Yeast functional assay of the p53 gene status in human cell lines maintained in our laboratory

We used a yeast functional assay (functional analysis of separated alleles in yeast: FASAY) to determine the p53 gene status of human cell lines maintained in our laboratory. This assay enables the researcher to score wild-type p53 expression on the basis of the ability of expressed p53 to transactivate the reporter gene HIS 3 via the p53-responsive GAL 1 promoter in Saccharomyces cerevisiae. The cell lines examined were ten hepatoma, two hepatoblastoma, three in vitro immortalized fibroblast, two osteosarcoma, a chondrosarcoma, an ovarian teratocarcinoma and a colon cancer cell line. Out of 20 cell lines, 11 cell lines had mutations in both alleles of the p53 gene, and another 8 cell lines had no mutation in the p53 gene. Thus, 55% of the cell lines examined had mutations in the p53. Interestingly, PA-1 cells had both the normal and the mutant p53 alleles, showing that FASAY is a useful method for detecting the wild-type and mutated p53 genes simultaneously. As for the three liver cell lines harboring HBsAg, there was no relationship between their p53 gene status and the presence of HBsAg. Two cell lines were normal for p53 status, while the other had a mutation of the p53 gene.</p

Depth of response may predict clinical outcome in patients with recurrent/metastatic head and neck cancer treated with pembrolizumab-containing regimens

BackgroundPembrolizumab-containing regimens are standards of care for recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). The depth of response (DpR) predicts the survival of patients with several types of solid cancers; however, its association with the survival outcomes of patients with R/M HNSCC treated with pembrolizumab-containing regimens remains unclear.MethodsThis study included 66 patients with R/M HNSCC who received a pemblolizumab-containing regimen as a first-line therapy at Tohoku University Hospital, Sendai, Japan. The patients’ characteristics, combined positive score, baseline tumor size, tumor response, DpR, overall survival (OS), progression-free survival (PFS), PFS2, and adverse events were reviewed. The associations between DpR and survival outcomes were analyzed.ResultsThe 1 year-OS and 1 year-PFS rates of pembrolizumab-containing regimens were 69.4% and 24.4%, respectively. The response rate was 28.8%. The mean and median values of tumor change from baseline were 5.1% and −9.0%. In the correlation analysis, a significant negative correlation was observed between tumor change rate from baseline and survival outcomes (OS: r= −0.41, p=0.0017; PFS: r=−0.49, p&lt;0.001). In the multivariate analysis, DpR with tumor change of ≤−45 was associated with better OS and PFS.ConclusionDpR induced by pembrolizumab-containing regimens may be a predictive factor for OS and PFS in patients with R/M HNSCC

A phase 2 basket trial of combination therapy with trastuzumab and pertuzumab in patients with solid cancers harboring human epidermal growth factor receptor 2 amplification (JUPITER trial)

Introduction: Human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. It is too difficult to conduct a conventional randomized, controlled trial in a rare fraction. Therefore, we have designed a organ-agnostic basket study, which covers a variety of solid cancers harboring HER2 amplification, in 1 study protocol. Methods/Design: This trial is a multicenter, single-arm, basket phase 2 study in Japan. Patients with solid cancers harboring HER2 amplification that have progressed with standard treatment, or rare cancers for which there is no standard treatment, will be eligible. Target cancers include bile duct, urothelial, uterine, ovarian, and other solid cancers where HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. A total of 38 patients will be treated with combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unmanageable toxicity, death, or patient refusal. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, and duration of response. Discussion: The aim of this trial is to evaluate the safety and efficacy of combination therapy with trastuzumab and pertuzumab in patients with locally advanced or metastatic, solid cancers harboring HER2 amplification. Instead of focusing on 1 organ type, our trial design uses a basket study focusing on HER2 amplification, regardless of the site or origin of the cancer. The results of our study will advance clinical and scientific knowledge concerning the treatment of locally advanced, rare solid cancers harboring HER2 amplification, using the combination of trastuzumab and pertuzumab. Trial registration: This trial was registered in Japan Registry of Clinical Trials (jCRT) on February 25, 2019, as jRCT2031180150

Phase II study of trifluridine/tipiracil (TAS‑102) therapy in elderly patients with colorectal cancer (T‑CORE1401): geriatric assessment tools and plasma drug concentrations as possible predictive biomarkers

Purpose The current study aimed to determine the efficacy of trifluridine/tipiracil for elderly patients with advanced colorectal cancer. Methods This single-arm, open-label, multicenter, phase II study included elderly patients aged 65 years or more who had fluoropyrimidine-refractory advanced colorectal cancer and received trifluridine/tipiracil (70 mg/m2, days 1–5 and 8–12, every 4 weeks). The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), overall response rate (ORR), toxicities, association between efficacy and geriatric assessment scores, and association between toxicity and plasma drug concentrations. Results A total of 30 patients with a mean age of 73 years were enrolled. Median PFS was 2.3 months (95% confidence interval, 1.9–4.3 months), while median OS was 5.7 months (95% confidence interval, 3.7–8.9 months). Patients had an ORR of 0%, with 57% having stable disease. Grade 4 neutropenia was observed in 13% of the patients. Patients with a higher G8 score (15 or more) showed longer PFS than those with a lower G8 score (median 4.6 vs. 2.0 months; p = 0.047). Moreover, patients with grade 3 or 4 neutropenia showed higher maximum trifluridine concentrations than those with grade 1 or 2 neutropenia (mean 2945 vs. 2107 ng/mL; p = 0.036). Discussion The current phase II trial demonstrated that trifluridine/tipiracil was an effective and well-tolerated option for elderly patients with advanced colorectal cancer. Moreover, geriatric assessment tools and/or plasma drug concentration monitoring might be helpful in predicting the efficacy and toxicities in elderly patients receiving this drug. Trial registration number UMIN000017589, 15/May/2015 (The University Hospital Medical Information Network

Upper arm central venous port implantation: a 6-year single institutional retrospective analysis and pictorial essay of procedures for insertion.

The requirement of central venous (CV) port implantation is increasing with the increase in the number of cancer patients and advancement in chemotherapy. In our division, medical oncologists have implanted all CV ports to save time and consultation costs to other departments. Recently, upper arm implantation has become the first choice as a safe and comfortable method in our unit. Here we report our experience and discuss the procedure and its potential advantages.All CV port implantations (n = 599) performed in our unit from January 2006 to December 2011 were analyzed. Procedural success and complication rates between subclavian and upper arm groups were compared.Both groups had similar patient characteristics. Upper arm CV port and subclavian implantations were equivalently successful and safe. Although we only retrospectively analyzed data from a single center, the upper arm group had a significantly lower overall postprocedural complication rate than the subclavian group. No pneumothorax risk, less risk of arterial puncture by ultrasound, feasibility of stopping potential arterial bleeding, and prevention of accidental arterial cannulation by targeting the characteristic solitary basilic vein were the identified advantages of upper arm CV port implantation. In addition to the aforementioned advantages, there is no risk of "pinch-off syndrome," possibly less patient fear of manipulation, no scars on the neck and chest, easier accessibility, and compatibility with the "peripherally inserted central catheter" technique.Upper arm implantation may benefit clinicians and patients with respect to safety and comfort. We also introduce our methods for upper arm CV port implantation with the videos