Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy

[Background] The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. [Patients and methods] A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. [Results] No SNPs exceeded the genome-wide significance (P < 5.0 × 10−8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. [Conclusion] Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice

Expression of asporin reprograms cancer cells to acquire resistance to oxidative stress

Asporin (ASPN), a small leucine-rich proteoglycan expressed predominantly by cancer associated fibroblasts (CAFs), plays a pivotal role in tumor progression. ASPN is also expressed by some cancer cells, but its biological significance is unclear. Here, we investigated the effects of ASPN expression in gastric cancer cells. Overexpression of ASPN in 2 gastric cancer cell lines, HSC-43 and 44As3, led to increased migration and invasion capacity, accompanied by induction of CD44 expression and activation of Rac1 and MMP9. ASPN expression increased resistance of HSC-43 cells to oxidative stress by reducing the amount of mitochondrial reactive oxygen species. ASPN induced expression of the transcription factor HIF1 alpha and upregulated lactate dehydrogenase A (LDHA) and PDH-E1 alpha, suggesting that ASPN reprograms HSC-43 cells to undergo anaerobic glycolysis and suppresses ROS generation in mitochondria, which has been observed in another cell line HSC-44PE. By contrast, 44As3 cells expressed high levels of HIF1 alpha in response to oxidant stress and escaped apoptosis regardless of ASPN expression. Examination of xenografts in the gastric wall of ASPN(-/-) mice revealed that growth of HSC-43 tumors with increased micro blood vessel density was significantly accelerated by ASPN; however, ASPN increased the invasion depth of both HSC-43 and 44As3 tumors. These results suggest that ASPN has 2 distinct effects on cancer cells: HIF1 alpha-mediated resistance to oxidative stress via reprogramming of glucose metabolism, and activation of CD44-Rac1 and MMP9 to promote cell migration and invasion. Therefore, ASPN may be a new therapeutic target in tumor fibroblasts and cancer cells in some gastric carcinomas

Quality of life comparison between esophagogastrostomy and double tract reconstruction for proximal gastrectomy assessed by Postgastrectomy Syndrome Assessment Scale (PGSAS)‐45

Abstract Aim The current study compared the postoperative quality of life (QOL) between the esophagogastrostomy method (PGEG) and double tract method (PGDT) after proximal gastrectomy using the Postgastretomy Syndrome Assessment Scale (PGSAS)‐45. Methods Among the 2364 patients who received the PGSAS‐45 questionnaire, 300 PGEG and 172 PGDT cases responded. The main outcomes measures (MOMs) consisted of seven subscales (SS) covering symptoms, meals (amount and quality), ability to work, dissatisfaction with daily life, physical and mental component summary of the 8‐Item Short Form Health Survey (SF‐8), and change in body weight, and were compared between PGEG and PGDT. Results Overall, PGDT promoted significantly better constipation SS scores (p < 0.05), whereas PGEG tended to promote better body weight (BW) loss% (p < 0.10). A stratified analysis based on the remnant stomach size revealed that among those with a remnant stomach size of 1/2, PGDT had significantly better constipation and dumping SS scores (p < 0.05) and tended to have better working conditions (p < 0.10) compared to PGEG. Even among those with the remnant stomach size of 2/3, PGDT had significantly better diarrhea SS scores, lesser dissatisfaction with symptoms, and better dissatisfaction with daily life SS scores (p < 0.05) and tended to have better constipation SS scores and lesser dissatisfaction with work (p < 0.10) compared to PGEG. Conclusions After comparing the QOLs of PGEG and PGDT, the stratified analysis according to remnant stomach sizes of 1/2 and 2/3 revealed that PGDT was relatively superior to PGEG for several MOMs