IntroductionNecitumumab plus gemcitabine and cisplatin (GCN) is a standard therapy for patients with advanced lung squamous cell carcinoma (LSqCC). However, the efficacy and tolerability of GCN in ...second-line or later treatment for patients previously treated with immune checkpoint inhibitors (ICIs) remain unknown.MethodsThis multicenter, retrospective, cohort study assessed the efficacy and tolerability of GCN initiated between November 1, 2019 and March 31, 2022 as second-line to fourth-line treatment in patients with advanced LSqCC who had been pretreated with ICIs. The primary end point was progression-free survival (PFS).ResultsA total of 93 patients from 35 institutions in Japan were enrolled. The median PFS, median overall survival (OS), and objective response rate were 4.4 months (95% confidence interval CI: 3.8-5.3), 13.3 months (95% CI: 9.6-16.5), and 27.3% (95% CI: 18.3-37.8), respectively. The median PFS, median OS, and objective response rate for second-line, third-line, and fourth-line treatment groups were 4.8 months, 3.8 months, and 4.3 months (p = 0.24); 15.7 months, 11.6 months, and 10.1 months (p = 0.06); and 31.0%, 13.6%, and 37.5% (p = 0.22), respectively. The severity of GCN-related skin disorders was associated with longer PFS (p < 0.05) and OS (p < 0.05). The frequencies of grade ≥3 skin disorders, hypomagnesemia, pneumonitis, and febrile neutropenia were 16.1%, 7.5%, 1.1%, and 4.3%, respectively. There were no treatment-related deaths.ConclusionsGCN for ICI-pretreated patients with LSqCC seems tolerable and offers promising efficacy regardless of treatment line, and ICI pretreatment might enhance GCN efficacy.
Spontaneous regression of cancer is a rare biological phenomenon and the mechanisms underlying it are poorly understood. There have been few reports of temporal changes in morphology and metabolism ...associated with spontaneous regression. Here, we report an 80-year-old man who presented with right upper quadrant pain. He was diagnosed with stage IVA lung cancer, but without treatment, rib metastasis disappeared 4 months after the diagnosis. Although mediastinal lymph node metastasis regressed partially it began to grow 10 months after the diagnosis. In this case, complete and partial spontaneous tumor regressions were observed in the patient, allowing for a comparison of morphological and metabolic changes during each occurrence by serial computed tomography (CT) and 18F-fluodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT). We observed that the rib metastasis with high FDG uptake on initial PET/CT was composed of cancer cells as well as intratumoral immune cells, whereas recurrent mediastinal lymph node metastasis with high FDG uptake on follow-up PET/CT was composed of cancer cells with few immune cells. Our findings suggest that hypermetabolism within the rib metastasis on initial PET/CT reflected immune activation, whereas hypermetabolism within the mediastinal lymph node on follow-up PET/CT reflected tumor activation.
Abstract Background Atrial fibrillation (AF) affects millions of individuals worldwide. The genome-wide association studies have identified robust genetic associations with AF. Methods We genotyped ...5461 participants of Japanese ancestry for 11 AF-related loci and determined the effects of carrying different numbers of risk alleles on disease development and age at disease onset. The weighted genetic risk score (GRS) was calculated, and its ability to predict AF was determined. Results Six single-nucleotide polymorphisms—rs593479 (1q24 in PRRX1 ), rs1906617 (4q25 near PITX2 ), rs11773845 (7q31 in CAV1 ), rs6584555 (10q25 in NEURL ), rs6490029 (12q24 in CUX2 ), and rs12932445 (16q22 in ZFHX3 ) ( P < 1.9 × 10−5 )—were confirmed as being associated with AF. Patients with a high total number of risk alleles (9-12) had a younger median age at onset of AF (58 years; 95% confidence interval CI, 55-60 years) than those with a low total number (1-4) (63 years; 95% CI, 61-64 years) ( P = 0.0015). We observed a 4.38-fold (95% CI, 3.69-5.19) difference in risk of AF between individuals with scores in the top and bottom quartiles of the GRS. Receiver operating characteristic analysis indicated an area under the curve of 0.641 (95% CI, 0.628-0.653; P < 0.0001). Conclusions Six loci were validated as associated with AF in a Japanese population. This study suggests that a combination of common genetic markers modestly facilitates discrimination of AF. This is the first report, to our knowledge, to demonstrate that the age of onset of AF is affected by common risk alleles.
To compare physicochemical properties of emulsions of ethiodized oil (Lipiodol; Guerbet, Villepinte, France) and epirubicin prepared using different techniques for conventional transarterial ...chemoembolization.
Lipiodol was mixed with epirubicin solution (8.33 mg/mL) by using a 3-way stopcock. The following technical parameters were compared: ratio of epirubicin solution to Lipiodol (1:2 vs 1:1), number of pumping exchanges through the stopcock (20 exchanges vs 10 exchanges), pumping speed (1 s/push vs 2 s/push), and first push syringe (epirubicin solution vs Lipiodol).
The mean percentage of water-in-oil was 70.45 ± 1.51 in the 1:2 epirubicin-Lipiodol ratio and 16.03 ± 2.95 in the 1:1 ratio (P < .001). The first push syringe did not influence emulsion type. Median droplet sizes were significantly larger in the slower pumping speed (52.0 μm in 2 s vs 33.7 μm in 1 s; P < .001), whereas there was no significant difference in number of pumping exchanges. Droplet sizes enlarged during 30 minutes after pumping. Viscosity was lower in the 1:1 ratio and the slower pumping speed. Viscosity decreased during 30 minutes after pumping.
The ratio of epirubicin to Lipiodol is a significant factor to form water-in-oil emulsions with higher viscosity. The percentage of water-in-oil is limited to 70% using current pumping techniques. The pumping speed strongly influences droplet size and viscosity.
To report the results of a phase I/II study of a transcatheter arterial chemoembolization protocol using cisplatin powder and degradable starch microspheres (DSM) for unresectable colorectal liver ...metastases after failure of FOLFOX (5-flourouracil, leucovorin plus oxaliplatin) chemotherapy conducted to determine the recommended dose of cisplatin powder and to assess the efficacy and safety of the protocol.
A fine-powder formulation of cisplatin was mixed with DSM and administered via the hepatic artery every 4 weeks. In phase I, three cohorts of patients received escalating doses of cisplatin powder: 50 mg/m(2), 65 mg/m(2), and 80 mg/m(2). In phase II, tumor response, toxicity, and survival times were assessed.
The study enrolled 24 patients. Previously, FOLFOX had been administered to all patients, an irinotecan-containing regimen had been administered to 12 patients, and bevacizumab or cetuximab or both had been administered to 14 patients. In phase I, dose-limiting toxicity did not appear at any level, and the recommended dose of cisplatin powder was determined to be 80 mg/m(2). In phase II, a tumor response rate of 61.1% was achieved. The median hepatic progression-free survival and overall survival were 8.8 months (95% confidence interval CI, 4.06-13.5 mo) and 21.1 months (95% CI, 8.37-33.8 mo). The following grade 3 toxicities were observed: thrombocytopenia (12.5%), aspartate transaminase elevation (33.3%), alanine transaminase elevation (12.5%), hyponatremia (8.3%), and cholecystitis (4.2%).
This study shows that transcatheter arterial chemoembolization with cisplatin powder at a dose of 80 mg/m(2) mixed with DSM is well tolerated and can produce a high response rate with a long survival time for patients with unresectable colorectal liver metastases after failure of FOLFOX.
To evaluate the pharmacokinetics of intraarterial (IA) administration of micellar nanoparticles incorporating SN-38 injection compared with intravenous (IV) administration in a rabbit liver tumor ...model.
In this animal care committee-approved study, 18 rabbits (mean weight, 3.89 kg; range, 3.20-4.70 kg) with VX2 liver tumors were divided into two groups (IA and IV). Micellar nanoparticles incorporating SN-38 (30 mg/kg) were injected through the left hepatic artery in the IA group and the right femoral vein in the IV group. NK012 and free SN-38 in the plasma, liver parenchyma, and tumors were measured within 24 hours. Histologic examinations were conducted at 2 and 24 hours.
There were no significant differences in the serum area under the concentration-time curve (0-24 h) for free SN-38, at 1,500 and 1,310 μg∙min/mL in the IA and IV groups, respectively (P = .152). The IA group showed significantly higher free SN-38 concentrations in tumor tissues at all time points compared with the IV group (P = .002 at 3 min, P = .011 at 2 h, and P = .047 at 24 h). Histologic findings showed that significantly higher tumor necrosis ratios were observed in the IA group compared with the IV group at 24 hours (P = .028).
Micellar nanoparticles could be a promising IA drug delivery system to achieve high tumor tissue concentrations of SN-38.
Abstract Background Chromosome 4q25 has been repeatedly identified as atrial fibrillation (AF)-sensitive locus in multiple genome-wide association studies (GWAS) and is considered to hold some clues ...to AF pathogenesis. We aimed to investigate the clinical utilities in Japanese and to unveil the function of the 4q25 locus in affecting transcription of adjacent genes. Methods We conducted AF GWAS in Japanese population (1382 AF cases and 1478 controls) and the replication panel (1666 AF cases and 1229 controls) with detailed clinical information which showed the acceleration of AF onset. Stepwise investigations with linkage disequilibrium analysis, histone code patterns, and reporter assay in the 4q25 locus were performed. Results The AF GWAS confirmed a significant association of rs4611994 and rs1906617 in chromosome 4q25 with AF. In the clinical analysis, AF onset of the individuals with risk allele accelerated 2.5 years compared with those with protective allele ( p = 0.00012). Next, in the functional analysis, three single nucleotide polymorphisms (SNPs) in the variant group selected by linkage disequilibrium analysis were identified as candidates for the cis -regulatory element toward adjacent genes in chromatin immunoprecipitation assay. Among them, rs4611994 and rs72900144 regions showed higher effects on the transcriptional activity of luciferase gene in the risk alleles than those in the protective alleles ( p < 0.0001, p < 0.005, respectively). Conclusions AF GWAS in Japanese confirmed the association with 4q25 locus and indicated that its SNP affected the acceleration of AF onset. The candidate regions of the causative SNPs, rs4611994 and rs72900144, could alter the adjacent gene expression level.
Immune thrombocytopenia (ITP) carries bleeding and thrombotic risks; however, thromboses associated with ITP have not been histologically examined. This report presents optical coherence tomography ...images of the culprit lesion and histology of coronary aspirates in very late stent thrombosis complicating severe ITP, providing evidence of platelet-rich thrombus formation. (Level of Difficulty: Advanced.)
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Abstract Objective Recent studies have suggested that high-sensitivity cardiac troponin T (hs-cTnT) may be useful for detecting subclinical atherosclerosis and assessing cardiovascular disease risk. ...The aim of this study was to investigate whether serum hs-cTnT is associated with the degree of coronary artery calcification. Methods We measured serum hs-cTnT concentrations and performed multidetector row coronary CT in 215 consecutive, stable patients with clinical suspicion of coronary artery disease. Nonenhanced coronary CT was performed to determine the coronary calcium score, and contrast-enhanced coronary CT was performed to identify obstructive coronary artery disease. We then evaluated the relationship between serum hs-cTnT concentrations and the degree of coronary calcium or obstructive coronary artery disease using multiple regression analysis and logistic regression models. Results Multiple regression analysis demonstrated that serum hs-cTnT concentrations and calcium score were independently associated after logarithmic transformation ( β = 0.348; P < .0001). Logistic regression analyses demonstrated that serum hs-cTnT concentration was associated with an increased odds of an Agatston score >10 (odds ratio, 1.250; 95% confidence interval CI, 1.150–1.378), an Agatston Score >400 (odds ratio, 1.101; 95% CI, 1.054–1.157), and obstructive coronary artery disease (odds ratio, 1.119; 95% CI, 1.066–1.185). Conclusion Serum hs-cTnT is associated with coronary calcium in individuals with suspected coronary disease and may therefore be a marker to detect subclinical atherosclerosis.
To compare the efficacy, complications, and inflammatory levels in partial splenic embolization (PSE) with coils or gelatin sponge (GS) particles with or without intraarterial antibiotic agents.
...Forty-four patients with hypersplenism treated by PSE were assessed. GS particles were used in 31 patients, and coils were used in 13 patients. In 17 of the 31 patients who received GS, GS suspended in antibiotic solution was injected via the splenic artery. In the other 14 patients, antibiotic agents were not used. In all 13 coil group patients, an antibiotic solution was intraarterially injected before embolization. Platelet counts were compared between the GS and coil groups. Complications and serum C-reactive protein (CRP) levels were compared among the three groups.
There were no significant differences in platelet counts and platelet increased ratios at 6 months (10.0 × 10(4)/µL and 193% in the GS group vs 9.0 × 10(4)/µL and 221% in the coil group), and no significant differences in frequencies of complications. However, one splenic abscess occurred in a patient treated with GS without antibiotics, resulting in death. The mean serum CRP level in the GS with antibiotic group at 2 weeks was significantly lower than in the other two groups.
The efficacy of PSE is similar with the use of coils versus GS particles. Prophylactic intraarterial antibiotic treatment could be useful in preventing inflammatory reactions after PSE.
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