Durvalumab after chemoradiotherapy in non-small cell lung cancer with EGFR mutation: A real-world study (HOT2101).

Durvalumab has been administered to patients with unresectable stage III non-small cell lung cancer (NSCLC). However, it remains unclear whether durvalumab benefits these patients with epidermal growth factor receptor (EGFR) mutation. We conducted a retrospective, multicenter study of patients with EGFR mutation who received chemoradiotherapy (CRT) between June 2018 and March 2021. We assessed patient characteristics, efficacy of durvalumab, and durvalumab safety before and after targeted therapy. We collected data on a total of 673 patients, of whom 401 (59.6%) underwent EGFR mutation testing. Fifty-one patients were EGFR positive and 311 were EGFR negative. In the EGFR-positive group, there were higher proportions of females, never-smokers, and patients with adenocarcinoma histology. Of the 51 patients in the positive group and 311 in the negative group who received CRT, 45 (88.2%) and 247 (79.4%) received durvalumab, with median progression-free survival of 23.0 and 24.2 months in the positive and negative groups, respectively (hazard ratio 1.03; 95% confidence interval: 0.64-1.67). The main adverse event was pneumonitis (positive group: 62.2%; 4.4% grade 3; negative group: 62.3%; 6.9% grade 3). No treatment-related deaths were observed. Of the 45 patients in the positive group who received durvalumab, 14 (31.1%) received targeted therapy after durvalumab at the data cutoff. One patient discontinued targeted therapy after developing pneumonitis. In patients with unresectable stage III NSCLC with EGFR mutation, durvalumab after CRT is potentially safe and effective. This may be a suitable treatment sequence for these patients.

Intrahepatic cholangiocarcinoma with a liver abscess due to hepatic actinomycosis.

BACKGROUND: Liver tumors with liver abscesses are unusual and rarely reported. In particular, studies of intrahepatic cholangiocarcinoma with liver abscesses due to hepatic actinomycosis have not been reported. CASE PRESENTATION: A 73-year-old woman presented with swelling of the right hypochondrium. Computed tomography revealed a mass lesion that was continuous with the abdominal wall in the right lobe of the liver, suggesting a liver tumor invading the abdominal wall. A liver biopsy revealed intrahepatic cholangiocarcinoma with a liver abscess. The histopathological specimen contained bacterial masses of actinomycosis, and the cause of the liver abscess was determined to be hepatic actinomycosis. As a result of percutaneous drainage and antibiotic therapy, the part of the tumor attached to the abdominal wall disappeared; therefore, we assumed that most of the lesion was not cholangiocarcinoma but a liver abscess due to hepatic actinomycosis. Radical surgery for residual intrahepatic cholangiocarcinoma was performed after chemotherapy. Currently, the patient is alive without recurrence 2 years and 9 months after the operation. CONCLUSION: We encountered a difficult-to-diagnose case of intrahepatic cholangiocarcinoma with a liver abscess due to hepatic actinomycosis. A needle biopsy allowed early diagnosis and percutaneous drainage was an effective treatment.

Targeted next-generation sequencing of 50 cancer-related genes in Japanese patients with oral squamous cell carcinoma.

Somatic mutation analysis is a standard of practice for human cancers to identify therapeutic sensitization and resistance mutations. We performed a multigene sequencing screen to explore mutational hotspots in cancer-related genes using a semiconductor-based sequencer. DNA from oral squamous cell carcinoma samples was used as a template to amplify 207 regions from 50 cancer-related genes. Of the 80 oral squamous cell carcinoma specimens from Japanese patients, including formalin-fixed paraffin-embedded samples, 56 specimens presented at least one somatic mutation among the 50 investigated genes, and 17 of these samples showed multiple gene somatic mutations. TP53 was the most commonly mutated gene (50.0%), followed by CDKN2A (16.3%), PIK3CA (7.5%), HRAS (5.0%), MET (2.5%), and STK11 (2.5%). In total, 32 cases (40.0%) were human papillomavirus positive and they were significantly less likely to have a TP53, mutation than human papillomavirus-negative oral squamous cell carcinomas (8/32, 25.0% vs 32/48, 66.7%, p = 0.00026). We also detected copy number variations, in which segments of the genome could be duplicated or deleted from the sequencing data. We detected the tumor-specific TP53 mutation in the plasma cell-free DNA from two oral squamous cell carcinoma patients, and after surgery, the test for these mutations became negative. Our approach facilitates the simultaneous high-throughput detection of somatic mutations and copy number variations in oral squamous cell carcinoma samples.

Profiling cancer-related gene mutations in oral squamous cell carcinoma from Japanese patients by targeted amplicon sequencing.

Somatic mutation analysis is a standard practice in the study of human cancers to identify mutations that cause therapeutic sensitization and resistance. We performed comprehensive genomic analyses that used PCR target enrichment and next-generation sequencing on Ion Proton semiconductor sequencers. Forty-seven oral squamous cell carcinoma (OSCC) samples and their corresponding noncancerous tissues were used for multiplex PCR amplification to obtain targeted coverage of the entire coding regions of 409 cancer-related genes (covered regions: 95.4% of total, 1.69 megabases of target sequence). The number of somatic mutations in 47 patients with OSCC ranged from 1 to 20 with a mean of 7.60. The most frequent mutations were in TP53 (61.7%), NOTCH1 (25.5%), CDKN2A (19.1%), SYNE1 (14.9%), PIK3CA (10.6%), ROS1 (10.6%), and TAF1L (10.6%). We also detected copy number variations (CNVs) in the segments of the genome that could be duplicated or deleted from deep sequencing data. Pathway assessment showed that the somatic aberrations within OSCC genomes are mainly involved in several important pathways, including cell cycle regulation and RTK-MAPK-PI3K. This study may enable better selection of therapies and deliver improved outcomes for OSCC patients when combined with clinical diagnostics.

CRKL oncogene is downregulated by p53 through miR-200s.

Tumor suppressive miRNAs that target oncogenes are frequently downregulated in cancers, and this downregulation leads to oncogene pathway activation. Thus, tumor suppressive miRNAs and their target oncogenes have been proposed as useful targets in cancer treatment. miR-200 family downregulation has been reported in cancer progression and metastasis. The miR-200 family consists of two gene clusters, miR-200b/200a/429 and miR-200c/141, which are located on human chromosomes 1 and 12, respectively. Here, we identified that p53 response elements are located around both clusters of the miR-200 family and confirmed that miR-200s are transcriptional targets of the p53 family. In silico analyses of miRNA targets established the CRKL oncogene as a potential target for miR-200b/200c/429. Moreover, miR-200b/200c/429 inhibited CRKL mRNA and protein expression by directly targeting its 3'-UTR region. Importantly, endogenous CRKL expression was decreased in cancer cells through the introduction of p53 family and endogenous p53 activation. Moreover, the downregulation of CRKL by siRNA inhibited cancer cell growth. The Oncomine database demonstrates that CRKL is overexpressed in a subset of cancer types. Furthermore, CRKL is significantly overexpressed in primary breast cancer tissues harboring mutant TP53. Our results demonstrate that the p53 target miR-200b/200c/429 miRNAs are negative regulators of the CRKL oncogene.

[CR obtained by CPT-11 and CDDP combination-therapy in a small-cell lung-cancer patient through effective pharmaceutical care].

We encountered a 64-year-old UGT1A1*28 heterotype patient who received CPT-11 and CDDP chemotherapy for Stage III A small-cell lung-cancer and developed grade 4 neutropenia as assessed by CTCAE v3.0 in Pharmaceutical Management. The therapeutic effect was good; 4 courses of chemotherapy could be safely administered at 1/3 of the applied dose of CPT-11, and CR was obtained. In this period, we participated in selecting antibiotics to neutropenia and CPT-11 closing regimen as pharmacists. Additionally, we carefully monitored patients about their bowel pattern and hematotoxicity, and collected information about gene searching for the patient and the Hospital Ethics Committee. The analysis of the gene polymorphism of CPT-11 is useful to predict the occurrence of serious side effects, but this judgment cannot easily be made clinically. In the event of a marked decrease in the neutrophil count of a patient during the first courses of treatment with CPT-11, we believe that it is important to consider gene polymorphism, to closely monitor the symptoms and laboratory parameters, and to give a smaller dose of the drug.