Clinical implications of Sokolow-Lyon voltage less than 3.5 mV in patients who have undergone transcatheter aortic valve replacement.

BACKGROUND: Degenerative severe aortic valve stenosis (AS) is increasingly prevalent in the aging population, leading to the adoption of transcatheter aortic valve replacement (TAVR) as a less invasive alternative. While TAVR indications have expanded, the procedure is associated with a substantial incidence of major adverse cardiac events (MACE). The study aims to establish a preoperative risk-stratification system for TAVR candidates based on Sokolow-Lyon voltage (SLV) and other relevant factors. METHODS: A total of 181 consecutive patients who underwent TAVR were retrospectively reviewed. Baseline characteristics, preoperative electrocardiogram (ECG) and echocardiography findings, and TAVR procedures were assessed. Low SLV (<3.5 mV) was defined based on ECG measurements. RESULTS: Baseline characteristics revealed a mean age of 84 years, with 71.8% females. The two-year incidence of MACE defined as a composite of cardiac death and hospitalization due to heart failure, was 11.6%, significantly higher in the low SLV group. Low SLV emerged as an independent prognostic factor. The Tokyo Bay Risk (TBR) Score, including low SLV, Body Mass Index <18.5 kg/m2, and previous coronary artery disease, effectively stratified MACE risk. Higher TBR scores (2 or 3) correlated with increased MACE risk. CONCLUSIONS: Patients with low SLV in pre-procedural ECG demonstrated a heightened risk of two-year MACE. The TBR score, incorporating low SLV, proved valuable for preoperative risk assessment. Careful consideration of TAVR indications, along with TBR score integration, is crucial for optimizing outcomes.

Real-world outcomes of FOLFOXIRI plus bevacizumab in patients with metastatic colorectal cancer: the JSCCR-TRIPON study.

BACKGROUND: FOLFOXIRI plus bevacizumab is a standard first-line chemotherapy for patients with metastatic colorectal cancer (mCRC). However, due to the severe toxicities, this regimen is not widely used. There is limited data on the real-world efficacy and safety. METHODS: We conducted a retrospective analysis of clinical data from mCRC patients who received FOLFOXIRI plus bevacizumab as first-line chemotherapy at 31 institutions. The initial dose was standardized according to the TRIBE regimen. Induction therapy was defined as a combination of oxaliplatin, irinotecan, and fluorouracil. RESULTS: Out of 104 patients who met the criteria, the median age was 58 years (range, 16-72). 81% of patients had an eastern cooperative oncology group performance status (PS) of 0. An initial dose reduction was observed in 63% of patients. The median number of preplanned induction therapy cycles was 12 (range, 4-12). The completion of scheduled induction therapy cycles was observed in 45% of patients, with treatment-related toxicities being the main reason for discontinuation (63%). The median progression-free survival and overall survival were 12.8 months (95% CI, 10.6-15.0) and 27.9 months (95% CI 21.6-34.2), respectively. The objective response rate and disease control rate were 63.7% and 98.9%, respectively. The R0 resection rate was 21.2%. The main grade 3 or higher toxicities were neutropenia (51%), febrile neutropenia (10%), and nausea/vomiting (5%). No treatment-related deaths were observed. CONCLUSION: In a real-world clinical setting, FOLFOXIRI plus bevacizumab demonstrated efficacy and safety comparable to previous clinical trials.

Clinical utility of BRCA and ATM mutation status in circulating tumour DNA for treatment selection in advanced pancreatic cancer.

BACKGROUND: Identification of homologous recombination deficiency (HRD) remains a challenge in advanced pancreatic cancer (APC). We investigated the utility of circulating tumour DNA (ctDNA) profiling in the assessment of BRCA1/2 and ATM mutation status and treatment selection in APC. METHODS: We analysed clinical and ctDNA data of 702 patients with APC enroled in GOZILA, a ctDNA profiling study using Guardant360. RESULTS: Inactivating BRCA1/2 and ATM mutations were detected in 4.8% (putative germline, 3.7%) and 4.4% (putative germline, 0.9%) of patients, respectively. Objective response (63.2% vs. 16.2%) and PFS (HR 0.55, 95% CI 0.32-0.93) on platinum-containing chemotherapy were significantly better in patients with putative germline BRCA1/2 (gBRCA) mutation than those without. In contrast, putative gBRCA mutation had no impact on the efficacy of gemcitabine plus nab-paclitaxel. In 2 patients treated with platinum-containing therapy, putative BRCA2 reversion mutations were detected. Three of seven patients with somatic BRCA mutations responded to platinum-containing therapy, while only one of four with putative germline ATM mutations did. One-third of somatic ATM mutations were in genomic loci associated with clonal haematopoiesis. CONCLUSION: Comprehensive ctDNA profiling provides clinically relevant information regarding HRD status. It can be a practical, convenient option for HRD screening in APC.

Indexed aortic valve area using multimodality imaging for assessing the severity of bicuspid aortic stenosis.

BACKGROUND: The impact of various imaging modalities on discordance/concordance between indexed aortic valve area (iAVA) and catheterization-derived mean transaortic pressure gradient (mPGcath) is unclear in patients with bicuspid aortic valve (BAV). This study aimed to compare iAVA measurements obtained using four different methodologies in BAV and tricuspid aortic valve (TAV) patients, using mPGcath as a reference standard. METHODS: We retrospectively reviewed patients who underwent comprehensive assessment of AS, including two-dimensional (2D) transthoracic echocardiography (TTE), three-dimensional (3D) transesophageal echocardiography (TEE), multidetector computed tomography (MDCT), and catheterization, at our institution between 2019 and 2022. iAVA was measured using the continuity eq. (CE) with left ventricular outflow tract area obtained by 2D TTE, 3D TEE, and MDCT, as well as planimetric 3D TEE. RESULTS AND CONCLUSIONS: Among 564 patients (64 with BAV and 500 with TAV), 64 propensity-matched pairs of patients with BAV and TAV were analyzed. iAVACE(2DTTE) led to overestimation of AS severity (BAV, 23.4%; TAV, 28.1%) and iAVACE(MDCT) led to underestimation of AS severity (BAV, 29.3%; TAV, 16.7%), whereas iAVACE(3DTEE) and iAVAPlani(3DTEE) resulted in a reduction in the discordance of AS grading. A moderate correlation was observed between mPGcath and iAVACE(3DTEE) (BAV, r = -0.63; TAV, r = -0.68), with iAVACE(3DTEE) corresponding to the current guidelines' cutoff value (BAV, 0.58 cm2/m2; TAV, 0.60 cm2/m2). Discordance/concordance between iAVA and mPGcath in evaluating AS severity varies depending on the methodology and imaging modality used. The use of iAVACE(3DTEE) is valuable for reconciling the discordant AS grading in BAV patients as well as TAV.

Prognostic Implication of Right Ventricular Free Wall Longitudinal Strain and Right Atrial Pressure Estimated By Echocardiography in Patients With Severe Functional Tricuspid Regurgitation.

BACKGROUND: The interaction between right ventricular (RV) function and pulmonary hypertension is crucial for prognosis of patients with severe functional tricuspid regurgitation. RV free wall longitudinal strain (RVFWLS) has been reported to detect RV systolic dysfunction earlier than other conventional parameters. Although pulmonary artery systolic pressure measured by Doppler echocardiography is often underestimated in severe functional tricuspid regurgitation, right atrial pressure (RAP) estimated by echocardiography may be viewed as a prognostic factor. Impact of RAP and RVFWLS on outcome in patients with severe functional tricuspid regurgitation remains unclear. The aim of the present study was to investigate prognostic implication of RAP, RVFWLS, and their combination in this population. METHODS AND RESULTS: We retrospectively examined 377 patients with severe functional tricuspid regurgitation. RAP, pulmonary artery systolic pressure, RV fractional area change, and RVFWLS were analyzed. RAP of 15 mm Hg was classified as elevated RAP. All-cause death at 2-year follow-up was defined as the primary end point. RVFWLS provided better prognostic information than RV fractional area change by receiver operating characteristic curve analysis. In the multivariable Cox regression analysis, elevated RAP and RVFWLS of ≤18% were independent predictors of clinical outcome. Patients with RVFWLS of ≤18% had higher risk of all-cause death than those without by Kaplan-Meier curve analysis. Furthermore, when patients were stratified into 4 groups by RAP and RVFWLS, the group with elevated RAP and RVFWLS of ≤18% had the worst outcome. CONCLUSIONS: Elevated RAP and RVFWLS of ≤18% were independent predictors of all-cause death. The combination of elevated RAP and RVFWLS effectively stratified the all-cause death.

Safety and Efficacy of Encorafenib, Binimetinib, and Cetuximab for BRAFV600E-Mutant Metastatic Colorectal Cancer: Results of the Japanese Expanded Access Program.

BACKGROUND: The phase 3 BEACON CRC study demonstrated the survival benefits of encorafenib and cetuximab, with or without binimetinib (the BEACON triplet or doublet regimen), for BRAFV600E-mutant metastatic colorectal cancer (mCRC). This expanded access program (EAP) and subsequent follow-up study assessed the efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAFV600E-mutant mCRC. MATERIALS AND METHODS: The EAP was an open-label, single-arm study including Japanese patients with BRAFV600E-mutant mCRC whose disease progressed after 1 to 2 prior regimens. The patients received the BEACON triplet regimen with 28-day cycles. The subsequent follow-up study assessed the survival outcomes following EAP completion. Safety was assessed only during the EAP. RESULTS: Among the 86 enrolled patients, 81 received the BEACON triplet regimen. The objective response rate and median progression-free survival were 27.6% (95% confidence interval [CI], 18.0%-39.1%) and 5.26 (95% CI, 4.14-5.52) months, respectively. Grade 3 to 4 adverse events and treatment-related adverse events occurred in 43.2% and 28.4% of patients, respectively. No new safety signals were observed during the EAP. Among 58 patients with confirmed survival at EAP completion, 57 were included in the follow-up study. With a median observation period of 9.17 months through the EAP and follow-up study, the median overall survival was 10.38 (95% CI, 9.00-16.16) months. CONCLUSION: The efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAFV600E-mutant mCRC were consistent with those reported in the BEACON CRC trial, supporting its use as a standard treatment for pretreated patients with BRAFV600E-mutant mCRC.

Impact of stroke volume assessment by three-dimensional transesophageal echocardiography on the classification of low-gradient aortic stenosis.

BACKGROUND: Accurate assessment of flow status is crucial in low-gradient aortic stenosis (AS). However, the clinical implication of three-dimensional transesophageal echocardiography (3DTEE) on flow status evaluation remains unclear. This study aimed to investigate the assessment of flow status using 3D TEE in low-gradient AS patients. METHODS: We retrospectively reviewed patients diagnosed with low-gradient AS and preserved ejection fraction at our institution between 2019 and 2022. Patients were categorized into low-flow/low-gradient (LF-LG) AS or normal-flow/low-gradient (NF-LG) AS based on two-dimensional transthoracic echocardiography (2DTTE). We compared the left ventricular outflow tract (LVOT) geometry between the two groups and reclassified them using stroke volume index (SVi) obtained by 3DTEE. RESULTS: Among 173 patients (105 with LF-LG AS and 68 with NF-LG AS), 54 propensity-matched pairs of patients were analyzed. 3DTEE-derived ellipticity index of LVOT was significantly higher in LF-LG AS patients compared to NF-LG AS patients (p = 0.012). We assessed the discordance in flow status classification between SVi2DTTE and SVi3DTEE in both groups using a cutoff value of 35 ml/m2. The LF-LG AS group exhibited a significantly higher discordance rate compared to the NF-LG AS group, with rates of 50% and 2%, respectively. The optimal cutoff values of SVi3DTEE for identifying low flow status, based on 2DTTE-derived cutoff values, were determined to be 43 ml/m2. CONCLUSIONS: LVOT ellipticity in low-gradient AS patients varies depending on flow status, and this difference contributes to discrepancies between SVi3DTEE and SVi2DTTE, particularly in LF-LG AS patients. Utilizing SVi3DTEE is valuable for accurately assessing flow status.

Long-Term Impact of Small Mitral Valve Orifice Area after Transcatheter Edge-to-Edge Mitral Valve Repair on Clinical Outcome: A Three-Dimensional Echocardiography Study.

BACKGROUND: Iatrogenic mitral stenosis is a complication associated with transcatheter edge-to-edge mitral valve repair. Some reports revealed the impact of mean transmitral pressure gradient after procedure on long-term clinical outcomes. However, the association between prognosis and mitral valve orifice area (MVA) after the procedure has been poorly studied. This study aimed to investigate the association between postprocedural small MVA, derived from three-dimensional (3D) transesophageal echocardiography (TEE), and long-term clinical outcomes in 2 cohorts: the degenerative mitral regurgitation (MR) cohort and the functional MR cohort. METHODS: This retrospective study assessed 279 consecutive patients with 3D TEE data during transcatheter edge-to-edge mitral valve repair between January 2010 and December 2016. Mitral valve orifice area after device implantation was measured by 3D planimetry. The patients with degenerative and functional MR were stratified separately into 2 groups according to postprocedural MVA: normal MVA (MVA > 1.5 cm2) group and small MVA (MVA ≤ 1.5 cm2) group. RESULTS: Of the 279 patients, 142 (51%) had degenerative MR and 137 (49%) had functional MR. The number of degenerative MR patients with small MVA was 38, whereas 42 patients were in the functional MR cohort. Patients with small MVA had higher rate of all-cause mortality in the degenerative MR group (log-rank test: P = .01) but not in the functional MR group (log-rank test: P = .52). In multivariate analysis small MVA was independently associated with all-cause mortality but not postprocedural transmitral pressure gradient. Neither small MVA nor transmitral pressure gradient was associated with all-cause mortality in patients with functional MR. CONCLUSION: Small MVA measured by 3D TEE after transcatheter mitral edge-to-edge repair was associated with poor prognosis in patients with degenerative MR.

Comparison of prognostic value among echocardiographic surrogates of right ventricular-pulmonary arterial coupling: A three-dimensional echocardiographic study.

OBJECTIVES: Right ventricular (RV)-pulmonary arterial (PA) coupling is important in various cardiac diseases. Recently, several echocardiographic surrogates for RV-PA coupling have been proposed and reported to be useful in predicting outcomes. However, it remains unclear which surrogate is the most clinically relevant. This study aimed to comprehensively compare the prognostic value of different echocardiographic RV-PA coupling surrogates. METHODS: We retrospectively reviewed 242 patients with various cardiac conditions who underwent comprehensive transthoracic echocardiography with three-dimensional RV data. In addition to conventional parameters including tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and PA systolic pressure (PASP), we analyzed RV free wall and global longitudinal strain (FWLS and GLS). We also obtained RV ejection fraction (RVEF), stroke volume (SV), and end-systolic volume (ESV) using three-dimensional RV analysis. RV-PA coupling surrogates were calculated as TAPSE/PASP, FAC/PASP, FWLS/PASP, GLS/PASP, RVEF/PASP, and SV/ESV. The study endpoint was a composite outcome of all-cause death or cardiovascular hospitalization within 1 year. RESULTS: In multivariable analysis, all the RV-PA coupling surrogates were independent predictors of the outcome. Among the surrogates, the model with TAPSE/PASP showed the lowest prognostic value in model fit and discrimination ability, whereas the model with RVEF/PASP exhibited the highest prognostic value. The partial likelihood ratio test indicated that the model with RVEF/PASP was significantly better than the model with TAPSE/PASP (p < .024). CONCLUSION: All the RV-PA coupling surrogates were independent predictors of the outcome. Notably, RVEF/PASP had the highest prognostic value among the surrogates.

Echocardiographic Characteristics of Left and Right Ventricular Longitudinal Function in Patients With a History of Cardiac Surgery.

Previous studies have indicated a reduction in right ventricular (RV) longitudinal motion after cardiac surgery. However, the long-term effect of cardiac surgery on longitudinal motion and the involvement of left ventricular (LV) motion remains unclear. Therefore, this study aimed to comprehensively investigate the longitudinal function of the right ventricle and left ventricle in patients who underwent cardiac surgery. The study included patients who underwent comprehensive transthoracic echocardiography with 3-dimensional RV data sets. By propensity score matching of the clinical and echocardiographic variables, including LV and RV ejection fraction, the echocardiographic parameters were compared between patients with and without a history of cardiac surgery (the surgery and nonsurgery groups, respectively). In this study, the surgery group had significantly lower LV global longitudinal strain values than the nonsurgery group, despite having similar LV ejection fraction. The tricuspid annular plane systolic excursion (TAPSE), tricuspid annular velocity, and RV free wall longitudinal strain were also significantly smaller in the surgery group, whereas the RV ejection fraction was comparable between the 2 groups. In addition, a subgroup analysis based on the time from previous surgery to transthoracic echocardiography (≤1 and >1 year) revealed that TAPSE was reduced in both postoperative phases. In conclusion, LV and RV longitudinal parameters were reduced after cardiac surgery, despite preserved LV and RV global functions. Moreover, TAPSE was reduced even after a long time after cardiac surgery. These findings emphasize the need for careful interpretation of biventricular longitudinal motion in patients with a history of cardiac surgery.

Trifluridine/Tipiracil Plus Bevacizumab for Vulnerable Patients With Pretreated Metastatic Colorectal Cancer: A Retrospective Study (WJOG14520G).

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab has shown clinical benefit for metastatic colorectal cancer (mCRC) refractory to standard therapy. However, few data have been available for patients with pretreated mCRC who are intolerant of intensive therapy (vulnerable). METHODS: We performed a multicenter retrospective study (WJOG14520G; TWILIGHT) of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC. Eligibility criteria included previous chemotherapy (although patients treated with all key cytotoxic agents, a fluoropyrimidine, oxaliplatin, and irinotecan, were excluded) and intolerance of full-dose combination therapy with oxaliplatin or irinotecan at the start of FTD/TPI plus bevacizumab. RESULTS: The median age of 93 evaluable patients was 79 years (range, 21-90). Intolerance of intensive therapy was attributable to an older age in 60 (65%) patients, serious concomitant disease in 24 (26%) patients, and a poor performance status in 19 (20%) patients. FTD/TPI plus bevacizumab was administered as second-line treatment in 74 (80%) patients and as third- or fourth-line treatment in 19 (20%) patients. The objective response rate was 4.9% (95% confidence interval [CI], 1.4%-12.2%), and the disease control rate was 67.9% (95% CI, 56.6%-77.8%). With a median follow-up time of 21.6 months, median overall survival and progression-free survival were 18.6 months (95% CI, 12.1-23.2) and 6.3 months (95% CI, 5.0-8.3), respectively. Neutropenia of grade ≥3 developed in 50 (54%) patients, whereas 2 (2%) patients experienced febrile neutropenia, and no treatment-related death was observed. CONCLUSION: Our data show the potential efficacy and acceptable safety profile of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC.

Evaluation of the photosensitizer activity of hydrophobic phosphorus(V)porphyrins using the absorption spectral change of 1-benzyl-1,4-dihydronicotinamide.

Under visible light irradiation, water-insoluble P(V)porphyrins oxidized 1-benzyl-1,4-dihydronicotinamide (BNADH), a model compound for nicotinamide adenine dinucleotide, and diminished the typical absorption of BNADH at around 340 nm. A singlet oxygen quencher, sodium azide, partially inhibited photosensitized BNADH oxidation. This BNADH oxidation photosensitized by P(V)porphyrins in the presence of sodium azide can be explained by electron transfer oxidation from BNADH to the photoexcited P(V)porphyrins. The quantum yields of BNADH oxidation via electron transfer by these P(V)porphyrins were larger than those of a singlet oxygen mechanism. Redox potential measurements supported the electron transfer mechanism from a thermodynamic point of view, and fluorescence lifetime measurement also suggests this mechanism. The process of this electron transfer oxidation involves the radical formation of BNADH and the further reaction of this radical to the oxidized form (cationic form of BNADH). Analysis of the quantum yields of BNADH photooxidation by P(V)porphyrins suggests that the photoinduced electron transfer from BNADH to photoexcited P(V)porphyrins triggers the radical chain reaction of BNADH oxidation. The electron transfer rate coefficient and this efficiency were increased with an increase in the Gibbs energy of electron transfer from tryptophan to photoexcited P(V)porphyrins (-ΔG). However, the BNADH oxidation quantum yield via electron transfer decreased with an increase in the -ΔG of electron transfer. These results suggest that reverse electron transfer inhibits the decomposition of BNAD radicals. This assay using BNADH can be used to evaluate the photosensitizer activity of water-insoluble compounds. These P(V)porphyrins may be used as photosensitizers for photodynamic therapy in a relatively hydrophobic environment in cancer tissues.

Effect of right ventricular free wall longitudinal strain on all-cause death in patients with isolated severe tricuspid regurgitation and atrial fibrillation.

Background: With the aging population and advanced catheter-based therapy, isolated tricuspid regurgitation (TR) with atrial fibrillation (AF) has gained increased attention; however, data on the prognostic effect of isolated TR with AF are limited because of the small number of patients among those with severe TR. Recently, right ventricular (RV) longitudinal strain by two-dimensional speckle-tracking echocardiography has been reported as an excellent indicator of RV dysfunction in severe TR. However, the prognostic implications of RV longitudinal strain in isolated severe TR associated with AF remain unclear. Therefore, this study aimed to reveal the prognostic value of this index in this population. Methods: We retrospectively studied patients with severe isolated TR associated with AF in the absence of other etiologies in the Cedars-Sinai Medical Center between April 2015 and March 2018. Baseline clinical and echocardiographic data were studied including RV systolic function evaluated by RV free wall longitudinal strain (FWLS) and conventional parameters. All-cause death was defined as the primary endpoint. Results: In total, 53 patients (median age, 85 years; female, 60%) with a median follow-up of 433 (60-1567) days were included. Fourteen patients (26%) died, and 66% had right heart failure (RHF) symptoms. By multivariable analysis, reduced RVFWLS was independently associated with all-cause death. Patients with RVFWLS of ≤18% had higher risk of all-cause death adjusted for age (log-rank P = 0.030, adjusted hazard ratio 4.00, 95% confidence interval, 1.11-14.4; P = 0.034). When patients were stratified into four groups by RHF symptoms and RVFWLS, the group with symptomatic and reduced RVFWLS had the worst outcome. Conclusion: Reduced RVFWLS was independently associated with all-cause death in patients with isolated severe TR and AF. Our subset classification showed the worst outcome from the combination of RHF symptoms and reduced RVFWLS.

Impact of eccentric jet on outcomes in patients with atrial functional mitral regurgitation: An echocardiographic study.

BACKGROUND: Previous studies have reported the mechanisms underlying atrial functional mitral regurgitation (A-FMR). Recently, A-FMR subtypes based on mitral regurgitation (MR) mechanisms were proposed: "central jet" due to insufficient leaflet remodeling and "eccentric jet" due to atriogenic tethering. However, their prognostic value remains unclear. Therefore, this study investigated the impact of A-FMR subtypes on clinical outcomes. METHODS: Outpatients with significant A-FMR between January 2013 and December 2016 were retrospectively reviewed. They were classified into two subtypes according to the MR jet's direction. All-cause mortality, heart failure hospitalization, and any mitral valve interventions were the primary composite endpoint. RESULTS: Among 101 patients with significant A-FMR, 32% had eccentric jet. The primary endpoint was observed in 56 patients during the follow-up period (median 0.7 years, range 0.1-4.2 years). Kaplan-Meier curves demonstrated that the composite endpoint was higher among patients with eccentric jet than those with central jet (log-rank p < 0.001). Eccentric jet (hazard ratio [HR] 2.46, 95% confidence interval [CI] 1.28-4.73; p = 0.007), age (HR 1.06, 95% CI 1.02-1.11; p = 0.002), symptoms (HR 6.22, 95% CI 2.18-17.8; p < 0.001), severe MR (HR 3.97, 95% CI 1.92-8.18; p < 0.001), and significant tricuspid regurgitation (TR; HR 2.00, 95% CI 1.01-3.97; p = 0.047) were independent predictors of the composite endpoint. CONCLUSIONS: Patients with eccentric jet had poorer outcomes than those with central jet. Eccentric jet, age, symptoms, severe MR, and significant TR were independently associated with poor outcomes.

Outcome of Patients With Both Moderate Aortic Stenosis and Moderate Mitral Stenosis.

Aims: This study aimed to investigate the symptoms and prognosis of patients with both moderate aortic stenosis (AS) and mitral stenosis (MS). Methods and Results: We studied 82 patients with moderate AS and MS diagnosed via transthoracic echocardiography. The patients had a mean age of 79 ± 13 years and 95% of patients had degenerative MS. Out of 82 patients, 34 (41%) had heart failure (HF) symptoms (New York Heart Association class ≥ Ⅱ) or a history of HF admission. Left ventricular ejection fraction, stroke volume index, atrial fibrillation, and right ventricular systolic pressure were independent determinants of HF symptoms. The median follow-up duration was 3.2 (interquartile range, 1.0-4.9) years and clinical events occurred in 48 (59%) patients, including death in 11 (13%) patients, aortic or mitral valve interventions in 22 (27%) patients, and HF hospitalization in 15 (18%) patients. The 5-year survival free of the combined endpoint of aortic or mitral valve interventions, HF hospitalization, or death was 19%. A multivariate predictor of clinical events was HF symptoms (hazard ratio [HR], 2.32; 95% confidence interval [CI], 1.30-4.14; p = 0.0045). Kaplan-Meier survival at 5 years was 61% without intervention and HF symptoms were not associated with mortality. Conclusions: Among patients with both moderate AS and MS, left ventricular ejection fraction, stroke volume index, atrial fibrillation, and right ventricular systolic pressure were strong determinants of HF symptoms. HF symptoms were independently predictive of clinical events.

[Rectal cancer with multiple metastases complicated by Crohn's disease 5 years after surgery:a case report].

In recent years, with the rising incidence of patients having long-term Crohn's disease, there has been an increase in the number of reports of carcinogenesis from dysplasia with chronic inflammation as the primary pathogenic factor. We hereby report a case of multiple metastases that appeared 5 years after surgery, in a patient with rectal cancer who had Crohn's disease. A man in his 50s was diagnosed with Crohn's disease which affected his small and large intestines 21 years back. The patient was being treated with oral steroids, 5-aminosalicylic acid, and modified nutrition. Infliximab was added to the treatment after it was introduced 11 years ago. He also had a history of rectal cancer and had undergone surgery for the same 5 years back. He was diagnosed with stage II cancer, and had not received any adjuvant chemotherapy. However, 5 years after surgery, multiple metastases recurred, and chemotherapy with mFOLFOX6 was administered. Additionally, for treating his Crohn's disease, which was also active, infliximab was changed to vedolizumab;however, the patient died a year later. Colorectal cancer accompanied with Crohn's disease has a higher risk of developing metastasis and is associated with poorer prognosis as compared to the noncomplicated colorectal cancer. Regarding treatment modalities, while searching for multidisciplinary treatment methods centered on surgical treatment in collaboration with medical oncologists and radiologists, the safety of treatment for Crohn's disease in patients with cancer must be borne in mind. The rising prevalence of cases of colorectal cancer with Crohn's disease is expected to lead to the formulation of specialized diagnostic and treatment strategies for these patients.

Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer.

BACKGROUND: Liquid biopsy is an alternative to tissue specimens for tumour genotyping. However, the frequency of genomic alterations with low circulating-tumour DNA (ctDNA) shedding is shown in pancreatic ductal adenocarcinoma (PDAC). We, therefore, investigated the prevalence of KRAS mutations and ctDNA fraction by the metastatic site in patients with PDAC. METHODS: This study enrolled previously treated PDAC patients from a plasma genomic profiling study; ctDNA analysis was performed using Guardant360 at disease progression before initiating subsequent treatment. RESULTS: In 512 patients with PDAC, KRAS mutations were detected in 57%. The frequency of KRAS mutation in ctDNA differed depending on the metastatic organ; among patients with single-organ metastasis (n = 296), KRAS mutation detection rate was significantly higher in patients with metastasis to the liver (78%). In addition, the median maximum variant allele frequency (VAF) was higher with metastasis to the liver (1.9%) than with metastasis to the lungs, lymph nodes, peritoneum or with locally advanced disease (0.2%, 0.4%, 0.2% and 0.3%, respectively). CONCLUSION: The prevalence of KRAS mutations and maximum VAF were higher in patients with metastasis to the liver than in those with metastasis to other sites. This study indicated the clinical utility of ctDNA analysis, especially in PDAC with liver metastases.

The Phase II Study of Panitumumab in Chemotherapy-Naïve Frail or Elderly Patients with RAS Wild-type Colorectal Cancer: OGSG 1602 Final Results.

BACKGROUND: We previously reported the response rate of a phase II OGSG1602 study on panitumumab in chemotherapy-naive frail or elderly patients with RAS wild-type unresectable colorectal cancer (CRC) [Terazawa T, Kato T, Goto M, et al. Oncologist. 2021;26(1):17]. Herein, we report a survival analysis. METHODS: Patients aged ≥65 years and considered unsuitable for intensive chemotherapy or aged ≥76 years were enrolled. Primary tumors located from the cecum to the transverse colon were considered right-sided tumors (RSTs); those located from the splenic flexure to the rectum were considered left-sided tumors (LSTs). RESULTS: Among the 36 enrolled patients, 34 were included in the efficacy analysis, with 26 and 8 having LSTs and RSTs, respectively. The median progression-free survival (PFS) and overall survival (OS) were 6.0 [95% CI, 5.4-10.0] and 17.5 months (95% CI, 13.8-24.3), respectively. Although no significant differences existed in PFS between patients with LST and RST {6.6 (95% CI, 5.4-11.5) vs. 4.9 months [95% CI, 1.9-not available (NA), P = .120]}, there were significant differences in OS [19.3 (95% CI, 14.2-NA) vs.12.3 months (95% CI, 9.9-NA), P = .043]. CONCLUSION: Panitumumab showed favorable OS in frail or elderly patients with RAS wild-type CRC and no prior exposure to chemotherapy. Panitumumab may be optimal for patients with LSTs (UMIN Clinical Trials Registry Number UMIN000024528).

TRESBIEN (OGSG 2101): encorafenib, binimetinib and cetuximab for early recurrent stage II/III BRAF V600E-mutated colorectal cancer.

The BRAF V600E mutation accounts for approximately 5% of colorectal cancer (CRC) cases and is an extremely poor prognostic factor. However, there are no clear recommendations regarding first-line therapy for patients with early recurrent BRAF V600E-mutated CRC, during or after adjuvant chemotherapy. Recently, a novel combination of encorafenib, binimetinib and cetuximab, showed a higher response rate than standard chemotherapy in patients with BRAF V600E-mutated CRC. Here we describe our plan for the TRESBIEN study (OGSG 2101), which is an open-label, multicenter, single-arm, phase II study designed to evaluate whether encorafenib, binimetinib and cetuximab are effective for patients with early recurrent BRAF V600E-mutated colorectal cancer, during or after adjuvant chemotherapy. The planned number of subjects is 25.

An ongoing study to evaluate encorafenib, binimetinib and cetuximab for people with early recurrent BRAF V600E-mutated colorectal cancer. BRAF V600E-mutated colorectal cancer (CRC) is a type of cancer caused by change (mutation) in a gene called BRAF. It is one of the most difficult types of CRC to treat because currently available drugs do not effectively treat the disease. Recently, two novel treatments, encorafenib and cetuximab, have been approved for use together in several countries for the treatment of advanced or metastatic BRAF V600E-mutated CRC. In Japan, these drugs are also approved to be given with another treatment called binimetinib, an approach called triplet therapy. This article describes the ongoing TRESBIEN study that is looking at how effective and how safe triplet therapy is for the treatment of people with early recurrent BRAF V600E-mutated CRC, during or after they have additional (adjuvant) chemotherapy. This study is ongoing, and the researchers are currently recruiting new participants. TRESBIEN will evaluate the percentage of participants whose tumors shrink with triplet therapy. The study will also look at any side effects. Clinical Trial Registration: jRCTs051210152 (ClinicalTrials.gov) (Japan Registry of Clinical Trials https://jrct.niph.go.jp/search?language=en&page=1).