data of different time scales by recovering signals of missing time points. We measured phosphorylation of ERK and CREB, immediate early gene expression products, and mRNAs of decoder genes for neurite elongation in PC12 cell differentiation and performed system identification, revealing the input-output relationships between signaling and gene expression with sensitivity such as graded or switch-like response and with time delay and gain, representing signal transfer efficiency. We predicted and validated the identified system using pharmacological perturbation. Thus, we provide a versatile method for system identification using data with different time scales.

Correction to: Multicenter phase II study of trastuzumab plus S-1 alone in elderly patients with HER2-positive advanced gastric cancer (JACCRO GC­06).

The correct name of the twelfth author should be ''Yasuhiro Yuasa", and not ''Yasuhiko Yuasa'' as given in the original publication of the article.