Different prognostic effect of lymph node metastasis between remnant gastric cancers and primary proximal gastric cancers.

BACKGROUND: Although the dissected lymph node number in remnant gastric cancer (RGC) may be smaller than in primary proximal gastric cancer (PGC), altered lymphatic flow provides different metastatic patterns in lymph nodes, which could potentially give rise to prognostic differences between RGC and PGC with nodal metastasis. METHODS: Between 1993 and 2020, 2546 consecutive patients with gastric cancer underwent gastrectomy. Of these, 53 RGC and 381 PGC patients with pStage I-III gastric cancer underwent curative gastrectomy. We reviewed their hospital records retrospectively. RESULTS: The number of dissected lymph nodes was significantly smaller in RGC patients than in PGC patients (P < 0.001: RGC: 13.0 vs. PGC: 34.5). Although the five-year overall survival (OS) rate did not differ between RGC and PGC in all patients, the prognosis in each pN stage of RGC was worse compared with that of PGC, suggesting that each lymph node metastasis has a greater prognostic effect in RGC. Specifically, even with pN1 (20.0%) or pN2 (40.0%) RGC patients, their five-year OS rates were poor and similar to those of pN3 PGC patients (35.7%). The presence of lymph node metastasis in RGC (HR: 4.41, 95% CI: 1.02-18.9, P = 0.045) was an independent and a similar prognostic impact in pN3 PGC (HR: 2.82, 95% CI: 1.57-5.07, P < 0.001). Lymph node metastasis in RGC more strongly affected peritoneal or lymph node recurrence rather than hematogenous recurrence. CONCLUSION: The presence of lymph node metastasis yielded a poorer prognosis in RGC patients compared with primary PGC patients. RGC patients with lymph node metastasis should be specifically targeted in an effort to improve their prognosis.

[Surgical Outcomes of Colorectal Cancer for Over 90-Year-Old Patients in Our Hospital].

The aim of this study was to investigate the short-term outcomes of surgery for colorectal cancer(CRC)in the elderly aged over 90 years old. We retrospectively analyzed 1,043 patients with stage Ⅰ-Ⅳ CRC who underwent curative surgery in our institutions between 2013 and 2022. The patients were divided into the super older(aged ≥90 years, 20 patients) and non-super older groups(aged 80-89 years, 243 patients). The short-term outcomes were compared between the 2 groups. There were no significant differences in tumor location, stage, surgical approach, duration of operation and blood loss. The incidence of severe postoperative complications did not differ between the 2 groups. In conclusion, our study suggested that surgery for colorectal cancer could be as safely performed in super elderly patients as in non-super elderly patients.

Impact of severe postoperative complications on the prognosis of older patients with colorectal cancer: a two-center retrospective study.

BACKGROUND: The occurrence of postoperative complications may affect short-term outcomes and prognosis of patients with various malignancies. However, the prognostic impact of these complications in older patients with colorectal cancer (CRC) remains unclear. Therefore, this study aimed to investigate the impact of severe postoperative complications on the oncological outcomes of older (aged ≥ 80 years) and non-older (aged < 80 years) patients with CRC. METHODS: We retrospectively analyzed 760 patients with stage I-III CRC who underwent curative surgery in two institutions between 2013 and 2019. The patients were categorized into older (aged ≥ 80 years, 191 patients) and non-older (aged < 80 years, 569 patients) groups. Short- and long-term outcomes were compared between the two groups. RESULTS: The incidence of severe postoperative complications did not differ between the two groups (p = 0.981). Cancer-specific survival (CSS) was significantly worse in older patients with severe complications than in those without severe complications (p = 0.007); meanwhile, CSS did not differ between the non-older patients with severe complications and those without severe complications. Survival analysis revealed that the occurrence of severe postoperative complications was an independent prognostic factor for CSS in older patients (hazard ratio = 4.00, 95% confidence interval: 1.27-12.6, p = 0.017). CONCLUSION: CRC surgery can be safely performed in older and non-older patients. Moreover, the occurrence of severe postoperative complications might more strongly affect the prognosis of older patients than that of non-older patients.

[Laparoscopic Surgery for Delayed Chylous Ascites in Unresectable Gastric Cancer Patient-A Case Report].

Chylous ascites is a rare post operative complication after gastrectomy, which commonly occurs in early postoperative period. Here, we successfully treated a patient with unresectable gastric cancer who occurred chylous ascites 9 months after first surgery and underwent laparoscopic surgery for chylous ascites. Since prolonged chylous ascites may cause malnutrition, surgical treatment should be considered for refractory chylous ascites.

Mathematical-based morphological classification of skin eruptions corresponding to the pathophysiological state of chronic spontaneous urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) is one of the most intractable human-specific skin diseases. However, as no experimental animal model exists, the mechanism underlying disease pathogenesis in vivo remains unclear, making the establishment of a curative treatment challenging. METHODS: A novel approach combining mathematical modelling, in vitro experiments and clinical data analysis was used to infer the pathological state of CSU patients from geometric features of the skin eruptions. RESULTS: Based on our hierarchical mathematical modelling, the eruptions of CSU were classified into five categories, each with distinct histamine, basophils, mast cells and coagulation factors network signatures. The analysis of 105 real CSU patients with this classification by six individual dermatologists achieved 87.6% agreement. Furthermore, our network analysis revealed that the coagulation status likely determines boundary/area pattern of wheals, while the state of spontaneous histamine release from mast cells may contribute to the divergence of size and outline of the eruptions. CONCLUSIONS: Our multi-faceted approach was accurate in defining pathophysiological states of disease based on geometric features offering the potential to improve the accuracy of CSU diagnosis and better management of the disease in the clinic.

Chronic spontaneous urticaria (CSU) is a persistent skin disease that causes red itchy skin eruptions, called wheals, that are of various shapes. These wheals repeatedly appear and disappear daily for up to weeks or even decades, severely impacting the quality of life of those affected. The causes, consequences or disease processes are largely understudied. Here, we developed a novel approach using mathematical modelling to analyse the geometric measurements of patients' wheals alongside laboratory experiments on human skin samples with eruptions to improve CSU diagnosis and clinical management. We find that geometric measurements of these skin eruptions can be classified into five categories, which could facilitate accurate diagnosis and consequently better clinical management of CSU and may be more widely applied to other skin diseases.

Laparoscopic Surgery for Elderly Colorectal Cancer Patients With High American Society of Anesthesiologists Scores.

BACKGROUND/AIM: To evaluate the safety of colorectomy in elderly colorectal cancer patients with high American Society of Anesthesiologists (ASA) scores compared to those with low scores. PATIENTS AND METHODS: Two hundred patients with stage I-IV colorectal cancer aged ≥80 years were retrospectively analyzed. Short- and long-term outcomes were compared between 136 patients with ASA scores ≤2 (low ASA group) and 64 patients with scores ≥3 (high ASA group). RESULTS: The incidence of postoperative complications, duration of postoperative hospital stay, and 5-year overall and cancer-specific survival rates did not differ significantly between the groups. Laparoscopic surgery was significantly associated with a lower incidence of postoperative complications than open surgery in the high ASA score group (p=0.041), whereas no difference was observed in the low ASA score group (p=0.639). In the high ASA group, open surgery (p=0.024) and higher body mass index (p=0.040) were independent risk factors for postoperative complications. CONCLUSION: Colorectal cancer resection can be safely performed in elderly patients with high ASA scores. Moreover, laparoscopic surgery may have a stronger contribution to the reduction of postoperative complications in elderly patients with colorectal cancer with high ASA scores than in those with low ASA scores.

Time Course of Priming Effect of TF Inducers on Synergistic TF Expression and Intra-Cellular Gap Formation of Human Vascular Endothelial Cells via the Extrinsic Coagulation Cascade.

Chronic spontaneous urticaria (CSU) is characterized by daily recurring wheal and flare with itch for more than 6 weeks. The extrinsic coagulation system has been shown to be activated in correlation with CSU severity. We have reported that tissue factor (TF), a trigger of the extrinsic coagulation cascade, is synergistically expressed on vascular endothelial cells by simultaneous stimulation with TF inducers (TFI), followed by activation of the extrinsic coagulation cascade and hyper permeability in vitro. However, vascular endothelial cells are not likely to be simultaneously stimulated by multiple TFIs under physiological conditions. Therefore, in order to know whether sequential, rather than simultaneous, stimuli with interval may induce synergistic activation of TF, we investigated the time course of the priming effects of each TFI for synergistic TF expression in vascular endothelial cells (HUVECs). We stimulated HUVECs with a TFI (first stimulation) and then stimulated cells with another TFI at indicated time points (second stimulation) and detected TF expression and activity. The TF expression induced by simultaneous stimulation diminished in a few hours. However, both synergistic enhancement of TF expression and activation level of the coagulation cascade were detected even when the second stimulation was added 18 or 22 h after the first stimulation. Thus, the priming effect of TFI for synergistic TF expression may persist for a half day or longer.

Basophil Characteristics as a Marker of the Pathogenesis of Chronic Spontaneous Urticaria in Relation to the Coagulation and Complement Systems.

Chronic spontaneous urticaria (CSU) is a common skin disorder characterized by daily or almost daily recurring skin edema and flare with itch and pruritus anywhere on the body for more than 6 weeks. Although basophil- and mast cell-released inflammatory mediators, such as histamine, play important roles in the pathogenesis of CSU, the detailed underlying mechanism is not clear. Since several auto-antibodies, IgGs which recognize IgE or the high-affinity IgE receptor (FcεRI) and IgEs against other self-antigens, are detected in CSU patients, they are considered to activate both mast cells in the skin and basophils circulating in the blood. In addition, we and other groups demonstrated that the coagulation and complement system also contribute to the development of urticaria. Here, we summarized the behaviors, markers and targets of basophils in relation to the coagulation-complement system, and for the treatment of CSU.

Basophils activation of patients with chronic spontaneous urticaria in response to C5a despite failure to respond to IgE-mediated stimuli.

Urticaria is characterized by the occurrence of wheals and flares in response to vasoactive mediators, such as histamine. Various studies have suggested the involvement of basophils in the pathogenesis of chronic spontaneous urticaria (CSU). However, histamine release from peripheral basophils in response to stimuli acting on the high affinity IgE receptor (FcϵRI) is impaired in many patients with CSU (non/low responders). We previously demonstrated that tissue factor (TF)s expressed on vascular endothelial cells in response to a combination of various stimuli, such as that of histamine and lipopolysaccharide (LPS), activates the extrinsic coagulation pathway and produces anaphylatoxin, complement 5a (C5a), which then activates basophils and mast cells via the C5a receptor (C5aR). We have revealed that histamine release was induced in response to C5a and formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP), regardless of the response to anti-IgE antibody, the reduced numbers of basophils and severity of urticaria. Moreover, we found that spontaneous release of histamine ex vivo from basophils of patients with CSU is higher than that from healthy individuals. These results suggest that basophils and the complement system, which could be activated by coagulation factors, may play a critical role in the pathogenesis of CSU, especially in cases refractory to treatment involving the IgE/FcϵRI pathway.

C-H▪▪▪S Hydrogen Bonds in Ampicillin and Amoxicillin Crystals Investigated by Sulfur K-Edge X-Ray Absorption Near-Edge Structure Spectroscopy and Single-Crystal X-Ray Structure Analysis.

Sulfur K-edge X-ray absorption near-edge structure (XANES) spectroscopy was evaluated for its ability to detect non-conventional C-H▪▪▪S hydrogen bonds in crystals of the sulfur-containing penam antibiotics ampicillin and amoxicillin. The XANES spectra of the nearly isomorphous crystals of ampicillin trihydrate and amoxicillin trihydrate were very similar, whereas that of ampicillin anhydrate displayed unique features. Single-crystal X-ray structure analyses revealed that the C-H▪▪▪S hydrogen bond geometries and the chemical types of the hydrogen donors differed between the isomorphous trihydrate crystals and ampicillin anhydrate crystal. These observations demonstrate that the shapes of the sulfur K-edge XANES spectra are dependent on the nature of the C-H▪▪▪S hydrogen bonds. Sulfur K-edge XANES spectroscopy shows promise for use in the detection and analysis of non-covalent interactions, including hydrogen bonds to sulfur atoms, within active pharmaceutical ingredients.

[A Case of Pembrolizumab Therapy Markedly Effective for Advanced Recurrent Colorectal Cancer].

We report a case of pembrolizumab therapy as the fourth-line therapy for colorectal cancer and multiple lymph node recurrence with high-frequency microsatellite instability(MSI-High). The patient was a 75-year-old woman diagnosed with ascending colon cancer(pT4aN2bM0, Stage Ⅲc)and underwent laparoscopic right hemicolectomy, D3 dissection, and functional end-to-end anastomosis after inserting a self-expandable metallic stent. Postoperative adjuvant chemotherapy was performed, and the patient was followed. Postoperative 1 year 8 months, lymph node recurrence was indicated, and FOLFOX plus panitumumab therapy was introduced. FOLFIRI plus ramucirumab therapy and FTD/TPI were introduced as the second-line and third-line treatments, respectively; however, recurrent lymph nodes were further exacerbated and showed treatment resistance. Lymph node biopsy confirmed MSI-High, and pembrolizumab therapy was initiated as the fourth-line treatment. After the therapy, the lymph nodes reduced markedly. The patient remains undergoing chemotherapy without any adverse events.

[Patient with Epstein-Barr Virus-Positive Esophagogastric Junctional Cancer with Splenic Metastasis and Underwent Metastasectomy following Immune Checkpoint Therapy].

Recurrent gastric cancer(GC)with splenic metastasis showed poor prognosis, and its treatment strategy remains unclear. Recently, studies identified the considerable prognostic effect of metastasectomy in GC following intensive chemotherapy. Here, we successfully treated a patient with Epstein-Barr virus-positive esophagogastric junctional cancer with splenic metastasis who underwent metastasectomy and obtained pathological complete response following immune checkpoint therapy and had long-term survival. We reviewed the literature to discuss the clinical significance of our treatment strategy.

Continuous Recurrent Laryngeal Nerve Monitoring During Single-Port Mediastinoscopic Radical Esophagectomy for Esophageal Cancer.

BACKGROUND: Although single-port mediastinoscopic radical esophagectomy is ultimate minimally invasive surgery for esophageal cancer without thoracotomy or the thoracoscopic approach, the high incidence of recurrent laryngeal nerve (RLN) palsy remains a pivotal clinical issue. METHODS: This study included 41 patients who underwent single-port mediastinoscopic radical esophagectomy with mediastinal lymphadenectomy between September 2014 and March 2022. Among these, continuous nerve monitoring (CNM) for RLN was done in 25 patients (CNM group), while the remaining 16 patients underwent without CNM (non-CNM group). Clinical benefits of CNM for RLN were evaluated. RESULTS: The overall incidence of postoperative RLN palsy was 14.6% (6/41). The CNM group showed a significantly lower incidence of postoperative RLN palsy as compared to the non-CNM group (P = 0.026: CNM vs. non-CRNM: 4.0% (1/25) vs. 31.2% (5/16)). The CNM group had a lower incidence of postoperative pneumoniae (CNM vs. non-CNM: 4.0% (1/25) vs. 18.8% (3/16)) and shorter days of postoperative hospital stay (CNM vs. non-CNM: 13 days vs. 41 days). Multivariate analysis revealed that the CNM use (odds ratio 0.07; 95% CI 0.05-0.98) was an independent factor avoiding postoperative RLN palsy. CONCLUSION: The CNM for RLN contributes to a remarkable reduction in the risk of postoperative RLN palsy and improvement in outcomes in single-port mediastinoscopic radical esophagectomy.

Night home enteral nutrition as a novel enforced and physiologically effective nutrition therapy following total gastrectomy for gastric cancer.

Enteral nutrition has been reported to be safe and effective in malnourished patients undergoing upper gastrointestinal surgery. In this study, we devised night home enteral nutrition (N-HEN) as a novel nutritional strategy and evaluated the efficacy in gastric cancer patients following total gastrectomy. Between January 2017 and March 2021, 24 patients were prospectively included in the protocol and supported by N-HEN for three postoperative months through a jejunostomy during the night (Elental:1200 kcal/day), and 22 patients without N-HEN were followed as a control group (CG). Body weight loss, nutritional indicators and tolerance to chemotherapy were evaluated. After 3 and 6 months, patients with N-HEN had significantly less body weight loss than CG (3 months P < 0.0001: N-HEN 4.0% vs. CG 15.2%, 6 months P < 0.0001: N-HEN 7.7% vs. CG 17.7%). Prealbumin was significantly higher in patients with N-HEN than CG after 3 and 6 months (3 months P < 0.0001, 6 months P = 0.0037). Albumin, total protein and hemoglobin, tended to be higher after 3 and 6 months in patients with N-HEN than CG, and total cholesterol after 6 months. Concerning the tolerance to adjuvant chemotherapy in Stage II-III patients, patients with N-HEN significantly had a higher completion rate (P = 0.0420: N-HEN 70% vs. CG 29%) and longer duration (P = 0.0313: N-HEN 458 days vs. CG 261 days) as planned. Continuous monitoring of blood glucose concentration in patients with N-HEN did not show nocturnal hypoglycemia or hyperglycemia. N-HEN could be a novel enforced and physiologically effective nutritional strategy to support potentially malnourished patients following total gastrectomy.

Modified Protein-Water Interactions in CHARMM36m for Thermodynamics and Kinetics of Proteins in Dilute and Crowded Solutions.

Proper balance between protein-protein and protein-water interactions is vital for atomistic molecular dynamics (MD) simulations of globular proteins as well as intrinsically disordered proteins (IDPs). The overestimation of protein-protein interactions tends to make IDPs more compact than those in experiments. Likewise, multiple proteins in crowded solutions are aggregated with each other too strongly. To optimize the balance, Lennard-Jones (LJ) interactions between protein and water are often increased about 10% (with a scaling parameter, λ = 1.1) from the existing force fields. Here, we explore the optimal scaling parameter of protein-water LJ interactions for CHARMM36m in conjunction with the modified TIP3P water model, by performing enhanced sampling MD simulations of several peptides in dilute solutions and conventional MD simulations of globular proteins in dilute and crowded solutions. In our simulations, 10% increase of protein-water LJ interaction for the CHARMM36m cannot maintain stability of a small helical peptide, (AAQAA)3 in a dilute solution and only a small modification of protein-water LJ interaction up to the 3% increase (λ = 1.03) is allowed. The modified protein-water interactions are applicable to other peptides and globular proteins in dilute solutions without changing thermodynamic properties from the original CHARMM36m. However, it has a great impact on the diffusive properties of proteins in crowded solutions, avoiding the formation of too sticky protein-protein interactions.

Role of Extracellular High-Mobility Group Box-1 as a Therapeutic Target of Gastric Cancer.

Background: High-mobility group box-1 (HMGB1) is involved in the tumorigenesis and metastasis of various cancers. The present study investigated the roles of extracellular HMGB1 in the progression of gastric cancer (GC) and the therapeutic effects of recombinant human soluble thrombomodulin (rTM) targeting HMGB1. Methods: The effects of extracellular HMGB1 and rTM on GC cells were assessed using proliferation and Transwell assays. Their effects on local tumor growth and metastasis were evaluated using subcutaneous tumor and liver metastasis mouse models, respectively. Plasma HMGB1 concentrations in GC patients were measured using ELISA. The relationships between plasma HMGB1 concentrations and the prognosis and clinicopathological factors of patients were also investigated. Results: GC proliferation, migration, and invasion abilities were promoted by increases in extracellular HMGB1 concentrations and alleviated by rTM. In the subcutaneous tumor model, local tumor growth was promoted by the addition of rhHMGB1 and alleviated by rTM. Similar changes occurred in the liver metastasis model. Recurrence-free survival (p < 0.01) and overall survival (p = 0.01) were significantly worse in patients with high plasma HMGB1 concentrations. Conclusion: Plasma HMGB1 concentrations are a prognostic marker in GC patients. Extracellular HMGB1 promotes cancer progression and has potential as a novel treatment target in GC cells for rTM.

Clinical course of more than 10 years in a patient with extensive skin burns who received cultured epidermal autograft transplantation.

Cultured epidermal autografts (CEAs) are used to treat extensive burns, giant congenital melanocytic nevi, and epidermolysis bullosa, but information about the long-term clinical course after CEA transplantation is scarce. Here we report 10 years' progress of a 7-year-old Japanese girl who suffered from a scald burn injury affecting 80% of her total body surface area and was treated with CEA transplantation. The skin of a child with extensive burns treated with CEAs appeared soft and of a good texture, even after 10 years, and recovery of skin pigmentation and scar condition were better at sites with a combination of CEAs and autologous skin grafts than those with CEAs alone.

[Novel Treatment Strategy Using Trafermin® Consisting of bFGF for Intractable Pancreatic Fistula-A Case Report].

Pancreatic fistula is one of the most critical complication following distal pancreatectomy. We report here a successfully treated case with intractable pancreatic fistula using Trafermin® consisting of basic fibroblast growth factor(bFGF). A 60- year-old man underwent laparoscopic distal pancreatectomy. After surgery, pancreatic fistula was occurred. Pancreatic fistula persisted for 3 months despite of several conservative treatments. After obtaining informed consent, we started to inject 50µg/day of Trafermin® through a drainage tube into the dehiscence of pancreas. Consequently, pancreatic fistula was successfully closed within a week. This technique could be one of the treatment choices for intractable pancreatic fistula following distal pancreatectomy.