Pre-clinical evaluation of the efficacy and safety of human induced pluripotent stem cell-derived cardiomyocyte patch.

BACKGROUND: Cell- or tissue-based regenerative therapy is an attractive approach to treat heart failure. A tissue patch that can safely and effectively repair damaged heart muscle would greatly improve outcomes for patients with heart failure. In this study, we conducted a preclinical proof-of-concept analysis of the efficacy and safety of clinical-grade human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) patches. METHODS: A clinical-grade hiPSC line was established using peripheral blood mononuclear cells from a healthy volunteer that was homozygous for human leukocyte antigens. The hiPSCs were differentiated into cardiomyocytes. The obtained hiPSC-CMs were cultured on temperature-responsive culture dishes for patch fabrication. The cellular characteristics, safety, and efficacy of hiPSCs, hiPSC-CMs, and hiPSC-CM patches were analyzed. RESULTS: The hiPSC-CMs expressed cardiomyocyte-specific genes and proteins, and electrophysiological analyses revealed that hiPSC-CMs exhibit similar properties to human primary myocardial cells. In vitro and in vivo safety studies indicated that tumorigenic cells were absent. Moreover, whole-genome and exome sequencing revealed no genomic mutations. General toxicity tests also showed no adverse events posttransplantation. A porcine model of myocardial infarction demonstrated significantly improved cardiac function and angiogenesis in response to cytokine secretion from hiPSC-CM patches. No lethal arrhythmias were observed. CONCLUSIONS: hiPSC-CM patches are promising for future translational research and may have clinical application potential for the treatment of heart failure.

Axillary Reverse Mapping in Clinically Node-Positive Breast Cancer Patients.

BACKGROUND: Axillary reverse mapping (ARM) nodes are involved in a significant proportion of clinically node-positive (cN+) breast cancer patients. However, neoadjuvant chemotherapy (NAC) is effective at decreasing the incidence of nodal metastases in cN+ patients. PATIENTS AND METHODS: One hundred forty-five cN+ patients with confirmed nodal involvement on ultrasound-guided fine needle aspiration cytology were enrolled in this study: one group underwent axillary lymph node dissection (ALND) without NAC (upfront surgery group), and the other group underwent ALND following NAC (NAC group). The patients underwent 18F-FDG-positron emission tomography/computed tomography (18F-FDG-PET/CT) before surgery, as well as an ARM procedure during ALND. RESULTS: the rates of involvement of ARM nodes in the NAC group were significantly lower than those of the upfront surgery group (36.6% vs. 62.2%, p < 0.01). Notably, involvement was significantly decreased after NAC in non-luminal-type tumors as compared to the luminal-type (18.4% vs. 48.5%: p < 0.01). Moreover, there was a significant difference in ARM node involvement after NAC between patients with or without axillary uptake of 18F-FDG (61.5% vs. 32.5%: p < 0.01). CONCLUSIONS: NAC significantly decreased the risk of ARM node metastases in cN+ patients, but 18F-FDG-PET/CT was not suitable to detect residual metastatic disease of the axilla after NAC.

Spatial heterogeneity of bone marrow endothelial cells unveils a distinct subtype in the epiphysis.

Bone marrow endothelial cells (BMECs) play a key role in bone formation and haematopoiesis. Although recent studies uncovered the cellular taxonomy of stromal compartments in the bone marrow (BM), the complexity of BMECs is not fully characterized. In the present study, using single-cell RNA sequencing, we defined a spatial heterogeneity of BMECs and identified a capillary subtype, termed type S (secondary ossification) endothelial cells (ECs), exclusively existing in the epiphysis. Type S ECs possessed unique phenotypic characteristics in terms of structure, plasticity and gene expression profiles. Genetic experiments showed that type S ECs atypically contributed to the acquisition of bone strength by secreting type I collagen, the most abundant bone matrix component. Moreover, these cells formed a distinct reservoir for haematopoietic stem cells. These findings provide the landscape for the cellular architecture in the BM vasculature and underscore the importance of epiphyseal ECs during bone and haematopoietic development.

B-Cell Lymphoma of the Middle Ear Treated with Multidrug Chemotherapy in a Cat.

Primary lymphoma of the middle ear is rare in cats, and little information has been accumulated on the treatment and course. An 11-year-old spayed female mixed-breed cat was brought to our hospital with facial nerve paralysis, which had been stable using prednisolone for 3 months. She was diagnosed with B-cell lymphoma of the right middle ear after otoscopic sampling, which showed evidence of the filling of bilateral tympanic bullae on computed tomography. Hepatic involvement was suspected, and she was treated with multidrug chemotherapy, resulting in clinical remission. On day 176, magnetic resonance imaging and computed tomography were performed at checkup, revealing tumor invasion into the nasopharyngeal region and the recurrence of hepatic lesions without any brain abnormality. Nasal congestion then worsened, and the patient died on day 228 after presenting with generalized seizures. Clinicians should be mindful of middle ear lymphoma as a differential diagnosis in cats who present with a sign of otitis media, especially whose condition does respond to corticosteroid treatment. The prognosis for feline middle ear lymphoma might not be as poor as previous reports, and multidrug chemotherapy might result in remission of the disease.

Anaplastic oligodendroglioma with nasal invasion and systemic metastasis in a dog.

An 11-year-old spayed female French bulldog was referred on suspicion of nasal tumor. Anaplastic oligodendroglioma in the olfactory bulb that was suspected to have invaded the nasal cavity was diagnosed from imaging and histopathology. Metastasis to cervical lymph nodes was suspected, with no other metastases identified. The brain-to-nasal lesion and lymph nodes were treated with hypo-fractionated radiation therapy. Nasal congestion soon resolved. About 3 months later, follow-up computed tomography revealed multiple hepatic and splenic masses, which were cytologically suspected as metastatic oligodendroglioma. Nimustine, followed by toceranib phosphate, seemed to have no effect, and the dog died on day 167. Postmortem examination revealed the primary tumor disappearance and systemic metastases. Canine oligodendroglioma can grow outside the cranial vault, and systemically metastasize.

Molecular evolutionary analyses of the fusion protein gene in human respirovirus 1.

Few evolutionary studies of the human respiratory virus (HRV) have been conducted, but most of them have focused on HRV3. In this study, the full-length fusion (F) genes in HRV1 strains collected from various countries were subjected to time-scaled phylogenetic, genome population size, and selective pressure analyses. Antigenicity analysis was performed on the F protein. The time-scaled phylogenetic tree using the Bayesian Markov Chain Monte Carlo method estimated that the common ancestor of the HRV1 F gene diverged in 1957 and eventually formed three lineages. Phylodynamic analyses showed that the genome population size of the F gene has doubled over approximately 80 years. Phylogenetic distances between the strains were short (< 0.02). No positive selection sites were detected for the F protein, whereas many negative selection sites were identified. Almost all conformational epitopes of the F protein, except one in each monomer, did not correspond to the neutralising antibody (NT-Ab) binding sites. These results suggest that the HRV1 F gene has constantly evolved over many years, infecting humans, while the gene may be relatively conserved. Mismatches between computationally predicted epitopes and NT-Ab binding sites may be partially responsible for HRV1 reinfection and other viruses such as HRV3 and respiratory syncytial virus.

Laparoscopic or transanal repair of rectocele? Comparison of a reduction in rectocele size.

PURPOSE: This study aimed to compare the reduction in rectocele size after laparoscopic ventral rectopexy (LVR) with that after transanal repair (TAR). METHODS: Forty-six patients with rectocele who underwent LVR and 45 patients with rectocele who received TAR between February 2012 and December 2022 were included. This was a retrospective analysis of prospectively collected data. All patients had clinical evidence of a symptomatic rectocele. Bowel function was evaluated using the constipation scoring system (CSS) and fecal incontinence severity index (FISI). Substantial symptom improvement was defined as at least a 50% reduction in the CSS or FISI scores. Evacuation proctography was performed before surgery and 6 months postoperatively. RESULTS: Constipation was substantially improved in 40-70% of the LVR patients and 70-90% of the TAR patients over 5 years. Fecal incontinence was markedly improved in 60-90% of the LVR patients across 5 years and in 75% of the TAR patients at 1 year. Postoperative proctography showed a reduction in rectocele size in the LVR patients (30 [20-59] mm preoperatively vs. 11 [0-44] mm postoperatively, P < 0.0001) and TAR patients (33 [20-55] mm preoperatively vs. 8 [0-27] mm postoperatively, P < 0.0001). The reduction rate of rectocele size in the LVR patients was significantly lower than that in the TAR patients (63 [3-100] % vs. 79 [45-100] %, P = 0.047). CONCLUSION: The reduction in rectocele size was lower in the patients who underwent LVR than in those who received TAR.

Cancer cell-derived CD69 induced under lipid and oxygen starvation promotes ovarian cancer progression through fibronectin.

Cancer tissues generally have molecular oxygen and serum component deficiencies because of poor vascularization. Recently, we revealed that ICAM1 is strongly activated through lipophagy in ovarian clear cell carcinoma (CCC) cells in response to starvation of long-chain fatty acids and oxygen and confers resistance to apoptosis caused by these harsh conditions. CD69 is a glycoprotein that is synthesized in immune cells and is associated with their activation through cellular signaling pathways. However, the expression and function of CD69 in nonhematological cells is unclear. Here, we report that CD69 is induced in CCC cells as in ICAM1. Mass spectrometry analysis of phosphorylated peptides followed by pathway analysis revealed that CD69 augments CCC cell binding to fibronectin (FN) in association with the phosphorylation of multiple cellular signaling molecules including the focal adhesion pathway. Furthermore, CD69 synthesized in CCC cells could facilitate cell survival because the CD69-FN axis can induce epithelial-mesenchymal transition. Experiments with surgically removed tumor samples revealed that CD69 is predominantly expressed in CCC tumor cells compared with other histological subtypes of epithelial ovarian cancer. Overall, our data suggest that cancer cell-derived CD69 can contribute to CCC progression through FN.

Estrogen receptor alpha signaling in dendritic cells modulates autoimmune disease phenotype in mice.

Estrogen is a disease-modifying factor in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) via estrogen receptor alpha (ERα). However, the mechanisms by which ERα signaling contributes to changes in disease pathogenesis have not been completely elucidated. Here, we demonstrate that ERα deletion in dendritic cells (DCs) of mice induces severe neurodegeneration in the central nervous system in a mouse EAE model and resistance to interferon beta (IFNß), a first-line MS treatment. Estrogen synthesized by extragonadal sources is crucial for controlling disease phenotypes. Mechanistically, activated ERα directly interacts with TRAF3, a TLR4 downstream signaling molecule, to degrade TRAF3 via ubiquitination, resulting in reduced IRF3 nuclear translocation and transcription of membrane lymphotoxin (mLT) and IFNß components. Diminished ERα signaling in DCs generates neurotoxic effector CD4+ T cells via mLT-lymphotoxin beta receptor (LTßR) signaling. Lymphotoxin beta receptor antagonist abolished EAE disease symptoms in the DC-specific ERα-deficient mice. These findings indicate that estrogen derived from extragonadal sources, such as lymph nodes, controls TRAF3-mediated cytokine production in DCs to modulate the EAE disease phenotype.

Exploring types of conversational agents for resolving cancer patients' questions and concerns: Analysis of 100 telephone consultations on breast cancer.

OBJECTIVE: This study was conducted to investigate the types of conversational agents (CA) that can help address questions and concerns ("lay topics" [LTs]). METHODS: We analyzed audio recordings of telephone consultations with 100 breast cancer patients and their families. (1) We identified the content and mode of expression of LTs about breast cancer raised during actual telephone consultations. (2) We checked for the presence of clue information (CI) that can help patients resolve their LTs. RESULTS: None of the 805 LTs of the 100 callers were the same. Treatment-related questions occurred in 70 of the 100 consultations. CIs were present in 52.5% of the LTs. CONCLUSION: The results suggest that chatbots (a type of CA) that offer CIs are more feasible than chatbots that answer each question directly in cancer consultations. Moreover, it is difficult to answer questions directly because preparing answers to all LTs in a breast cancer consultation is challenging owing to LT differences. Therefore, preparing high-quality CIs focused on treatments is required. PRACTICE IMPLICATIONS: An increasing number of cancer patients are seeking information to resolve their LTs. CAs can help supplement the limited human resources available if they are supplied with appropriate CIs.

Reappraising the Role of Enterocele in the Obstructed Defecation Syndrome: Is Radiological Impaired Rectal Emptying Significant in Enterocele?

Objectives: The role of enterocele in the obstructed defecation syndrome (ODS) has remained to be controversial, as patients with enterocele frequently exhibit multiple risk factors, including aging, parity, concomitant different abnormalities, previous histories of pelvic surgery, and incomplete emptying of the rectum. Thus, in this study, we aimed to investigate the association between enterocele and ODS using multivariate analysis. Methods: Between June 2013 and June 2021, 336 women underwent defecography as they had symptoms of ODS. Of those, 293 women (87%) who had anatomical abnormalities were included in this study. Results: Enterocele was detected in 104 (36%) patients. More women with enterocele had histories of hysterectomy compared to those without enterocele (29% vs. 10%, P < 0.0001). The frequency of radiological incomplete emptying was found to be significantly lower in women with enterocele (36%) than in those without enterocele (50%), whereas the mean (95% confidence interval) ODS scores in women with enterocele were significantly higher than those without enterocele [12.1 (11.0-13.3) versus 10.8 (10.5-11.5), P = 0.023]. As per the results of our multivariate analysis, it was determined that the presence of enterocele was associated with higher ODS scores (P = 0.028). However, the small differences in the mean score (1.3) would be clinically negligible. The specific radiological type of enterocele which compressed the rectal ampulla at the beginning of defecation was not associated with the increased ODS scores. Conclusions: The presence of enterocele may not be a primary cause of ODS. Other anatomical abnormalities combined with enterocele, or the hernia itself, may have a role in causing ODS.

Lipophagy-ICAM-1 pathway associated with fatty acid and oxygen deficiencies is involved in poor prognoses of ovarian clear cell carcinoma.

BACKGROUND: Serum starvation and hypoxia (SSH) mimics a stress condition in tumours. We have shown that intercellular adhesion molecule-1 (ICAM-1) protein is synergistically expressed in ovarian clear cell carcinoma (CCC) cells under SSH in response to an insufficient supply of fatty acids (FAs). This ICAM-1 expression is responsible for resistance against the lethal condition, thereby promoting tumour growth. However, the underlying mechanisms that link SSH-driven ICAM1 gene expression to impaired FA supply and its clinical relevance are unclear. METHODS: The underlying mechanisms of how FA deficiency induces ICAM-1 expression in cooperation with hypoxia were analysed in vitro and in vivo. Clinical significance of CCC cell-derived ICAM-1 and the mechanism associated with the transcriptional synergism were also investigated. RESULTS: ICAM-1 expression was mediated through lipophagy-driven lipid droplet degradation, followed by impaired FA-lipid droplet flow. Lipophagy induced ICAM1 expression through stabilisation of NFκB binding to the promoter region via Sam68 and hTERT. Analyses of clinical specimens revealed that expression of ICAM-1 and LC3B, an autophagy marker associated with lipophagy, significantly correlated with poor prognoses of CCC. CONCLUSIONS: The lipophagy-ICAM-1 pathway induced under a tumour-like stress conditions contributes to CCC progression and is a potential therapeutic target for this aggressive cancer type.

The Minimal Important Difference of the Fecal Incontinence Quality of Life (FIQL) Questionnaire for Patients with Posterior Compartment Prolapse: A Prospective Cohort Study.

OBJECTIVES: The minimally important difference (MID) of the Fecal Incontinence Quality of Life (FIQL) scale has never been determined. Thus, in this study, we aimed to estimate the MID of the Japanese FIQL for patients with posterior compartment prolapse (PCP). METHODS: For 3-months after surgery, we followed a prospective cohort of 136 patients with PCP combined with fecal incontinence (FI) who had undergone ventral rectopexy between 2012 and 2018. Usable data from 114 patients were analyzed. Patients have both completed the FIQL and the 36-Item Short Forum Health Survey (SF-36) before and after surgery. Distribution-based MID values were estimated at 1/2 SD and the standard error of measurement (SEM) for domain and total scores across time points. Changes in the domain scores anchored to changes in a SF-36 overall health assessment question were used to estimate anchor-based MID. To be interpreted as true change, the median, anchor-based MID values that were greater than the corresponding SEM were proposed as estimates of the MID for the FIQL. RESULTS: Distribution-based MID of 1/2 SD for each domain and total score ranged between 0.3 and 0.4, whereas SEM ranges were between 0.2 and 0.3. The anchor-based approach resulted in the median MID estimates of 0.4 to 1.0. Final estimates of MID for each FIQL and total score were as follows: lifestyle (0.6-1.1), coping/behavior (0.8-1.4), depression/self-perception (0.4-0.8), embarrassment (1.0-1.6), and total score (0.7-1.1). CONCLUSIONS: The results provide a basis for clinically important differences in FIQL scores after surgery for patients with PCP and FI.

Early postoperative outcomes of a novel nonexcisional technique using aluminum potassium sulfate and tannic acid sclerotherapy with mucopexy on patients with grade III hemorrhoids.

PURPOSE: Aluminum potassium sulfate and tannic acid (ALTA; Zion, Mitsubishi Pharma Corp.) is an effective sclerosing agent for internal hemorrhoids. ALTA therapy with a rectal mucopexy (AM) is a new approach for treating hemorrhoidal prolapse. This study compared the early postoperative outcomes of AM surgery with Doppler-guided transanal hemorrhoidal dearterialization and mucopexy (DM) in patients with third-degree hemorrhoids. METHODS: AM surgery was performed on 32 patients with grade III hemorrhoids and was compared with a cohort of 22 patients who underwent DM surgery in a previous randomized controlled trial. RESULTS: The pain scores during defecation were significantly lower in the AM patients beginning 4 days after surgery. The total use of analgesics 2 weeks postoperatively was significantly lower in the AM patients than in the DM patients (3.5 tablets [range 1.6-5.5] vs. 7.6 tablets [range 3.3-11.9], P=0.04). The length of operation, blood loss, and incidence of postoperative complications were significantly lower in the AM patients than in the DM patients. During 12 months follow-up, recurrence of prolapse occurred in 1 patient who underwent AM surgery. CONCLUSION: AM surgery is effective, with lower complication rates and postoperative analgesic requirements, and is a less invasive treatment for patients with grade III hemorrhoids compared to DM surgery.

Social frailty is independently associated with geriatric depression among older adults living in northern Japan: A cross-sectional study of ORANGE registry.

AIM: To clarify prevalence of social frailty among older adults living in a rural Japanese community, and factors associated with social frailty status. METHODS: In total, 322 adults aged ≥65 years living in a Japanese rural community took part in the study from 2018 to 2020. Social frailty was defined as deficiencies of: (i) living alone; (ii) talking with someone every day; (iii) feeling helpful to friends or family; (iv) going out less frequently compared with last year; and (v) visiting friends sometimes. Social frail status was categorized as robust (0), social prefrail (1), and social frail (≥2), according to the summated score of Makizako's criteria. Multiple logistic regression analysis was applied to clarify factors associated with social frailty status. RESULTS: Final samples were classified into 68 persons with social frailty, 98 persons with social prefrailty and 147 persons as robust. We observed the prevalence of social frailty (21.7%) and social prefrailty (31.3%) and the GDS-15 had significantly high scores in the social frail groups. Social frailty was significantly associated with the GDS-15 score (odds ratio, 1.33; 95% CI, 1.19-1.49) and TMT-A (odds ratio, 1.04; 95% CI, 1.01-1.08) and GDS-15 (odds ratio, 1.13; 95% CI, 1.03-1.26) were extracted as independent variables of social prefrail status, with adjustment for demographics, polypharmacy and lifestyle-related diseases. CONCLUSIONS: Our results suggest that social frailty tends to be increasing gradually in a Japanese rural area, and social prefrailty might be potentially associated with attentional function, as well as the GDS-15 score. Geriatr Gerontol Int 2022; 22: 145-151.

Predictive Factors for Recurrence of External Rectal Prolapse after Laparoscopic Ventral Rectopexy.

OBJECTIVES: This study aimed to evaluate factors that contribute to the recurrence of external rectal prolapse (ERP) following laparoscopic ventral rectopexy (LVR). METHODS: All patients who underwent LVR using synthetic meshes between 2011 and 2018 were prospectively included. A standard questionnaire including the Fecal Incontinence Severity Index (FISI) and Constipation Scoring System (CSS) was administered preoperatively and postoperatively. Defecography was performed 6 months postoperatively. Univariate and backward stepwise multivariate Cox analysis was performed to determine the prognostic factors of recurrence. RESULTS: In total, 132 patients with a median follow-up of 46 months were included. The overall recurrence rate was 6.8% (n = 9), as confirmed by defecography at 6 months in six of the patients. None of the patients developed mesh erosion. FISI and CSS scores were significantly reduced at 3 months and remained significantly reduced for 3 years. Multivariate analyses revealed that the predictors of recurrence included male sex (hazards ratio, 11.3; 95% confidence interval, 3.0-43.0) and age >80 years (hazards ratio, 10.7; 95% confidence interval, 1.3-86.3). Eight patients with recurrence underwent surgery via Delorme's procedure (n = 7) and posterior rectopexy (n = 1). Two patients with new-onset rectoanal intussusception and one with uncorrected sigmoidocoele underwent repeat LVR. CONCLUSIONS: LVR is effective in treating ERP with low morbidity and low recurrence. Male patients and patients older than 80 years are at increased risk of recurrence. Hence, the LVR technique should be modified or coupled with other perineal procedures when treating ERP, especially in male patients.

Increasing rates of laparoscopic gastrointestinal surgery and decreasing rates of surgical site infections: an observational study in Japan from 2012-2017.

BACKGROUND: Surgical site infections (SSI) are the most common healthcare-associated infection, and gastrointestinal surgery is frequently followed by a high incidence of SSI. Epidemiological analysis of the temporal trends in SSI following gastrointestinal surgery has yet to be performed in Japan. Our purpose was to descriptively investigate these trends. METHODS: Extracting national surveillance data from the Japan Nosocomial Infections Surveillance (JANIS) system, we analyzed the frequency of SSI events following gastrointestinal surgery, which consisted of seven surgical procedures, from 2012-2017. We calculated the standardized infection ratio to compute risk-adjusted SSI frequency, and used the trend test to detect time-dependent changes. RESULTS: The frequency of SSI events, except for those associated with surgery of the upper gastrointestinal tract, revealed a decreasing time-dependent trend. The use of laparoscopic surgery increased dramatically over time (p < 0.01 for the six applicable surgical sites), while the frequency of SSI events during laparoscopic surgery remained unchanged. CONCLUSIONS: The increasing use of laparoscopic surgery was identified, and the observation coincided with the decreasing trend in SSI, especially in lower gastrointestinal tract surgery. If the relationship is causal, the overall SSI incidence among previously healthy individuals is expected to decrease, because the use of laparoscopic surgery has large growth potential in Japan.

Successful use of prednisolone and radiation therapy in a dog with intracranial histiocytic sarcoma.

The ideal treatment for intracranial histiocytic sarcoma (HS) remains unclear. Herein, we report a case of intracranial HS that was successfully treated using prednisolone and radiation therapy. The patient was a 9-year-old spayed female Pembroke Welsh Corgi that presented with epileptic seizures. Magnetic resonance imaging revealed a contrast-enhancing mass adjacent to the right piriform lobe. Prednisolone administration (1 mg/kg/day) decreased the lesion size. Additional palliative radiation therapy (total dose, 37 Gy) resulted in complete disappearance of the lesion. However, on day 164, the dog's neurological signs deteriorated, and she was euthanized. Necropsy revealed an intracranial metastasis of HS via the cerebrospinal fluid without any extracranial metastasis. Nonetheless, combined prednisolone and radiation therapy might be effective in treating intracranial HS.

Early dynamics of circulating tumor DNA predict chemotherapy responses for patients with esophageal cancer.

We investigated whether early circulating tumor DNA (ctDNA) changes, measured using digital PCR (dPCR), can predict later chemotherapy responses in esophageal squamous cell cancer (ESCC). We compared the dynamics of ctDNA and tumor volumes during chemotherapy in 42 ESCC. The accuracy of predictions of later chemotherapy responses was evaluated by the ratio of the variant allele frequency of ctDNA (post-/pre-ctDNA) and the total tumor volume (post-/pre-volume) before and after an initial chemotherapy cycle using a receiver-operating characteristic curve analysis. Total positive and negative objective responses (ORs) were defined as either >50 or ≤50% reductions, respectively, in the total tumor volume at the end of first-line chemotherapy. Mutation screening of 43 tumors from 42 patients revealed 96 mutations. The pretreatment dPCR-ctDNA data were informative in 38 patients, using 70 selected mutations (1-3 per patient). The areas under the curve (AUCs) for the post-/pre-volume and post-/pre-ctDNA levels used in predicting the total OR were 0.85 and 0.88, respectively. The optimal cutoff value of post-/pre-ctDNA was 0.13. In 20 patients with post-/pre-volume ≥50%, the total OR could be predicted by the post-/pre-ctDNA with high accuracy; the AUC by post-/pre-ctDNA was higher than that by post-/pre-volume (0.85 versus 0.76, respectively). Patients with low post-/pre-ctDNA (n = 18) had a significantly better overall survival rate than those with high post-/pre-ctDNA (n = 20; P = 0.03). Early ctDNA changes after an initial cycle of chemotherapy predict later responses to treatment with high accuracy in ESCC patients.

Tissue factor and its procoagulant activity on cancer-associated thromboembolism in pancreatic cancer.

Pancreatic cancer frequently involves cancer-associated thromboembolism, which is strongly associated with poor prognosis. Tissue factor, a blood coagulation factor largely produced in cancer patients as a component of extracellular vesicles, plays a key role in the incidence of cancer-associated thromboembolism in patients with pancreatic cancer. However, no prospective studies have been published on the relationship between tissue factor and cancer-associated thromboembolism or patient clinical characteristics, including recent chemotherapy regimens. Thus, we aimed to address this in a Japanese cohort of 197 patients and 41 healthy volunteers. Plasma tissue factor levels were measured by ELISAs preevaluated by tissue factor specificity. Multivariable analysis was used to identify independent predictors of cancer-associated thromboembolism. We found that the cancer-associated thromboembolism rate in the patient cohort was 6.6% (4.6%, venous thromboembolism; 2.0%, arterial thromboembolism). Tissue factor levels of 100 pg/mL or higher at patient registration were predictive of cancer-associated thromboembolism, with positive and negative predictive values of 23.1% and 94.6%, respectively. Multivariable analysis showed that plasma tissue factor levels were an independent predictive factor for cancer-associated thromboembolism, with a risk ratio of 5.54 (95% confidence interval, 1.02-30.09). Unlike in healthy volunteers and patients without cancer-associated thromboembolism, tissue factor levels were highly correlated with extracellular vesicles' procoagulant activity in patients developing cancer-associated thromboembolism. Taken together, our data show that the tissue factor levels at patient registration were a predictive factor for cancer-associated thromboembolism in this cohort of patients with pancreatic cancer.