Coronary bypass surgery guided by computed tomography in a low-risk population.

BACKGROUND AND AIMS: In patients with three-vessel disease and/or left main disease, selecting revascularization strategy based on coronary computed tomography angiography (CCTA) has a high level of virtual agreement with treatment decisions based on invasive coronary angiography (ICA). METHODS: In this study, coronary artery bypass grafting (CABG) procedures were planned based on CCTA without knowledge of ICA. The CABG strategy was recommended by a central core laboratory assessing the anatomy and functionality of the coronary circulation. The primary feasibility endpoint was the percentage of operations performed without access to the ICA. The primary safety endpoint was graft patency on 30-day follow-up CCTA. Secondary endpoints included topographical adequacy of grafting, major adverse cardiac and cerebrovascular (MACCE), and major bleeding events at 30 days. The study was considered positive if the lower boundary of confidence intervals (CI) for feasibility was ≥75% (NCT04142021). RESULTS: The study enrolled 114 patients with a mean (standard deviation) anatomical SYNTAX score and Society of Thoracic Surgery score of 43.6 (15.3) and 0.81 (0.63), respectively. Unblinding ICA was required in one case yielding a feasibility of 99.1% (95% CI 95.2%-100%). The concordance and agreement in revascularization planning between the ICA- and CCTA-Heart Teams was 82.9% with a moderate kappa of 0.58 (95% CI 0.50-0.66) and between the CCTA-Heart Team and actual treatment was 83.7% with a substantial kappa of 0.61 (95% CI 0.53-0.68). The 30-day follow-up CCTA in 102 patients (91.9%) showed an anastomosis patency rate of 92.6%, whilst MACCE was 7.2% and major bleeding 2.7%. CONCLUSIONS: CABG guided by CCTA is feasible and has an acceptable safety profile in a selected population of complex coronary artery disease.

Distance-dependent neuromodulation effect during thermal ablation for atrial fibrillation.

INTRODUCTION: Thermal atrial fibrillation (AF) ablation exerts an additive treatment effect on the cardiac autonomic nervous system (CANS). This effect is mainly reported during ablation of the right superior pulmonary vein (RSPV), modulating the right anterior ganglionated plexus (RAGP), which contains parasympathetic innervation to the sinoatrial node in the epicardial fat pad between RSPV and superior vena cava (SVC). However, a variable response to neuromodulation after ablation is observed, with little to no effect in some patients. Our objective was to assess clinical and anatomic predictors of thermal ablation-induced CANS changes, as assessed via variations in heart rate (HR) postablation. METHODS: Consecutive paroxysmal AF patients undergoing first-time PV isolation by the cryoballoon (CB) or radiofrequency balloon (RFB) within a 12-month time frame and with preprocedural cardiac computed tomography (CT), were evaluated. Preablation and 24-h postablation electrocardiograms in sinus rhythm were collected and analyzed to assess HR. Anatomic evaluation by CT included the measurement of the shortest distance between the SVC and RSPV ostium (RSPV-SVC distance). RESULTS: A total of 97 patients (CB, n = 50 vs. RFB, n = 47) were included, with similar baseline characteristics between both groups. A significant HR increase postablation (ΔHR ≥ 15 bpm) occurred in a total of 37 patients (38.1%), without difference in number of patients between both thermal ablation technologies (CB, 19 [51%]), RFB, 18 [49%]). Independent predictors for increased HR were RSPV-SVC distance (odds ratio [OR]: 0.49, CI: 0.34-0.71, p value < .001), and age (OR: 0.94, CI: 0.89-0.98, p value = .003). CONCLUSIONS: Thermal balloon-based PV isolation influences the CANS through its effect on the RAGP, especially in younger patients and patients with shorter RSPV-SVC distance.

Impact of vessel morphology on CT-derived fractional-flow-reserve in non-obstructive coronary artery disease in right coronary artery.

OBJECTIVES: Computed tomography (CT)-derived fractional flow reserve (FFRCT) decreases continuously from proximal to distal segments of the vessel due to the influence of various factors even in non-obstructive coronary artery disease (NOCAD). It is known that FFRCT is dependent on vessel-length, but the relationship with other vessel morphologies remains to be explained. PURPOSE: To investigate morphological aspects of the vessels that influence FFRCT in NOCAD in the right coronary artery (RCA). METHODS: A total of 443 patients who underwent both FFRCT and invasive coronary angiography, with < 50% RCA stenosis, were evaluated. Enrolled RCA vessels were classified into two groups according to distal FFRCT: FFRCT ≤ 0.80 (n = 60) and FFRCT > 0.80 (n = 383). Vessel morphology (vessel length, lumen diameter, lumen volume, and plaque volume) and left-ventricular mass were assessed. The ratio of lumen volume and vessel length was defined as V/L ratio. RESULTS: Whereas vessel-length was almost the same between FFRCT ≤ 0.80 and > 0.80, lumen volume and V/L ratio were significantly lower in FFRCT ≤ 0.80. Distal FFRCT correlated with plaque-related parameters (low-attenuation plaque, intermediate-attenuation plaque, and calcified plaque) and vessel-related parameters (proximal and distal vessel diameter, vessel length, lumen volume, and V/L ratio). Among all vessel-related parameters, V/L ratio showed the highest correlation with distal FFRCT (r = 0.61, p < 0.0001). Multivariable analysis showed that calcified plaque volume was the strongest predictor of distal FFRCT, followed by V/L ratio (ß-coefficient = 0.48, p = 0.03). V/L ratio was the strongest predictor of a distal FFRCT ≤ 0.80 (cut-off 8.1 mm3/mm, AUC 0.88, sensitivity 90.0%, specificity 76.7%, 95% CI 0.84-0.93, p < 0.0001). CONCLUSIONS: Our study suggests that V/L ratio can be a measure to predict subclinical coronary perfusion disturbance. CLINICAL RELEVANCE STATEMENT: A novel marker of the ratio of lumen volume to vessel length (V/L ratio) is the strongest predictor of a distal CT-derived fractional flow reserve (FFRCT) and may have the potential to improve the diagnostic accuracy of FFRCT. KEY POINTS: • Physiological FFRCT decline depends not only on vessel length but also on the lumen volume in non-obstructive coronary artery disease in the right coronary artery. • FFRCT correlates with plaque-related parameters (low-attenuation plaque, intermediate-attenuation plaque, and calcified plaque) and vessel-related parameters (proximal and distal vessel diameter, vessel length, lumen volume, and V/L ratio). • Of vessel-related parameters, V/L ratio is the strongest predictor of a distal FFRCT and an optimal cut-off value of 8.1 mm3/mm.

Morphine Versus Oxycodone for Cancer Pain Using a Catechol-O-methyltransferase Genotype Biomarker: A Multicenter, Randomized, Open-Label, Phase III Clinical Trial (RELIEF Study).

BACKGROUND: We hypothesized that the high-dose opioid requirement in patients carrying the rs4680-GG variant in the COMT gene encoding catechol-O-methyltransferase would be greater for patients taking morphine than for those taking oxycodone, thus providing a much-needed biomarker to inform opioid selection for cancer pain. METHODS: A randomized, multicenter, open-label trial was conducted at a Japanese hospital's palliative care service. Patients with cancer pain treated with regular doses of nonsteroidal anti-inflammatory drugs or acetaminophen were enrolled and randomized (1:1) into morphine (group M) and oxycodone (group O) groups. The minimum standard dose of immediate-release (IR) oral opioids was repeatedly administered by palliative care physicians to achieve pain-reduction goals (Pain reduction ≥ 33% from baseline and up to ≤ 3 on a numerical rating scale). The primary endpoint was the proportion of subjects requiring high-dose opioids on day 0 with the GG genotype. RESULTS: Of 140 participants who developed cancer-related pain among 378 subjects registered and pre-screened for the genotype, 139 were evaluated in the current study. Among patients carrying a COMT rs4680-GG genotype, 48.3% required high-dose opioids in group M, compared with the 20.0% in group O (95% CI, 3.7%-50.8%; P = .029). Of those with the non-GG genotype, 41.5% treated with morphine and 23.1% with oxycodone required high-dose opioids (95% CI, 3.3%-38.3%; P = 0.098). CONCLUSION: Using the COMT rs4680 genotype alone is not recommended for selecting between morphine and oxycodone for pain relief.

Clinical outcomes and failure patterns after postoperative radiotherapy for oral cavity squamous cell carcinoma.

PURPOSE: This study aimed to assess recurrence patterns and identify the optimal dose and target volumes of postoperative radiotherapy (PORT) in patients with oral cavity squamous cell carcinoma (OSCC). METHODS: Data of 111 patients who received PORT for OSCC between January 2010 and April 2020 were retrospectively reviewed. The median age was 68 years (range 19-88). PORT was administered as initial treatment to 63 patients and as salvage treatment for recurrent tumors to 48 patients. The median prescribed dose was 60 Gy (range 50-66) administered in 30 fractions (range 25-33). RESULTS: Median follow-up time was 73 months (range 24-147). Overall survival (OS), progression-free survival (PFS), local control (LC), and locoregional control (LRC) at 3 years were 55.6%, 45.6%, 74.6%, and 63.1%, respectively. There were no significant differences in OS, PFS, LC, and LRC between the initially diagnosed and postoperative recurrent cases. Of 22 patients (20%) who developed regional nodal recurrences, 17 (15%) and 11 (10%) had in-field and out-of-field recurrences, respectively. Of 105 patients who received irradiation to the primary tumor bed, 24 (23%) developed recurrence at the primary site. The PFS and LC rates were significantly worse in patients receiving ≤ 56 Gy to the primary site than those receiving > 56 Gy (p = 0.016 and p = 0.032, respectively). CONCLUSION: PORT was effective for postoperative recurrences as well as for initially diagnosed oral cavity cancer. Doses greater than 56 Gy to the primary site may be required in PORT for OSCC.

Impact of coronary bifurcation angle on computed tomography derived fractional flow reserve in coronary vessels with no apparent coronary artery disease.

OBJECTIVES: Computed tomography (CT) derived fractional flow reserve (FFRCT) decreases from the proximal to the distal part due to a variety of factors. The energy loss due to the bifurcation angle may potentially contribute to a progressive decline in FFRCT. However, the association of the bifurcation angle with FFRCT is still not entirely understood. This study aimed to investigate the impact of various bifurcation angles on FFRCT decline below the clinically crucial relevance of 0.80 in vessels with no apparent coronary artery disease (CAD). METHODS: A total of 83 patients who underwent both CT angiography including FFRCT and invasive coronary angiography, exhibiting no apparent CAD were evaluated. ΔFFRCT was defined as the change in FFRCT from the proximal to the distal in the left anterior descending artery (LAD) and left circumflex artery (LCX). The bifurcation angle was calculated from three-dimensional volume rendered images. Vessel morphology and plaque characteristics were also assessed. RESULTS: ΔFFRCT significantly correlated with the bifurcation angle (LAD angle, r = 0.35, p = 0.001; LCX angle, r = 0.26, p = 0.02) and vessel length (LAD angle, r = 0.30, p = 0.005; LCX angle, r = 0.49, p < 0.0001). In LAD, vessel length was the strongest predictor for distal FFRCT of ≤ 0.80 (ß-coefficient = 0.55, p = 0.0003), immediately followed by the bifurcation angle (ß-coefficient = 0.24, p = 0.02). The bifurcation angle was a good predictor for a distal FFRCT ≤ 0.80 (LAD angle, cut-off 31.0°, AUC 0.70, sensitivity 74%, specificity 68%; LCX angle, cut-off 52.6°, AUC 0.86, sensitivity 88%, specificity 85%). CONCLUSIONS: In vessels with no apparent CAD, vessel length was the most influential factor on FFRCT, directly followed by the bifurcation angle. KEY POINTS: • Both LAD and LCX bifurcation angles are factors influencing FFR CT. • Bifurcation angle is one of the predictors of a distal FFRCT of ≤ 0.80 and an optimal cut-off value of 31.0° for the LAD and 52.6° for the LCX. • Bifurcation angle should be taken into consideration when interpreting numerical values of FFRCT.

Coronary artery disease in atrial fibrillation ablation: impact on arrhythmic outcomes.

AIMS: Catheter ablation (CA) is an established treatment for atrial fibrillation (AF). A computed tomography (CT) may be performed before ablation to evaluate the anatomy of pulmonary veins. The aim of this study is to investigate the prevalence of patients with coronary artery disease (CAD) detected by cardiac CT scan pre-ablation and to evaluate the impact of CAD and revascularization on outcomes after AF ablation. METHODS AND RESULTS: All consecutive patients with AF diagnosis, hospitalized at Universitair Ziekenhuis Brussel, Belgium, between 2015 and 2019, were prospectively screened for enrolment in the study. Inclusion criteria were (i) AF diagnosis, (ii) first procedure of AF ablation with cryoballoon CA, and (iii) contrast CT scan performed pre-ablation. A total of 576 consecutive patients were prospectively included and analysed in this study. At CT scan, 122 patients (21.2%) were diagnosed with CAD, of whom 41 patients (7.1%) with critical CAD. At survival analysis, critical CAD at CT scan was a predictor of atrial tachyarrhythmia (AT) recurrence during the follow-up, only in Cox univariate analysis [hazard ratio (HR) = 1.79] but was not an independent predictor in Cox multivariate analysis. At Cox multivariate analysis, independent predictors of AT recurrence were as follows: persistent AF (HR = 2.93) and left atrium volume index (HR = 1.04). CONCLUSION: In patients undergoing CT scan before AF ablation, critical CAD was diagnosed in 7.1% of patients. Coronary artery disease and revascularization were not independent predictors of recurrence; thus, in this patient population, AF ablation should not be denied and can be performed together with CAD treatment.

Evaluation of coronary artery disease in patients undergoing atrial fibrillation ablation: a non-invasive FFR computed tomography study.

To evaluate coronary artery disease (CAD) with computed tomography coronary angiography (CTCA)-derived fractional flow reserve (FFR) in patients with atrial fibrillation (AF) requiring ablation. The study population consisted of 151 patients who underwent CTCA before AF ablation (AF group), and a control group of 151 patients from the outpatient clinic who underwent CTCA without any history of AF (non-AF group), matched for age, sex, BMI, and angina symptomatology. All study patients underwent CTCA with subdivision of coronary lesion type into severe (≥ 70% luminal narrowing), moderate (50% ≤ luminal narrowing < 70%), and mild stenosis (< 50% luminal narrowing). In patients with ≥ 1 moderate or severe stenosis, non-invasive FFR was calculated from CTCA (FFRCT). Baseline characteristics and CAD risk factors were similar between the 2 groups. During CTCA, 38% of the patients in the AF group were in ongoing atrial arrhythmia (either AF or regular atrial tachycardia). The number of patients with severe (10 (6.6%) vs 10 (6.6%), P = 1.00), moderate (14 (9.5%) vs 10 (6.7%), P = 0.4), and mild stenosis (43 (28.5%) vs 56 (37.1%), P = 0.11) was not significantly different between the 2 groups. Performance of FFRCT was feasible in 32/44 patients (73%), and failed in 27% of the patients (7 and 5 patients in the AF and non-AF group, respectively, P = 0.74). No difference was observed in the prevalence of hemodynamically significant stenosis (FFRCT ≤ 0.80) (15 (9.9%) vs 12 (7.9%), P = 0.85). Our study showed technical feasibility of CTCA in all patients of both groups, including the patients with AF as presenting rhythm. The FFRCT add-on analysis failed equally frequent in patients of the AF versus non-AF group. An equal rate of CAD was observed in the AF group and non-AF group, favoring the concept of shared associated risk factors for CAD and AF.

Impact of ramus coronary artery on computed tomography derived fractional flow reserve (FFRCT ) in no apparent coronary artery disease.

BACKGROUND: The ramus artery contributes to the development of turbulence, which may influence computed tomography (CT) derived fractional flow reserve (FFRCT ) even without coronary artery disease (CAD). The relationship between ramus-induced turbulence and FFRCT is unclear. METHOD AND RESULTS: A total of 120 patients with <20% coronary stenosis assessed by both FFRCT and invasive coronary angiography were evaluated. The patients were divided into three groups: absent-ramus (n = 72), small-ramus that could not be analyzed by FFRCT (n = 18), and large-ramus that could be analyzed by FFRCT (n = 30). FFRCT measurements were performed at the proximal and distal segments of the left anterior descending (LAD), left circumflex (LCX), and ramus artery. With absent-ramus and small-absent ramus groups, FFRCT was measured at the distal end of the left main trunk at the same level for the proximal segments of the LAD and LCX. In absent-ramus group, proximal FFRCT showed no significant differences between three vessels (LAD = .96 ± .02; MID = .97 ± .02; LCX = .97 ± .02). However, in small and large-ramus groups, proximal FFRCT was significantly higher in the ramus artery than LAD and LCX (small-ramus, LAD = .95 ± .03, Ramus = .97 ± .02, LCX = .95 ± .03; large-ramus: LAD = .95 ± .03, Ramus = .98 ± .01; LCX = .96 ± .03; p < .05). A large ramus was associated with a higher prevalence of a distal FFRCT ≤.80 (odds ratio 7.0, 95% CI 1.2-40.1, p = .03). A proximal ramus diameter predicted distal FFRCT ≤.80 (cut-off 2.1 mm, AUC .76, sensitivity 100%, specificity 52%, 95% CI .61-.90). CONCLUSIONS: The presence of a large-ramus artery may cause an FFRCT decline in no apparent CAD.

The impact of iodine contrast agent on radiation dose of heart and blood: a comparison between coronary CT angiography and cardiac calcium scoring CT.

BACKGROUND: Iodine contrast agent (CA) is widely used in cardiac computed tomography (CT). The CA can increase the organ radiation doses due to the photoelectric effect. PURPOSE: To investigate the impact of CA on radiation dose in cardiac CT by comparing the radiation dose between contrast coronary CT angiography (CCTA) and non-contrast calcium scoring CT (CSCT). MATERIAL AND METHODS: Radiation doses were computationally calculated for 30 individual patients who received CSCT and CCTA in the same exam session. The geometry and acquisition parameters were modeled in the simulations based on individual patient CT images and acquisitions. Doses in the presence and absence of CA were obtained in the aorta, left ventricle (LV), right ventricle (RV), and myocardial tissue (MT). The dose values were normalized by size-specific dose estimate (SSDE). The dose enhancement factors (DEFSSDE) were calculated as the ratio of doses in CCTA over doses in CSCT. RESULTS: Compared to the CSCT scans, doses increase in the CCTA scans in the aorta (DEFSSDE = 2.14 ± 0.20), LV (DEFSSDE = 1.78 ± 0.26), and RV (DEFSSDE = 1.31 ± 0.22). A linear relation is observed between the local CA concentrations and the dose increase in the heart; DEFSSDE = 0.07*I(mg/mL) + 0.80 (R2 = 0.8; p < 0.01). The DEFSSDE in the MT (DEFSSDE = 0.96 ± 0.08) showed no noticeable impact of CA on the dose in this tissue. In addition, patient variability in the dose distributions was observed. CONCLUSION: A linear causal relation exists between local CA concentration and increase in radiation dose in cardiac CT. For the same CT exposure, dose to the heart is on average 55% higher in contrast cardiac CT.

A patient- and acquisition-tailored injection approach for improving consistency of CT enhancement towards a target CT value in coronary CT angiography.

BACKGROUND: Unoptimized coronary CT angiography (CTA) exams typically result in a highly variable arterial enhancement (HUa ) across patients. This study aimed at harmonizing arterial enhancement by implementing a patient-, contrast- and kV-tailored injection protocol. METHODS: First, the optimal body size metric to predict HUa was identified by retrospectively analysing images of 76 patients, acquired with 70 ml contrast media (G1). Second, using phantom experiments, correction factors for the effect of kV and contrast concentration on HUa were determined. Third, a model was developed, prescribing the optimal contrast dose to be injected to obtain a diagnostically appropriate arterial target enhancement HUtarget . The model was then validated on 278 prospectively collected patients, in two groups with two different HUtarget : 525 HU (207 patients, G2A) and 425 HU (71 patients, G2B). The HUa histograms were compared among groups and to the target enhancement through their mean and standard deviation (SD) at 100 kVp reference level. Also, signal-to-noise ratio was obtained and compared among the groups. RESULTS: Fat free mass (FFM) showed the highest correlation with HUa (r = 0.69). KVp correction factors ranged from 0.65 at 70 kVp to 1.22 at 140 kVp. The obtained model reduced the group heterogeneity (SD) from 101HU for reference G1 to 75HU (p < 0.001) for G2A and 68HU (p < 0.001) for G2B. The mean HUa of 506HU in G2A was slightly below HUtarget  = 525HU (p = 0.01) whereas in G2B, the mean HUa of 414HU was not significantly different from HUtarget  = 425HU (p = 0.54). The total iodine dose was lowered from 19.5 g-I to 17.6 g-I and 14.2 g-I from G1 to G2A and G2B, on average. CONCLUSION: A contrast injection model, based on patient's fat free mass and accounting for the contrast agent concentration and the planned CT-scan tube voltage, harmonized arterial enhancement among patients towards a predefined target enhancement in coronary CTA scanning, without affecting the bolus timing.

Stereocontrolled Synthesis of C20S-C26 and C20R-C26 Fragments of Amphidinolide L.

Amphidinolide L is a cytotoxic macrolide isolated from marine symbiotic dinoflagellates of the genus Amphidinium. While its planar structure and the absolute stereochemistry of the C21-C26 part have been determined, six stereocenters have remained unassigned. Aiming at structure determination, we have developed a synthetic route to the C20S-C26 and C20R-C26 fragments via the Li-mediated stereocontrolled aldol reaction. Two aldehydes, 16 with the C22-hydroxy group and 19 with the C22-TES ether, were synthesized from lactone 4. The aldol reactions using the Li-enolate of 4-methyl-2-pentanone in THF provided the C20S-C26 fragment 20 from 16 and a 1:3.5 mixture of the C20-C26 fragment 22 favoring the C20R-isomer. Mechanistic studies based on an extensive search of transition states in explicit solvents indicated that the C20S-isomer would be generated via a tri-solvated transition state, while the C20R-isomer would be formed via a di-solvated transition state. The calculation emphasizes the importance of the coordination network as a higher-order complex composed of solvent molecules, aldehyde, enolate, and Li atoms in the reaction of 16 to minimize steric interactions but maximize the stabilizing effect by the coordination of solvents. The presence of the rotationally free aldehyde in the reaction of 19 results in moderate diastereoselectivity.

Human papillomavirus-related oropharyngeal carcinoma.

It was not until around 2000 that human papillomavirus-related oropharyngeal carcinoma was recognized as carcinoma with clinical presentations different from nonrelated head and neck carcinoma. Twenty years after and with the revision of the tumor-node-metastasis classification in 2017, various clinical trials focused on human papillomavirus-related oropharyngeal carcinoma to improve the prognosis and quality of life of patients with this disease. However, the incidence of human papillomavirus-related cancers is increasing, which is expected to be particularly prominent in Japan, where human papillomavirus vaccination is not widely available. In this review, we describe the current status of clinical trials (mainly focused on initial surgery and radiation dose reduction) for, primary and secondary prevention of, and the present status of human papillomavirus-related oropharyngeal carcinoma in Japan.

Systemic therapy for salivary gland malignancy: current status and future perspectives.

Salivary gland malignancies are rare neoplasms that have a broad histological spectrum and a variety of biologic behaviors. Salivary gland malignancies are known as chemo-resistant tumors, which render optimal treatment challenging. This review summarizes the role of systemic therapy for salivary gland malignancies. To date, the advantage of adding concurrent chemotherapy has remained undefined for both postoperative and inoperable locally advanced salivary gland malignancy patients undergoing radiotherapy. For recurrent/metastatic disease, local and/or systemic treatment options should be discussed in a multidisciplinary setting with consideration to both patient needs and tumor factors. For symptomatic patients or those who may compromise organ function, palliative systemic therapy can be a reasonable option based on the results of phase II studies. Platinum combination regimens as first-line therapy have been widely accepted. Personalized therapies have become established options, particularly for androgen receptor-positive, HER2-positive and NTRK fusion-positive salivary gland malignancies (i.e. androgen receptor and HER2 in salivary duct carcinoma and NTRK3 in secretory carcinoma). For patients with adenoid cystic carcinoma, multi-targeted tyrosine kinase inhibitors have also been developed. Anti-PD1 checkpoint inhibitors have shown limited activity to date. Investigation of active systemic treatments for salivary gland malignancy remains a significant unmet need. Future directions might include a more comprehensive genomic screening approach (usually next-generation sequencing-based) and combination strategies using immune checkpoint inhibitors. These are rare malignancies that require ongoing effort in the conduct of high-quality clinical trials.

First-line pembrolizumab ± chemotherapy for recurrent/metastatic head and neck cancer: Japanese subgroup of KEYNOTE-048.

BACKGROUND: Here, we report the results of the Japanese subgroup of the phase 3 KEYNOTE-048 study of pembrolizumab alone, pembrolizumab plus platinum and 5-fluorouracil (pembrolizumab-chemotherapy), or cetuximab plus platinum and 5-fluorouracil (EXTREME) in previously untreated recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). METHODS: Primary end points were overall survival (OS) and progression-free survival (PFS). Efficacy was evaluated in patients with PD-L1 combined positive score (CPS) ≥ 20 and ≥ 1 and the total Japanese subgroup (n = 67). RESULTS: At data cutoff (25 February 2019), pembrolizumab led to longer OS versus EXTREME in the PD-L1 CPS ≥ 20 subgroup (median, 28.2 vs. 13.3 months; HR, 0.29 [95% CI 0.09-0.89]) and to similar OS in the total Japanese (23.4 vs. 13.6 months; HR, 0.51 [95% CI 0.25-1.05]) and CPS ≥ 1 subgroups (22.6 vs. 15.8 months; HR, 0.66 [95% CI 0.31-1.41]). Pembrolizumab-chemotherapy led to similar OS versus EXTREME in the PD-L1 CPS ≥ 20 (median, 18.1 vs. 15.8 months; HR, 0.72 [95% CI 0.23-2.19]), CPS ≥ 1 (12.6 vs. 15.8 months; HR, 1.19 [95% CI 0.55-2.58]), and total Japanese subgroups (12.6 vs. 13.3 months; unadjusted HR, 1.10 [95% CI 0.55-2.22]). Median PFS was similar for pembrolizumab and pembrolizumab-chemotherapy versus EXTREME in all subgroups. Grades 3-5 treatment-related adverse events occurred in 5 (22%), 19 (76%), and 17 (89%) patients receiving pembrolizumab, pembrolizumab-chemotherapy, and EXTREME, respectively. One patient receiving pembrolizumab-chemotherapy died because of treatment-related pneumonitis. CONCLUSION: These results support the use of first-line pembrolizumab and pembrolizumab-chemotherapy for Japanese patients with R/M HNSCC. Clinical trial registry ClinicalTrials.gov, NCT02358031.

Paradoxical changes of coronary computed tomography derived fractional flow reserve.

A total of 1335 outpatients with suspected coronary artery disease and who underwent computed tomography derived fractional flow reserve (FFRCT ) analysis were examined. Only four patients showed reverse increase of FFRCT from the proximal to the distal vessel and all of them had a large ramus artery (RAM). Of all parameters (vessel length, lumen volume, plaque volume, and left ventricular mass), only the bifurcation angle was significantly higher in reverse increase of FFRCT with RAM group (106.0 ± 15.8°) than normal FFRCT with RAM group (82.6 ± 21.7°) and normal FFRCT without RAM group (66.9 ± 21.1°).

Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts.

BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects. METHODS: We performed a preclinical study to evaluate whether nintedanib might enhance antitumour immunity by targeting CAFs and thereby improve the response to immune checkpoint blockade (ICB). RESULTS: Whereas nintedanib did not suppress the growth of B16-F10 melanoma cells in vitro, it prolonged survival in a syngeneic mouse model of tumour formation by these cells, suggestive of an effect on the TME without direct cytotoxicity. Gene expression profiling indeed showed that nintedanib influenced antitumour immunity and fibrosis. Tumoural infiltration of CD8+ T cells and granzyme B production were increased by nintedanib, and its antitumour activity was attenuated by antibody-mediated depletion of these cells, indicating that nintedanib suppressed tumour growth in a CD8+ T cell-dependent manner. Moreover, nintedanib inhibited the proliferation and activation of fibroblasts. Finally, the combination of nintedanib with ICB showed enhanced antitumour efficacy in B16-F10 tumour-bearing mice. CONCLUSIONS: Our results suggest that nintedanib targeted CAFs and thereby attenuated the immunosuppressive nature of the TME and promoted the intratumoural accumulation and activation of CD8+ T cells, with these effects contributing to enhanced antitumour activity in combination with ICB.

Phase I/II Study of Cisplatin plus Nab-Paclitaxel with Concurrent Thoracic Radiotherapy for Patients with Locally Advanced Non-Small Cell Lung Cancer.

LESSONS LEARNED: The combination of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer is a promising therapeutic strategy. Further investigation is warranted. BACKGROUND: We conducted a phase I/II trial of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (NSCLC) to determine the recommended dose (RD) of nab-paclitaxel and to evaluate the safety and efficacy of this regimen. METHODS: In the phase I study, escalating doses of weekly nab-paclitaxel were administered together with cisplatin at 75 mg/m2 every 3 weeks and concurrent radiotherapy. In the phase II study, nab-paclitaxel was administered at the RD. RESULTS: In the phase I study, whereas no dose-limiting toxicity (DLT) was observed with nab-paclitaxel at 50 or 60 mg/m2 , one of six patients experienced DLT (esophagitis of grade 3) at 70 mg/m2 , determined as the RD. Twenty-four patients at RD were evaluable for safety and efficacy in phase II. Common toxicities included esophagitis (87.5%) and leukopenia (79.2%). Pneumonitis and treatment-related deaths were not observed, but 20 patients (83.3%) experienced radiation pneumonitis, with one case of grade 3 and four of grade 2, after completion of concurrent chemoradiotherapy. The 2-year overall survival and progression-free survival rates were 73.9% and 56.5% (95% confidence interval [CI], 34.3%-74.7%), respectively. CONCLUSION: Concurrent chemoradiation with nab-paclitaxel at 70 mg/m2 and cisplatin at 75 mg/m2 every 3 weeks showed encouraging feasibility and activity for locally advanced NSCLC.

Clinical Application of the FoundationOne CDx Assay to Therapeutic Decision-Making for Patients with Advanced Solid Tumors.

BACKGROUND: Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors. MATERIALS AND METHODS: We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel-which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)-to patients with advanced or recurrent solid tumors before its approval in Japan. RESULTS: A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21-126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death-ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy. CONCLUSION: The FoundationOne CDx assay was performed with formalin-fixed, paraffin-embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs. IMPLICATIONS FOR PRACTICE: This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy.

Safety and efficacy of cetuximab-containing chemotherapy after immune checkpoint inhibitors for patients with squamous cell carcinoma of the head and neck: a single-center retrospective study.

Immunotherapy has been shown to prolong survival in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) in front-line use; however, subsequent systemic therapy has not been optimized. This study aimed to evaluate the safety and efficacy of cetuximab-containing chemotherapy after immunotherapy. We retrospectively analyzed patients with recurrent or metastatic SCCHN who underwent cetuximab-containing regimens after progression on immunotherapy. Of the 22 patients who met the inclusion criteria, 21 received paclitaxel and cetuximab, and 1 carboplatin and fluorouracil and cetuximab after immunotherapy. Nine patients achieved a partial response, 10 patients had stable disease as their best response on cetuximab-containing chemotherapy, yielding an overall response rate and disease control rate of 40.9 and 86.4%, respectively. The median progression-free survival was 5.2 months, and the median overall survival was 14.5 months. Ten patients developed grade 3-4 adverse events, including neutropenia (31.8%), acneiform rash (9.1%), anemia (4.5%), hypertransaminasemia (4.5%) and stomatitis (4.5%). The most frequent cetuximab-related toxicities across all grades were skin reactions (77.3%), hypomagnesemia (40.9%), stomatitis (27.3%), paronychia (13.6%) and keratitis (4.5%). There was no treatment-related death. Taken together, cetuximab-containing chemotherapy was effective and feasible even after immunotherapy.