Potent therapeutic strategy in gastric cancer with microsatellite instability-high and/or deficient mismatch repair.

Gastric cancer (GC) is a common malignancy that presents challenges in patient care worldwide. The mismatch repair (MMR) system is a highly conserved DNA repair mechanism that protects genome integrity during replication. Deficient MMR (dMMR) results in an increased accumulation of genetic errors in microsatellite sequences, leading to the development of a microsatellite instability-high (MSI-H) phenotype. Most MSI-H/dMMR GCs arise sporadically, mainly due to MutL homolog 1 (MLH1) epigenetic silencing. Unlike microsatellite-stable (MSS)/proficient MMR (pMMR) GCs, MSI-H/dMMR GCs are relatively rare and represent a distinct subtype with genomic instability, a high somatic mutational burden, favorable immunogenicity, different responses to treatment, and prognosis. dMMR/MSI-H status is a robust predictive biomarker for treatment with immune checkpoint inhibitors (ICIs) due to high neoantigen load, prominent tumor-infiltrating lymphocytes, and programmed cell death ligand 1 (PD-L1) overexpression. However, a subset of MSI-H/dMMR GC patients does not benefit from immunotherapy, highlighting the need for further research into predictive biomarkers and resistance mechanisms. This review provides a comprehensive overview of the clinical, molecular, immunogenic, and therapeutic aspects of MSI-H/dMMR GC, with a focus on the impact of ICIs in immunotherapy and their potential as neoadjuvant therapies. Understanding the complexity and diversity of the molecular and immunological profiles of MSI-H/dMMR GC will drive the development of more effective therapeutic strategies and molecular targets for future precision medicine.

Efficacy and Safety of Trastuzumab Deruxtecan and Nivolumab as Third- or Later-Line Treatment for HER2-Positive Advanced Gastric Cancer: A Single-Institution Retrospective Study.

PURPOSE: Determination of optimal treatment strategies for HER2-positive advanced gastric cancer (AGC) in randomized trials is necessary despite difficulties in direct comparison between trastuzumab deruxtecan (T-DXd) and nivolumab as third or later-line treatments. MATERIALS AND METHODS: This single-institution, retrospective study aimed to describe the real-world efficacy and safety of T-DXd and nivolumab as ≥ third line treatments for HER2-positive AGC between March 2016 and May 2022. Overall, 58 patients (median age, 64 years; 69% male) were eligible for the study (T-DXd group, n=20; nivolumab group, n=38). RESULTS: Most patients exhibited a HER2 3+ status (72%) and presented metastatic disease at diagnosis (66%). The response rates of 41 patients with measurable lesions in the T-DXd and nivolumab groups were 50% and 15%, respectively. The T-DXd and nivolumab groups had a median progression-free survival of 4.8 months (95% confidence interval [CI], 3.3, 7.0) and 2.3 months (95% CI, 1.5, 3.5), median overall survival (OS) of 10.8 months (95% CI, 6.9, 23.8) and 11.7 months (95% CI, 7.6, 17.1), and grade 3 or greater adverse event rates of 50% and 2%, respectively. Overall, 64% patients received subsequent treatment. Among 23 patients who received both regimens, the T-DXd-nivolumab and nivolumab-T-DXd groups had a median OS of 14.0 months (95% CI, 5.0, not reached) and 19.3 months (95% CI, 9.5, 25.1), respectively. CONCLUSIONS: T-DXd and nivolumab showed distinct efficacy and toxicity profiles as ≥ third line treatments for HER2-positive AGC. Considering the distinct features of each regimen, they may help clinicians personalize optimal treatment approaches for these patients.

Single-organ pulmonary metastasis is a favorable prognostic factor in metastatic colorectal cancer patients treated with FOLFIRI and vascular endothelial growth factor inhibitors.

BACKGROUND: Few studies have focused on the impact of single-organ pulmonary metastases on progression-free survival and overall survival in patients with metastatic colorectal cancer. Recognizing differences in prognosis and chemotherapeutic efficacy based on metastasized organs may help in optimizing treatment strategies. The exploratory study was conducted to evaluate the comparative clinical outcomes and prognoses of patients with metastatic colorectal cancer presenting with single-organ pulmonary metastases and treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy. METHODS: This retrospective study included 289 patients with metastatic colorectal cancer treated with second-line folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors. The response rate, disease control rate, progression-free survival, and overall survival were assessed in the participants. RESULTS: Among the 289 patients enrolled, 26 (9.0%) had single-organ pulmonary metastasis with left-sided primary locations, lower levels of tumor markers at the initiation point of chemotherapy, a significantly higher disease control rate (96.2% vs. 76.7%, P = .02), and a longer progression-free survival (median 29.6 months vs. 6.1 months, P < .001) and overall survival (median 41.1 months vs. 18.7 months, P < .001) than patients with other forms of metastatic colorectal cancer. Multivariate analysis showed that single-organ pulmonary metastasis was an independent predictor of longer progression-free survival (hazard ratio 0.35, P = .00075) and overall survival (hazard ratio 0.2, P = .006). CONCLUSION: Single-organ pulmonary metastasis was a strong predictor of progression-free survival and overall survival in patients with metastatic colorectal cancer treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy; this provides preliminary evidence for medical guidelines and clinical decision-making on novel therapeutic strategies for these patients.

End-to-end dialogue structure parsing on multi-floor dialogue based on multi-task learning.

A multi-floor dialogue consists of multiple sets of dialogue participants, each conversing within their own floor. In the multi-floor dialogue, at least one multi-communicating member who is a participant of multiple floors and coordinates each to achieve a shared dialogue goal. The structure of such dialogues can be complex, involving intentional structure and relations that are within or across floors. In this study, We proposed a neural dialogue structure parser with an attention mechanism that applies multi-task learning to automatically identify the dialogue structure of multi-floor dialogues in a collaborative robot navigation domain. Furthermore, we propose to use dialogue response prediction as an auxiliary objective of the multi-floor dialogue structure parser to enhance the consistency of the multi-floor dialogue structure parsing. Our experimental results show that our proposed model improved the dialogue structure parsing performance more than conventional models in multi-floor dialogue.

Clinical Usefulness of Postoperative Serum Carcinoembryonic Antigen in Patients with Colorectal Cancer with Liver Metastases.

BACKGROUND: Colorectal cancer with liver metastasis (CLM) has high postoperative recurrence rates; therefore, optimizing perioperative treatment is imperative. Postoperative carcinoembryonic antigen (CEA) can aid in detecting minimal residual disease in colon cancer following curative resection. This study aimed to identify the potential role of serum CEA following liver resection in patients with CLM. METHODS: This retrospective study was conducted at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from 2004 to 2018 and enrolled patients with CLM who underwent complete resection of primary tumors and CLM. Associations between perioperative CEA levels and characteristics of recurrence were investigated. RESULTS: Recurrence was detected during a median follow-up period of 90.1 months in 343 (54.2%) out of 633 analyzed patients. Patients in the postoperative CEA level > 5 ng/ml group had a significantly higher recurrence rate (75.7% versus 50.0%, p < 0.01) and shorter time until recurrence (4.4 versus 36.9 months, p < 0.01) than those in the postoperative CEA level ≤ 5 ng/ml group. Multivariate analysis revealed that postoperative CEA level > 5 ng/ml was an independent predictor, with hazard ratios of 2.77 (p < 0.01) for recurrence-free survival (RFS) and 3.18 (p < 0.01) for overall survival (OS). Additionally, RFS was significantly shorter among patients in the postoperative CEA level > 5 ng/ml group who did not have normalized CEA levels following adjuvant chemotherapy than among those in the normalized CEA group. CONCLUSIONS: The postoperative and post-adjuvant chemotherapy CEA levels in the CEA level > 5 ng/ml group may be predictors of RFS and OS.

Supraspinatus tendon thickness and subacromial impingement characteristics in younger and older adults.

BACKGROUND: Subacromial impingement (SAI) may be a cause of age-related rotator cuff abnormalities; therefore, the purpose of this study was to compare SAI characteristics between younger and older adults. In addition to the fact that thickened supraspinatus tendon (SST) indicates tendon abnormalities, SAI characteristics have been recognized as follows: greater SST thickness, reduced acromiohumeral distance (AHD), greater reduction of AHD (∆AHD) with arm elevation, and a higher percentage of SST within AHD (i.e., occupation ratio: OcAHD). Furthermore, we investigated the relationships between SST thickness and AHD, as well as SST thickness and ∆AHD to clarify the effect of SAI on rotator cuff abnormalities. METHODS: Healthy younger (n = 18, 21-24-year-old) and older (n = 27, 45-80-year-old) adults without any shoulder symptoms participated in this study. We measured their SST thickness and AHD at rest and at arm elevation (30° and 60°) in the scapular plane using ultrasound, and calculated ∆AHD as the relative change expressed as a percentage of the baseline. OcAHD was expressed as the ratio of SST thickness at rest to AHD at rest and in elevated positions. RESULTS: The older subjects had approximately one mm thicker SST (P = 0.003, 95% Confidence interval [CI] = 0.410 to 1.895) and approximately 1.0 to 1.3 mm greater AHD than the younger subjects (P = 0.011, 95%CI = 0.284 to 2.068 at rest; P = 0.037, 95%CI = 0.082 to 2.609 for 30° of arm elevation; P = 0.032, 95%CI = 0.120 to 2.458 for 60° of arm elevation). However, there were no differences in ΔAHD and OcAHD between the groups. CONCLUSION: This study demonstrated that, compared with the younger subjects, the older subjects showed thicker supraspinatus tendon but no other SAI characteristics including decreases in AHD and increases in OcAHD. Thus, this study suggests that older subjects showed age-related SST abnormalities without SAI, although the magnitude of the differences in SST thickness is notably small and the clinical significance of this difference is unclear.

Anterior glenohumeral capsular ligament reconstruction with hamstring autograft for internal impingement with anterior instability of the shoulder in baseball players: preliminary surgical outcomes.

BACKGROUND: Shoulder pain and dysfunction are common in baseball players, and although "internal impingement" is recognized as one of the most common pathologies of shoulder dysfunction, the optimal surgical treatment for internal impingement with anterior instability of the shoulder remains controversial. This study evaluated baseball players' preliminary outcomes following anterior glenohumeral capsular ligament reconstruction for internal impingement with anterior instability of the shoulder. METHODS: Twelve baseball players (all male; mean age, 20.5 ± 2.2 years) with internal impingement and anterior instability managed via anterior glenohumeral capsular ligament reconstruction were examined. The mean follow-up period was 25.3 ± 4.6 months. Anterior glenohumeral capsular ligament reconstruction was performed with a knee hamstring autograft for balanced stability and laxity with two major targets: to prevent hyperangulation and translation in horizontal abduction and to mimic the individual arm cocking position at the final decision of tension. Preoperative and final follow-up evaluations were performed using Jobe's postoperative grading system; the Kerlan-Jobe Orthopaedic Clinic Overhead Athletes Shoulder and Elbow Score; Disabilities of the Arm, Shoulder and Hand sports module; plain radiographs; and magnetic resonance imaging. RESULTS: Jobe's postoperative grading system score, the Kerlan-Jobe Orthopaedic Clinic Overhead Athletes Shoulder and Elbow Score, and the Disabilities of the Arm, Shoulder and Hand sports module score improved significantly from 20.4 ± 12.2, 28.4 ± 8.3, and 80.2 ± 11.1 points preoperatively to 88.8 ± 13.6, 80.8 ± 7.7, and 22.4 ± 18.7 points postoperatively, respectively (P < .001, .0025, <0.001, respectively). Both clinical and imaging evaluations revealed improved internal impingement with anterior instability after anterior glenohumeral capsular ligament reconstruction. The mean external rotation at abduction significantly decreased from 113° preoperatively to 104° postoperatively. At follow-up, 10 of the 12 athletes (83.3%) returned to their prior competitive level. Plain radiographs and magnetic resonance imaging revealed no obvious loosening of the graft or screws. CONCLUSIONS: Anterior glenohumeral capsular ligament reconstruction resulted in preferable clinical outcomes for young baseball players who experienced pain during the throwing motion. Stabilization of the glenohumeral joint with autografting of the knee hamstring may thus represent a solution for internal impingement with anterior instability in overhead throwing athletes.

Effect of Concomitant Lafutidine on Adjuvant S-1 for Head and Neck Cancer: A Comparative Study.

BACKGROUND/AIM: This study evaluated the utility of the histamine H2-receptor antagonist lafutidine in patients taking oral fluorouracil (S-1) for head and neck squamous cell carcinoma (HNSCC), by comparing patients with and without concomitant lafutidine. PATIENTS AND METHODS: Study subjects comprised 63 patients who received adjuvant S-1 following curative resection of HNSCC at our institutions between August 1, 2013 and December 31, 2019. The primary endpoint was the completion rate of S-1 therapy. RESULTS: For the lafutidine-treated group, the median completion rate was significantly greater (94.4% vs. 24.6%, p=0.01), and progression-free and overall survival were both significantly prolonged compared to the non-lafutidine group. In terms of adverse events, the incidence of diarrhoea was significantly reduced (p<0.00189) in the lafutidine-treated group. CONCLUSION: Taking lafutidine during S-1 treatment appeared to reduce gastrointestinal disturbance and increased the S-1 completion rate, improving both progression-free and overall survival as a result.

Effect of neutropenia on survival outcomes of patients with metastatic colorectal cancer receiving trifluridine/tipiracil plus bevacizumab.

Trifluridine (FTD)/tipiracil (TPI) plus bevacizumab (Bev) is a promising late-line treatment in metastatic colorectal cancer (mCRC). Although chemotherapy-induced neutropenia (CIN) is a well-known predictor of FTD/TPI efficacy, whether CIN is a predictive marker of efficacy for FTD/TPI + Bev remains unclear. Thus, the present study aimed to investigate the clinical outcomes of FTD/TPI + Bev and the predictive markers of its efficacy. Clinical data of patients with mCRC who received FTD/TPI + Bev at the Cancer Institute Hospital between January 2017 and August 2020 were retrospectively collected. Disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety were assessed. In addition, subgroup analyses of prognostic and predictive efficacy markers were performed. In total, 94 patients (median age, 60.0 years; age range, 32-82 years; 37 men and 57 women) were included in the present study. The DCR was 44.7%, the median PFS time was 2.9 months (2.3-4.1 months) and the median OS time was 10.0 months (7.3-11.1 months). Grade 3 or 4 CIN within the first cycle of treatment occurred in 27.7% of patients, which was significantly associated with a longer PFS time than those who did not develop CIN [3.8 months (2.3-8.4 months) vs. 2.7 months (1.8-4.0 months); P=0.008]. Furthermore, the DCR was higher in patients with grade 3 or 4 CIN within the first cycle of treatment than those without CIN (61.5 vs. 38.2%; P=0.07). Multivariate Cox regression analysis revealed that grade 3 or 4 CIN within the first cycle of treatment are independent predictors for a longer PFS time (P=0.01). Taken together, the results of the present study suggest that grade 3 or 4 CIN within the first cycle of treatment are early predictors of the efficacy of FTD/TPI + Bev.

[Malignant Spinal Cord Compression].

Malignant spinal cord compression(MSCC)is defined as a compression of the spinal cord or cauda equina with neuropathy caused by tumor spreading to the vertebral body. The common symptoms of MSCC are back pain, neck pain, muscle weakness, sensory reduction, bladder and rectal disturbance. The risk of MSCC is relatively high in patients with lung cancer, breast cancer, and prostate cancer. MSCC is one of the oncologic emergencies that requires prompt diagnosis and treatment to preserve and improve neurological function. Evaluation by magnetic resonance imaging(MRI)and computed tomography( CT)are useful for the diagnosis. The prognosis of these patients is often poor at the time of diagnosis of MSCC, thus it is important for deciding the treatment strategy to consider the prognosis and background of the patient in addition to the objective findings including the degree of MSCC and spinal instability. Treatment options consist of medical, surgical, and radiation therapy. We need a multidisciplinary approach because the pathology of MSCC involves multiple departments, such as medical oncology, orthopedics, and radiology. Supportive care including rehabilitation and preventing skeletal related events are also important. The cancer board, in which each physician and multidisciplinary health care professionals regularly have a discussion and review the cases, is required.

High frequencies and co-existing of myositis-specific autoantibodies in patients with idiopathic inflammatory myopathies overlapped to rheumatoid arthritis.

A small proportion of patients with rheumatoid arthritis (RA) develop idiopathic inflammatory myopathies (IIM); however, the clinical and immunological characteristics of these patients have not been elucidated. In the present study, we evaluate the frequency of autoantibodies and the accompanying clinical features in patients with IIM overlapped to RA (IIM-RA) and in patients with IIM without RA. Twelve patients with IIM-RA were selected from 142 patients with IIM who were admitted to our hospital. Clinical and laboratory data, including autoantibody test results, were collected from patient medical records. Myositis-specific antibodies (MSAs) were analyzed by immunoprecipitation. Clinically, patients with IIM-RA were more likely to be male, to have polymyositis, and to be older at the time of IIM onset than patients with IIM without RA. Patients with IIM-RA had been treated for 2-25 years prior to the onset of IIM with more than two disease-modifying antirheumatic drugs (DMARDs). Patients with IIM-RA had a high frequency (75.0%) of positivity for MSAs, including anti-Jo-1, anti-PL-7, anti-PL-12, or anti-signal recognition particle (SRP) antibodies; anti-Jo-1 antibody was detected in 4 patients (33.3%). In addition, 2 out of 12 patients with IIM-RA were concurrently positive for two different MSAs, anti-Jo-1, and anti-PL-7 antibodies. In 3 other patients with IIM-RA, anti-Jo-1 antibody, or anti-PL-7 antibody was detected in serum samples collected 6-18 months prior to development of myositis. High frequency and coexistence of MSAs were detected in patients with IIM-RA. MSAs detected in patients with RA even without symptoms of myositis may indicate possible future development of myositis.

CB-12181, a new azasugar-based matrix metalloproteinase/tumor necrosis factor-alpha converting enzyme inhibitor, inhibits vascular endothelial growth factor-induced angiogenesis in vitro and retinal neovascularization in vivo.

To evaluate the anti-angiogenic efficacy of CB-12181 [an azasugar derivative that has inhibitory actions against matrix metalloproteinases (MMPs) and tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE)], we investigated the suppressing ability on in vitro (tube formation by endothelial cells) and in vivo (retinal neovascularization on murine ischemia-induced proliferative retinopathy) models of angiogenesis. For in vitro analysis, a capillary-like tube formation model using human umbilical vein endothelial cells (HUVECs) and fibroblasts co-culture assay was employed. Tube formation of HUVECs was stimulated by vascular endothelial growth factor (VEGF) and incubated with different concentrations of CB-12181 (0.1-100 microM) for 11 days. For in vivo analysis, mice were exposed to 75% oxygen between postnatal days 7 and 12 (P7 to P12). Then, the mice were removed from the oxygen treatment and treated with CB-12181 (1, 15, or 50 mg/kg) by daily subcutaneous injection from the time of reintroduction to room air at P12 until P16. At P17, pathological and physiological angiogenesis was quantified using retinal flat-mounts visualized by fluorescent angiography. In the in vitro angiogenesis model, CB-12181 significantly suppressed VEGF-induced HUVEC tube formation. Furthermore, in the in vivo angiogenesis model, administration of CB-12181 significantly suppressed retinal neovascularization without any apparent side effects on physiological revascularization to the oxygen-induced obliteration area. These results suggest that CB-12181 might be useful in the treatment of various diseases that depend on pathologic angiogenesis, and especially valuable for the treatment of diabetic retinopathy and retinopathy of prematurity.

Acute destruction of the hip joints and rapid resorption of femoral head in patients with rheumatoid arthritis.

We report three rheumatoid arthritis (RA) cases with acute destruction of hip joint and rapid resorption of femoral head. The condition occurred in less than 6 months and closely resembled rapid destructive coxarthrosis. All three patients were postmenopausal women with active RA who had been taking steroids. Two of the patients were taking prednisolone (PSL) of over 20 mg as maximum dose per day, and all patients were resistant to disease-modifying anti-rheumatic drugs (DMARDs). Other than the problems of their hip joints, one had a giant bursitis around the pathological side of the hip joint, another had multiple rheumatoid nodules and skin infarction, and the other suffered from insufficiency fracture of the contralateral femoral subcapital lesion. As a result, all of them had total hip arthroplasty. We recommend taking repetitive radiographs for RA patients with continuing severe hip pain.

ADAM binding protein Eve-1 is required for ectodomain shedding of epidermal growth factor receptor ligands.

A disintegrin and metalloproteases (ADAMs) are implicated in the ectodomain shedding of epidermal growth factor receptor (EGFR) ligands in EGFR transactivation. However, the activation mechanisms of ADAMs remain elusive. To analyze the regulatory mechanisms of ADAM activation, we performed yeast two-hybrid screening using the cytoplasmic domain of ADAM12 as bait, and identified a protein that we designated Eve-1. Two cDNAs were cloned and characterized. They encode alternatively spliced isoforms of Eve-1, called Eve-1a and Eve-1b, that have four and five tandem Src homology 3 (SH3) domains in the carboxyl-terminal region, respectively, and seven proline-rich SH3 domain binding motifs in the amino-terminal region. The short forms of Eve-1, Eve-1c and Eve-1d, translated at Met-371 are human counterparts of mouse Sh3d19. Northern blot analysis demonstrated that Eve-1 is abundantly expressed in skeletal muscle and heart. Western blot analysis revealed the dominant production of Eve-1c in human cancer cell lines. Knockdown of Eve-1 by small interfering RNA in HT1080 cells reduced the shedding of proHB-EGF induced by angiotensin II and 12-O-tetradecanoylphorbol-13-acetate, as well as the shedding of pro-transforming growth factor-alpha, promphiregulin, and proepiregulin by 12-O-tetradecanoylphorbol-13-acetate, suggesting that Eve-1 plays a role in positively regulating the activity of ADAMs in the signaling of EGFR-ligand shedding.