A CRAF/glutathione-S-transferase P1 complex sustains autocrine growth of cancers with KRAS and BRAF mutations

The Ras/RAF/MEK/ERK pathway is an essential signaling cascade for various refractory cancers, such as those with mutant KRAS (mKRAS) and BRAF (mBRAF). However, there are unsolved ambiguities underlying mechanisms for this growth signaling thereby creating therapeutic complications. This study shows that a vital component of the pathway CRAF is directly impacted by an end product of the cascade, glutathione transferases (GST) P1 (GSTP1), driving a previously unrecognized autocrine cycle that sustains proliferation of mKRAS and mBRAF cancer cells, independent of oncogenic stimuli. The CRAF interaction with GSTP1 occurs at its N-terminal regulatory domain, CR1 motif, resulting in its stabilization, enhanced dimerization, and augmented catalytic activity. Consistent with the autocrine cycle scheme, silencing GSTP1 brought about significant suppression of proliferation of mKRAS and mBRAF cells in vitro and suppressed tumorigenesis of the xenografted mKRAS tumor in vivo. GSTP1 knockout mice showed significantly impaired carcinogenesis of mKRAS colon cancer. Consequently, hindering the autocrine loop by targeting CRAF/GSTP1 interactions should provide innovative therapeutic modalities for these cancers

IRIS plus panitumumab for metastatic CRC

Background Irinotecan plus S-1 (IRIS) is the only oral fluoropyrimidine-based regimen reported to be non-inferior to FOLFIRI and widely used in clinical practice for metastatic colorectal cancer (mCRC) patients. However, the combination of IRIS plus an anti-EGFR agent has not been evaluated previously. This study aimed to investigate the feasibility and efficacy of IRIS with panitumumab as second-line therapy for wild-type KRAS mCRC. Methods Main inclusion criteria were patients with wild-type KRAS mCRC refractory to one prior chemotherapy regimen for mCRC, ECOG PS 0-2, and age ≥ 20 years. Patients received panitumumab (6mg/kg) and irinotecan (100mg/m2) on days 1 and 15 and S-1 (40-60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was the feasibility of the therapy. The secondary endpoints were response rate (RR), progression-free survival (PFS), and overall survival (OS). Results A total of 36 patients received protocol treatment in eight centers. Of these, 23 patients (63.9%) completed protocol treatment, demonstrating achievement of the primary endpoint. The most frequent grade 3/4 toxicities were diarrhea (16.7%), acne-like rash (13.9%), and neutropenia (11.1%). The overall RR was 33.3% (12/36). Of these 4 five underwent conversion surgery. Median PFS and OS were 9.5 months (95% CI 3.5-15.4 months) and 20.1 months (95% CI 16.7-23.2 months), respectively. Conclusion IRIS plus panitumumab has an acceptable toxicity profile and a promising efficacy in patients with previously treated wild-type KRAS mCRC. Accordingly, this regimen can be an additional treatment option for second-line chemotherapy in wild-type KRAS mCRC

Real-World Outcomes of Systemic Therapy in Japanese Patients with Cancer (Tokushukai REAl-World Data Project: TREAD): Study Protocol for a Nationwide Cohort Study

Cohort studies using large-scale databases have become increasingly important in recent years. The Tokushukai Medical Group is a leading medical group in Japan that includes 71 general hospitals nationwide from Hokkaido to Okinawa, with a total of 18,000 beds, and a unified electronic medical record system. This retrospective cohort study aims to evaluate the real-world outcomes of systemic therapy for Japanese patients with cancer using this merit of scale. All adult patients with cancer who received systemic therapy using a centrally registered chemotherapy protocol system at 46 hospitals from April 2010 to March 2020 will be identified (~48,850 patients). Key exclusion criteria include active double cancer and inadequate data extraction. Data will be obtained through electronic medical records, diagnosis procedure combination data, medical prescription data, and the national cancer registration system that includes sociodemographic variables, diagnostic and laboratory tests, concomitant drug prescriptions, cost, and overall survival. Kaplan–Meier estimates will be calculated for time-to-event analyses. Stratified/conventional Cox proportional hazards regression analyses will be conducted to examine the relationships between overall survival and related factors. Our findings provide important insights for future research directions, policy initiatives, medical guidelines, and clinical decision-making

A rare case of an infected tracheal diverticulum requiring emergency intervention: A case report

AbstractIntroductionRecent advancement in radiological imaging has revealed an increasing amount of asymptomatic abnormalities. Tracheal diverticula are relatively rare entities and are incidentally found on radiological imaging such as computed tomography. Here, we present a case of an infected tracheal diverticulum presenting as a paratracheal mass, which required emergency intervention.Case presentationA 65-year-old Japanese nonsmoker man presented with a fever, lower neck pain, and the aggravation of dyspnea for a week. An enhanced computed tomography scan demonstrated that the trachea was displaced by a paratracheal mass with a well-defined thin wall. His respiratory status was so urgent that emergency intubation and surgical drainage of the abscess were performed. A computed tomography scan performed 4days after admission demonstrated shrinking of the abscess, and he was extubated and discharged 7days after admission without any complications.ConclusionTo the best of our knowledge, this is the first report to confirm an infected tracheal diverticulum presenting as a paratracheal abscess, which required emergency intervention. Moreover, computed tomography plays an important role in the differentiation of paratracheal masses