Hereditary colorectal cancer (HCRC) accounts for < 5% of all colorectal cancer cases. Some of the unique characteristics commonly encountered in HCRC cases include early age of onset, ...synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics necessitate different management approaches, including diagnosis, treatment or surveillance, from sporadic colorectal cancer management. There are two representative HCRC, named familial adenomatous polyposis and Lynch syndrome. Other than these two HCRC syndromes, related disorders have also been reported. Several guidelines for hereditary disorders have already been published worldwide. In Japan, the first guideline for HCRC was prepared by the Japanese Society for Cancer of the Colon and Rectum (JSCCR), published in 2012 and revised in 2016. This revised version of the guideline was immediately translated into English and published in 2017. Since then, several new findings and novel disease concepts related to HCRC have been discovered. The currently diagnosed HCRC rate in daily clinical practice is relatively low; however, this is predicted to increase in the era of cancer genomic medicine, with the advancement of cancer multi-gene panel testing or whole genome testing, among others. Under these circumstances, the JSCCR guidelines 2020 for HCRC were prepared by consensus among members of the JSCCR HCRC Guideline Committee, based on a careful review of the evidence retrieved from literature searches, and considering the medical health insurance system and actual clinical practice settings in Japan. Herein, we present the English version of the JSCCR guidelines 2020 for HCRC.
This phase III study compared treatment with weekly paclitaxel and biweekly irinotecan in patients with advanced gastric cancer refractory to treatment with fluoropyrimidine plus platinum.
Patients ...were randomly assigned to receive either paclitaxel (80 mg/m(2) on days 1, 8, and 15, every 4 weeks) or irinotecan (150 mg/m(2) on days 1 and 15, every 4 weeks). Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, adverse events, and proportion of patients who received third-line chemotherapy.
Of 223 patients, 219 were eligible for analysis. Median OS was 9.5 months in 108 patients allocated to the paclitaxel group and 8.4 months in 111 patients allocated to the irinotecan group (hazard ratio HR, 1.13; 95% CI, 0.86 to 1.49; P = .38). Median PFS was 3.6 months in the paclitaxel group and 2.3 months in the irinotecan group (HR, 1.14; 95% CI, 0.88 to 1.49; P = .33). Response rate was 20.9% in the paclitaxel group and 13.6% in the irinotecan group (P = .24). Common grade 3 to 4 adverse events were neutropenia (paclitaxel group, 28.7%; irinotecan group, 39.1%), anemia (21.3%; 30.0%), and anorexia (7.4%; 17.3%). Treatment-related deaths occurred in two patients (1.8%) in the irinotecan group. Third-line chemotherapy was administered in 97 patients (89.8%) after paclitaxel treatment and in 80 patients (72.1%) after irinotecan treatment (P = .001).
No statistically significant difference was observed between paclitaxel and irinotecan for OS. Both are reasonable second-line treatment options for advanced gastric cancer.
Some elderly cancer patients, even with good Eastern Cooperative Oncology Group performance status (ECOG-PS), have poor survival outcomes and cannot tolerate standard therapy. Few studies have ...detailed the associations between the G8 screening tool, ECOG-PS, and overall survival (OS) in such patients.
Cancer patients, aged 70 years or older, were assessed for G8 and classified into three groups according to their G8 score: <11 as the low score group, 11-14 as the intermediate score group, and >14 as the high score group. We retrospectively analyzed the association between G8 score and OS in all patients and for each ECOG-PS-categorized group.
Out of 264 enrolled patients, most patients (87%) with solid tumor were categorized as TNM stage IV. ECOG-PS was 0 or 1 in 215 patients and ≥2 in 48; there was missing data for one patient. Among all patients, the low score group with a median OS of 7.7 months survived significantly less than both the high score group with a median OS of 25.6 months Hazard ratio (HR) 3.48; 95% confidence interval (CI), 1.96-6.63; p < 0.0001 and the intermediate score group with a median of 15.6 months (HR 1.83; 95% CI, 1.28-2.65; p < 0.001). In the multivariate analysis, TNM stage and G8 score were independent prognostic factors for OS. When patients with an ECOG-PS of 0 or 1 were analyzed, patients with a lower G8 score showed significantly shorter OS than patients with a higher score when any two groups were compared.
This novel classification of the G8 score contributes to prompt identification of patients with poor prognosis and improved the prognostic value of ECOG-PS. Using G8 with ECOG-PS may be helpful in deciding treatment for elderly patients with advanced cancer.
Romidepsin (FK228, depsipeptide) is a potent histone deacetylase (HDAC) inhibitor that has FDA approval for the treatment of cutaneous and peripheral T‐cell lymphomas. We have previously reported ...that FK228 and its analogs have an additional activity as phosphatidylinositol 3‐kinase (PI3K) inhibitors, and are defined as HDAC/PI3K dual inhibitors. Because a combination of an HDAC inhibitor and a PI3K inhibitor induces apoptosis in human cancer cells in a synergistic manner, development of an HDAC/PI3K dual inhibitor will provide an attractive novel drug for cancer therapy. Using structure‐based optimization of the analogs, FK‐A11 was identified as the most potent analog. FK‐A11 inhibited phosphorylation of AKT and accelerated histone acetylation at lower concentrations, resulting in stronger cytotoxic effects than FK228 and the other analogs in human cancer cells. In this study, we have characterized the biochemical, biological and structural properties of FK228 analogs as PI3K inhibitors. First, FK‐A11 is an ATP competitive PI3K inhibitor. Second, FK‐A11 is a pan‐p110 isoform inhibitor. Third, FK‐A11 selectively inhibits PI3K among 22 common cellular kinases. Fourth, conformational changes of FK228 analogs by reduction of an internal disulfide bond have no effect on PI3K inhibitory activity, unlike HDAC inhibitory activity. Finally, molecular modeling of PI3K‐FK228 analogs and analyses of the binding affinities identified the structure that defines potency for PI3K inhibitory activity. These results prove our concept that a series of FK228 analogs are HDAC/PI3K dual inhibitors. These findings should help in the development of FK228 analogs as novel HDAC/PI3K dual inhibitors.
FK228 and its analogs have been defined as HDAC/PI3K dual inhibitors. This study identified the novel analog, FK‐A11 as the most potent inhibitor, and demonstrated the biochemical, biological, and structural properties as HDAC/PI3K dual inhibitors.
Activation of phosphatidylinositol 3‐kinase (PI3K) signaling is involved in carcinogenesis and cancer progression. The PI3K inhibitors are considered candidate drugs for cancer treatment. Here, we ...describe a drug screening system for novel PI3K inhibitors using Saccharomyces cerevisiae strains with deleterious mutations in the ATP‐binding cassette transporter genes, because wild‐type S. cerevisiae uses drug efflux pumps for reducing intracellular drug concentrations. By screening the chemical library of the Screening Committee of Anticancer Drugs, we identified the histone deacetylase (HDAC) inhibitor romidepsin (FK228) and its novel analogs. In vitro PI3K activity assays confirmed that these compounds directly inhibit PI3K activity at μM‐range concentrations. FK‐A5 analog was the most potent inhibitor. Western blotting revealed that these compounds inhibit phosphorylation of protein kinase B and downstream signaling components. Molecular modeling of the PI3K–FK228 complex indicated that FK228 binds to the ATP‐binding pocket of PI3K. At μM‐range concentrations, FK228 and FK‐A5 show potent cytotoxicity, inducing apoptosis even in HDAC inhibitor‐resistant cells. Furthermore, HDAC/PI3K dual inhibition by FK228 and FK‐A5 at μM‐range concentrations potentiates the apoptosis induction, mimicking the effect of combining specific HDAC and PI3K inhibitors. In this study, we showed that FK228 and its analogs directly inhibit PI3K activity and induce apoptosis at μM‐range concentrations, similar to HDAC/PI3K dual inhibition. In future, optimizing the potency of FK228 and its analogs against PI3K may contribute to the development of novel HDAC/PI3K dual inhibitors for cancer treatment.
Anti‐epidermal growth factor receptor (EGFR) treatment is an effective option for metastatic colorectal cancer (CRC) treatment. However, there are few reliable biomarkers to predict the clinical ...response to anti‐EGFR treatment. We investigated the genome‐wide DNA methylation status in metastatic colorectal cancer to identify associations between the methylation status and clinical response to anti‐EGFR antibody. We retrospectively reviewed the medical records of 97 patients (45 patients for the first cohort and 52 patients for the second cohort) who received anti‐EGFR treatment for KRAS wild‐type metastatic CRC. Then we analyzed the associations between genome‐wide DNA methylation status and clinical response to anti‐EGFR treatment, and evaluated the predictive power and value of the methylation status statistically. As a result, each cohort was classified into highly methylated CRC and low methylated CRC subgroups by unsupervised clustering analyses. In the first cohort, clinical outcomes were significantly better in the low methylated CRC subgroup than in the highly methylated CRC subgroup (response rate, 35.7% vs 6.3%, P = 0.03; disease control rate, 75% vs 31.3%, P = 0.005; hazard ratio for progression‐free survival, 0.27; 95% confidence interval, 0.13–0.57, P < 0.001; overall survival, 0.19; 95% confidence interval, 0.06–0.54, P < 0.001). These results were reproducible in the second cohort. The genome‐wide methylation status was a predictive factor of progression‐free survival and overall survival independently of RAS mutation status. In conclusion, we found that the genome‐wide DNA methylation status is a powerful epigenetic predictor of anti‐EGFR treatment in patients with KRAS wild‐type metastatic colorectal cancer (UMIN000005490).
We investigated the genome‐wide DNA methylation status in metastatic colorectal cancer to identify associations between the methylation status and clinical response to anti‐EGFR antibody. We found that the genome‐wide DNA methylation status is a powerful epigenetic predictor of the anti‐EGFR treatment in patients with KRAS wild‐type metastatic colorectal cancer.
The aim of this study was to identify miRNAs specifically dysregulated in BRAF-mutated colorectal cancer, which could lead to a better understanding of the molecular mechanisms underlying oncogenesis ...of this malignant subtype of colorectal cancer.
Candidate dysregulated miRNAs were selected in genome-wide miRNA expression array analysis using a screening set composed of 15 BRAF-mutated and 15 non-KRAS/BRAF-mutated colorectal cancers. The miRNA expressions were validated in another set of patients. The functional roles of the miRNAs were analyzed by cell growth and invasion assays. The association between miRNA expression status and the clinical outcome of patients treated with various chemotherapies was analyzed.
Within the top five of the miRNAs screened, we validated miRNA-31 (miR-31) and miR-135b as up-regulated, while miR-193a-3p was down-regulated in BRAF-mutated cancer. Moreover, miR-193a-3p inhibited cell growth, and invasion of colorectal cancer cells. Low miR-193a-3p expression was associated with shorter progression-free survival in patients who received anti-EGFR therapy.
Our results disclose a novel tumor suppressive role of miR-193a-3p in colorectal cancer. These results could lead to novel therapeutic strategies for colorectal cancer, particularly in BRAF-mutated colorectal cancer.
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.
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