Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial.

BACKGROUND: Erdafitinib is an oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved to treat locally advanced/metastatic urothelial carcinoma (mUC) in patients with susceptible FGFR3/2 alterations (FGFRalt) who progressed after platinum-containing chemotherapy. FGFR-altered tumours are enriched in luminal 1 subtype and may have limited clinical benefit from anti-programmed death-(ligand) 1 [PD-(L)1] treatment. This cohort in the randomized, open-label phase III THOR study assessed erdafitinib versus pembrolizumab in anti-PD-(L)1-naive patients with mUC. PATIENTS AND METHODS: Patients ≥18 years with unresectable advanced/mUC, with select FGFRalt, disease progression on one prior treatment, and who were anti-PD-(L)1-naive were randomized 1 : 1 to receive erdafitinib 8 mg once daily with pharmacodynamically guided uptitration to 9 mg or pembrolizumab 200 mg every 3 weeks. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS: The intent-to-treat population (median follow-up 33 months) comprised 175 and 176 patients in the erdafitinib and pembrolizumab arms, respectively. There was no statistically significant difference in OS between erdafitinib and pembrolizumab [median 10.9 versus 11.1 months, respectively; hazard ratio (HR) 1.18; 95% confidence interval (CI) 0.92-1.51; P = 0.18]. Median PFS for erdafitinib and pembrolizumab was 4.4 and 2.7 months, respectively (HR 0.88; 95% CI 0.70-1.10). ORR was 40.0% and 21.6% (relative risk 1.85; 95% CI 1.32-2.59) and median duration of response was 4.3 and 14.4 months for erdafitinib and pembrolizumab, respectively. 64.7% and 50.9% of patients in the erdafitinib and pembrolizumab arms had ≥1 grade 3-4 adverse events (AEs); 5 (2.9%) and 12 (6.9%) patients, respectively, had AEs that led to death. CONCLUSIONS: Erdafitinib and pembrolizumab had similar median OS in this anti-PD-(L)1-naive, FGFR-altered mUC population. Outcomes with pembrolizumab were better than assumed and aligned with previous reports in non- FGFR-altered populations. Safety results were consistent with the known profiles for erdafitinib and pembrolizumab in this patient population.

EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma.

INTRODUCTION: This exploratory analysis evaluated efficacy and safety data for enfortumab vedotin versus chemotherapy over a median follow-up of ∼2 years from EV-301. MATERIALS AND METHODS: Patients with locally advanced/metastatic urothelial carcinoma with prior platinum-containing chemotherapy and disease progression during/after programmed cell death protein 1/ligand 1 inhibitor treatment were randomized to enfortumab vedotin or chemotherapy (docetaxel, paclitaxel, vinflunine). Endpoints were overall survival (primary), progression-free survival (PFS), objective response, and safety. RESULTS: In total, 608 patients were included (enfortumab vedotin, n = 301; chemotherapy, n = 307). With a median follow-up of 23.75 months, 444 deaths had occurred (enfortumab vedotin, n = 207; chemotherapy, n = 237). Risk of death was reduced by 30% with enfortumab vedotin versus chemotherapy [hazard ratio (HR) 0.70 (95% confidence interval [CI] 0.58-0.85); one-sided, log-rank P = 0.00015]; PFS improved with enfortumab vedotin [HR 0.63 (95% CI 0.53-0.76); one-sided, log-rank P < 0.00001]. Treatment-related adverse event rates were 93.9% for enfortumab vedotin and 91.8% for chemotherapy; grade ≥ 3 event rates were 52.4% and 50.5%, respectively. Grade ≥ 3 treatment-related decreased neutrophil count (14.1% versus 6.1%), decreased white blood cell count (7.2% versus 1.4%), and anemia (7.9% versus 2.7%) were more common with chemotherapy versus enfortumab vedotin; maculopapular rash (7.4% versus 0%), fatigue (6.8% versus 4.5%), and peripheral sensory neuropathy (5.1% versus 2.1%) were more common with enfortumab vedotin. Of special interest adverse events, treatment-related skin reactions occurred in 47.3% of patients receiving enfortumab vedotin and 15.8% of patients receiving chemotherapy; peripheral neuropathy occurred in 48.0% versus 31.6%, respectively, and hyperglycemia in 6.8% versus 0.3%. CONCLUSIONS: After a median follow-up of ∼2 years, enfortumab vedotin maintained clinically meaningful overall survival benefit versus chemotherapy, consistent with findings from the EV-301 primary analysis; PFS and overall response benefit remained consistent. Adverse events were manageable; no new safety signals were observed.

Nuclear and magnetic spin structure of the antiferromagnetic triangular lattice compound LiCrTe2 investigated by [Formula: see text]SR, neutron and X-ray diffraction.

Two-dimensional (2D) triangular lattice antiferromagnets (2D-TLA) often manifest intriguing physical and technological properties, due to the strong interplay between lattice geometry and electronic properties. The recently synthesized 2-dimensional transition metal dichalcogenide LiCrTe[Formula: see text], being a 2D-TLA, enriched the range of materials which can present such properties. In this work, muon spin rotation ([Formula: see text]SR) and neutron powder diffraction (NPD) have been utilized to reveal the true magnetic nature and ground state of LiCrTe[Formula: see text]. From high-resolution NPD the magnetic spin order at base-temperature is not, as previously suggested, helical, but rather collinear antiferromagnetic (AFM) with ferromagnetic (FM) spin coupling within the ab-plane and AFM coupling along the c-axis. The value if the ordered magnetic Cr moment is established as [Formula: see text]. From detailed [Formula: see text]SR measurements we observe an AFM ordering temperature [Formula: see text] K. This value is remarkably higher than the one previously reported by magnetic bulk measurements. From [Formula: see text]SR we are able to extract the magnetic order parameter, whose critical exponent allows us to categorize LiCrTe[Formula: see text] in the 3D Heisenberg AFM universality class. Finally, by combining our magnetic studies with high-resolution synchrotron X-ray diffraction (XRD), we find a clear coupling between the nuclear and magnetic spin lattices. This suggests the possibility for a strong magnon-phonon coupling, similar to what has been previously observed in the closely related compound LiCrO[Formula: see text].

Methylation in p14(ARF) is frequently observed in colorectal cancer with low-level microsatellite instability.

Colorectal cancer (CRC) can be classified as high-level microsatellite instability (MSI-H), low-level MSI (MSI-L) and microsatellite stable (MSS) depending on levels of MSI. MSI-H CRC relies on a distinct molecular pathway due to the mismatch repair (MMR) deficiency and shows methylation in multiple gene promoters. The genetic pathway leading to MSI-L is unknown, although higher levels of promoter methylation are observed in this group compared with MSS CRCs. This study explored how promoter methylation affects MSI phenotype, by analysing the methylation status of eight CRC-related promoters, MSI phenotype and KRAS/BRAF mutations in a series of 234 CRCs. Promoter methylation of p14(ARF) was significantly related to MSI-L CRC with KRAS mutation. The MSI-H phenotype was related to methylation of MLH1 as expected, while the MSS phenotype was related to methylation of p16(INK4a) and O(6)-methylguanine-DNA methyltransferase, although this was not statistically significant. Thus, promoter methylation of p14(ARF) could be a significant alteration leading to CRC with MSI-L.

No duplicate KRAS mutation is identified on the same allele in gastric or colorectal cancer cells with multiple KRAS mutations.

Codon 12 and 13 mutations in 170 colorectal cancer (CRC) and 66 gastric cancer (GC) specimens were analysed by an 'enriched' polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. All identified mutations were verified by direct sequencing of the second PCR products. Among the 170 CRC specimens, mutations were identified in 47 (28%) and 13 (7.6%) cases in codons 12 and 13, respectively. In the 66 GC specimens examined, however, mutations in codons 12 and 13 were only detected in two (3.0%) and one (1.5%) cases, respectively. Mutations in both codon 12 and 13 were found in 3/170 (1.8%) CRCs and 1/66 (1.5%) GCs. Duplicate mutations were never identified in the same allele, which was confirmed by direct sequencing of the second amplified products. The majority of colorectal and gastric cancer cells with KRAS mutations are homogeneous because they have the same KRAS mutation. A few colorectal or gastric cancers, however, showed heterogeneity, as verified by the fact that single mutations were identified in the same allele.

Intra-articular Localized Haemangioma of the Knee Mimicking Localized Pigmented Villonodular Synovitis: A Case Report.

Intra-articular synovial haemangioma of the knee is a benign tumour. However, diagnostic delay leads to degenerative changes in the cartilage and osteoarthritis due to recurrent haemarthrosis. Therefore, treatment should be performed immediately. We report the case of a localized synovial haemangioma arising from the medial plica in a 38-year old female presenting with pain and restricted range of motion in the right knee joint. Initially, we diagnosed this case as a localized pigmented villonodular synovitis (LPVS) based on MRI and arthroscopic findings and performed only arthroscopic en bloc excision of the mass and synovectomy around the mass for diagnostic confirmation. Fortunately, there was no difference in the treatment approaches for LPVS and localized haemangioma and the synovial haemangioma had not recurred at the 3-month postoperative follow-up with MRI. The patient's clinical symptoms resolved and had not relapsed two years after surgery.

Dynamic gadolinium-enhanced fat-suppressed T1-weighted MRI (chemical shift selective images) for remitting seronegative symmetrical synovitis with pitting edema.

A 75-year-old man suddenly suffered from polyarthralgia and pitting edema in his distal extremities. Laboratory tests revealed inflammation, negative rheumatoid factor, and positive B7 human leukocyte antigen typing. Severe synovitis was observed in dynamic gadolinium-enhanced fat-suppressed (DGEFS) T1-weighted images of his right hand. Our diagnosis was remitting seronegative symmetrical synovitis with pitting edema (RS(3)PE syndrome). He responded dramatically to low-dose corticosteroids, after which his synovitis remarkably improved as observed with DGEFS imaging. DGEFS imaging is useful for distribution of synovitis in patients with RS(3)PE syndrome as well as assessing the efficacy of treatment.

Effect of colostomy on intestinal carcinogenesis by methylazoxymethanol acetate in rats.

The effect of the fecal stream on the induction of intestinal tumors was studied in 3 groups of SD rats. Rats in group 1 were subjected to single-barreled colostomies for the complete exclusion of the fecal stream at the proximal one-third level of the colons and were given consecutive iv injections of methylazoxymethanol acetate. Rats in group 2 were given methylazoxymethanol acetate alone. Rats in group 3 were not treated and served as controls. Tumors were noted in the small and large intestines of almost all rats in both groups 1 and 2. Even animals with single-barreled colostomies frequently developed tumors in the colon distal to the colostomy where the mucosa did not have contact with the fecal stream. These results indicated that carcinogens could probably reach the intestinal mucosa via the vascular system as well as by biliary transport.

Induction of hepatic tumors in rats by senkirkine and symphytine.

The carcinogenicity of the pyrrolizidine alkaloids senkirkine and symphytine was studied in male inbred ACI rats. Animals were divided into 3 groups: Group I received ip injections of freshly prepared senkirkine at a dose of 10% of the median lethal dose (LD50) twice weekly for 4 weeks and then once a week for 52 weeks. Group II received ip injections of symphytine at a dose of 10% of the LD50 by the same injection schedule as in group I. The control group was given ip injections of a 0.9% NaCl solution following the same injection schedule as in experimental groups. All group I rats survived for more than 290 days after the start of injections, and 9 of 20 rats developed liver cell adenoma. All group II animals survived for more than 330 days after the start of injections. Of 20 rats, 4 had liver tumors, 3 had hemangioendothelial sarcomas, and 1 had liver cell adenoma. The hemangioendothelial sarcomas showed metastasis in the lungs of 2 rats. The control group had no liver tumors.

Cell preparation of Enterococcus faecalis strain EC-12 prevents vancomycin-resistant enterococci colonization in the cecum of newly hatched chicks.

The use of antimicrobials in broilers is considered to be a cause of the appearance of vancomycin-resistant enterococci (VRE). Once VRE penetration occurs, whatever its origin, it is difficult to expel the enterococci from the intestine because of their multiple resistance, whether natural or acquired. In this study, we evaluated the prevention of VRE colonization by the dietary supplementation of a cell-wall preparation of Enterococcus faecalis strain EC-12 (EC-12) in newly hatched broilers that were challenged by experimental infection with VRE. The chicks were fed a basal diet supplemented with 0.05% (wt/wt) EC-12 powder for 15 d. The control group and that administered Lactobacillus sp. were fed the basal diet. The VRE challenge was administered orally when the chicks were 2 d old (d 0). Dietary EC-12 reduced VRE colonization in the intestine from d 3 to 14. Total IgA in the cecal digesta and total IgG in the serum were higher on d 14 in the EC-12 treatment group. However, VRE-specific and EC-12-specific antibodies were not affected in serum. Hence, it appeared that dietary EC-12 stimulated the gut immune system and reinforced the immune reaction against the VRE challenge to accelerate its defecation from the chick intestine.

High frequency of low-level microsatellite instability in early colorectal cancer.

Molecular events in early colorectal cancers (CRCs) have not been well elucidated because of the low incidence of early CRCs in clinical practice. Therefore, we studied 104 sporadic early CRCs with invasion limited to submucosa compared with 116 advanced CRCs. Loss of heterozygosity as well as microsatellite instability (MSI) status was examined. A significantly high frequency of low-level MSI (MSI-L) phenotype was detected in early CRCs (51.0%) compared with advanced CRCs (25.9%; P = 0.0001). In early and advanced CRCs, samples with MSI-L phenotype differed from microsatellite stable (MSS) phenotype with respect to loss of heterozygosity at 1p32 and 8p12-22. MSI-L is a frequent genetic event in early CRCs and may be a novel pathway in colorectal carcinogenesis distinct from both MSI-H and MSS.

Genetic alterations of candidate tumor suppressor ING1 in human esophageal squamous cell cancer.

Overexpression of ING1, a candidate tumor suppressor gene, efficiently blocks cell growth or induces apoptosis in different experimental systems. ING1 maps to chromosome 13q33-34, and because loss of the terminal region of chromosome 13q has been implicated in esophageal squamous cell cancer (ESCC), we examined ESCC for genetic alterations of ING1. Among 31 informative cases of ESCC, 58.9% of the tumors showed allelic loss at chromosome 13q33-34, and we detected four tumor-specific missense nucleotide changes. These alterations were found within the PHD finger domain and nuclear localization motif of the ING1 and may be functionally involved in the development of ESCC. Because immunohistochemical study revealed that all of the ESCC samples showed loss of ING1 protein expression, genetic or epigenetic alterations that abrogate the normal function of ING1 may contribute to esophageal squamous cell carcinogenesis.

Close correlation between mutations of E2F4 and hMSH3 genes in colorectal cancers with microsatellite instability.

Defects in mismatch repair function can lead to the microsatellite instability (MI+; replication error) phenotype in certain human cancers. We previously reported that MI+ tumor-specific repeat number alteration at 13 consecutive trinucleotide (CAG) repeats within a coding exon of the E2F4 gene is a possible target of the defective repair pathway. Additional investigations revealed that E2F4 mutations are common (11 of 17 cases, 65%, mostly deletions) in a subset of human colorectal cancers with extensive MI+ phenotype, with respect to the proportion of loci affected and that most of these E2F4-mutated tumors (9 of 11, 82%) were accompanied by frameshift mutations in a polyadenine stretch within the seventh exon of the hMSH3 gene, a known mismatch repair gene that is responsible for repair of mismatch loops of two to four nucleotides. However, neither of these mutations was detected in 15 tumors with a lower incidence of MI+ loci. Similar repeat number alterations were less frequent in CAG repeats from other genes in all of the MI+ tumors we examined. These results indicate the presence of a novel cascade of mutational events that may be involved in acquisition of the malignant phenotype of human colorectal cancers with genetic instability.

Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors.

The E2F group of transcription factors transactivates genes that promote progression through the G1-S transition of the cell cycle. Members of the retinoblastoma (Rb) family of proteins bind to E2Fs and inhibit this function. E2F-4, one example of the E2F group, functions as an oncogene when transfected into nontransformed cells in vitro. On the other hand, mice that are homozygously lacking a normal E2F-1 gene develop cancers, consistent with a tumor-suppressive role for this gene. The exact function of E2Fs has thus been unclear; moreover, direct involvement of this gene in primary human tumorigenesis has not been shown. We, therefore, investigated mutation within the E2F-4 coding region in 16 primary gastric adenocarcinomas, 12 ulcerative colitis-associated neoplasms, 46 sporadic colorectal carcinomas, 9 endometrial cancers, and 3 prostatic carcinomas. We limited our investigation to the serine repeat within E2F-4, reasoning that this tract might be altered in genetically unstable tumors (replication error-positive, or RER+). All tumors were RER+, with the exception of a control group of 15 RER- sporadic colorectal carcinomas. PCR with incorporation of [32P]dCTP was performed using primers flanking the serine trinucleotide (AGC) repeat. Twenty-two of 59 gastrointestinal tumors (37%) contained E2F-4 mutations; these comprised 5 of 16 gastric tumors (31%), 4 of 12 ulcerative colitis-associated neoplasms (33%, including 1 dysplastic lesion), and 13 of 31 sporadic colorectal cancers (42%). No mutation was present in any of the endometrial, prostate, or RER- colorectal tumors. Of note, homozygous mutations occurred in three cases, and two of seven informative patients showed loss of one E2F-4 allele in their tumors. Furthermore, the RER+ sporadic colorectal tumors were evaluated at trinucleotide repeats within the genes for N-cadherin and B-catenin; no tumors demonstrated mutation of these genes. These data suggest that E2F-4 is a target of defective DNA repair in these tumors.

Differing roles of protein kinase C on the signal transduction of tumour necrosis factor-alpha and -beta on PANC-1 cells: in vitro autoradiographic investigation.

We investigated alterations in protein kinase C (PKC) activity of PANC-1 cells following treatment with tumour necrosis factor (TNF)-alpha or TNF-beta by an in vitro autoradiographic method. Binding studies performed on whole cells using [3H]phorbol-12,13-dibutyrate (PDBu) as a ligand revealed strong activation of PKC by TNFs within 30 min. The effect was similar to that seen after 30 min treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). After treatment for 24 h, TNF-beta caused a marked down-regulation of PKC similar to that seen after 24 h treatment with TPA; significant activation persisted, however, in the cells treated for 24 h with TNF-alpha. Our data suggest that PKC activation may play a more important role in the TNF-alpha signal transduction pathway than in that of TNF-beta.

Association between high levels of ornithine decarboxylase activity and favorable prognosis in human colorectal carcinoma.

Several studies have documented increased expression of ornithine decarboxylase (ODC) in neoplastic colorectal tissue versus normal-appearing colonic mucosa. The present study was undertaken to determine whether there is an association between the degree of overexpression of ODC in colorectal carcinomas and survival in a series of 74 patients. A high level of tumor ODC expression was found to be significantly associated with greater survival in our patient series. Patients with tumor ODC activities greater than the median and especially in the highest quartile experienced a more favorable outcome than those patients with ODC values below the median or in the lowest quartile (P = 0.03 and 0.02, respectively). The presence of a GTP-activatable isoform of ODC was also significantly associated with a favorable prognosis but only in tumors of the right colon (P = 0.01). There was no association found between ODC activity and tumor grade, tumor size, or patient age, sex, or race. Our results demonstrate that high levels of ODC expression (and presence of a GTP-activatable isoform for right-sided colon tumors) predict a favorable prognosis in human colorectal carcinoma. Knowledge of a patient's ODC status at the time of surgery may be useful in decisions regarding adjuvant therapy. Understanding the mechanism(s) involved should lead to new therapeutic approaches for advanced colorectal carcinoma.

Possible involvement of free radical scavenging properties in the action of tumor necrosis factor-alpha.

Constitutive production of hydroxyl radicals from four established cancer cell lines was detected as spin adducts of 5,5-dimethyl-l-pyroline-N-oxide (DMPO), using an electron spin resonance spectrometer. The generated hydroxyl radicals was decreased in three out of four cancer cell lines when incubated in vitro for 3 h with TNF-alpha No direct scavenging effect of TNF-alpha on hydroxyl radicals or superoxide anions was observed in the in vitro radical generation system. The modulation of intracellular reactive oxygen species of these cancer cells by adding menadione or CuDIPS to the culture medium changed the antiproliferative effect of TNF-alpha on the cells. The ultrastructural localization of the radical-generating sites in cancer cells was visualized using the diaminobenzidine/horseradish peroxide histochemical system at the electron microscopic level. The hydrogen peroxide-dependent formation of electron-dense materials localized at the mitochondrial membranes was decreased after the treatment of the cancer cells with TNF-alpha. These data indicate that the reduction of radical generation in cancer cells by TNF-alpha may be an early mechanism that contributes to the antiproliferative effect of this cytokine on some cancer cells.

Creutzfeldt-Jakob disease in a patient with a cadaveric dural graft.

We report a 26-year-old woman with Creutzfeldt-Jakob disease (CJD) who had received cadaveric dural material 33 months before the onset of neurologic symptoms. This is the fourth case in which a dural graft was the putative source of the CJD agent. All four cases had the grafting before changes in the sterilization procedure adopted in 1987 to inactivate the CJD agent.

Effects of spontaneous respiration on right and left ventricular function: evaluation by respiratory and ECG gated radionuclide ventriculography.

To clarify the mechanism of inspiratory reduction of left ventricular (LV) stroke volume (SV) during spontaneous respiration, we measured right and left ventricular volume changes from expiration to inspiration using radionuclide ventriculography with respiratory gating technique. In this method, scintigraphic data were acquired in a list mode with ECG R wave triggers and respiratory volume curve derived from respiratory flowmeter. Cardiac cycles occurring during the second halves of inspiratory and expiratory phases were separately selected and used to produce multigated images for the respective phases. Twelve patients with normal LV ejection fraction (EF) (greater than 50%) and right ventricular (RV) EF (greater than 40%) and without pulmonary diseases were studied. LV end-diastolic volume (EDV) decreased during inspiration in all subjects (by 11 +/- 5%), whereas LV end-systolic volume (ESV) was insignificantly changed. Accordingly, LVSV decreased during inspiration in all subjects (by 17 +/- 7%). LVEF decreased from 64 +/- 6% during expiration to 60 +/- 6% during inspiration (p less than 0.001). In contrast to the left ventricle, RVEDV and RVSV increased during inspiration by 13 +/- 11% and 22 +/- 18%, respectively. RVESV did not change significantly. RVEF increased from 48 +/- 6% during expiration to 52 +/- 5% during inspiration (p less than 0.05). These results indicate that inspiratory reduction of LVSV during spontaneous respiration is due to a decrease in LVEDV which may be derived from an increase in RVEDV during inspiration through the mechanism of ventricular interdependence.

Metabolic changes in hibernating myocardium after percutaneous transluminal coronary angioplasty and the relation between recovery in left ventricular function and free fatty acid metabolism.

To elucidate the changes in oxidative metabolism in hibernating myocardium after coronary revascularization, we performed myocardial single-photon emission computed tomography with a free fatty acid analog, I-123 beta-methyliodophenylpentadecanoic acid (BMIPP), and thallium-201 before and 1 month after percutaneous transluminal coronary angioplasty (PTCA) in 11 patients with angina pectoris caused by single artery stenosis. All patients had improvement in wall motion after PTCA at the region with coronary stenosis; the wall motion abnormality score evaluated by left ventriculography decreased from 5.5+/-0.8 (mean +/- SE) to 2.1+/-0.9, p <0.01) after PTCA. The defect score of I-123 BMIPP images was significantly larger than that of thallium-201 images either before (14+/-1.3 vs 8.9+/-1.1, p <0.01) or 1 month after (7.4+/-1.5 vs 3.7+/-0.8, p <0.01) PTCA. The decrease in the defect score of both images was significant (p <0.01). Changes in the wall motion abnormality score showed a significant correlation with both the change in the defect score of thallium-201 images (r = 0.58, p < 0.01) and that of I-123 BMIPP images (r = 0.75, p <0.01). These results indicate that the metabolism of free fatty acid is impaired in hibernating myocardium, and that improvement in left ventricular function after successful PTCA is strongly associated with the recovery of oxidative metabolism.