Predicting exacerbation of renal function by DNA methylation clock and DNA damage of urinary shedding cells: a pilot study.

Recent reports have shown the feasibility of measuring biological age from DNA methylation levels in blood cells from specific regions identified by machine learning, collectively known as the epigenetic clock or DNA methylation clock. While extensive research has explored the association of the DNA methylation clock with cardiovascular diseases, cancer, and Alzheimer's disease, its relationship with kidney diseases remains largely unexplored. In particular, it is unclear whether the DNA methylation clock could serve as a predictor of worsening kidney function. In this pilot study involving 20 subjects, we investigated the association between the DNA methylation clock and subsequent deterioration of renal function. Additionally, we noninvasively evaluated DNA damage in urinary shedding cells using a previously reported method to examine the correlation with the DNA methylation clock and worsening kidney function. Our findings revealed that patients with an accelerated DNA methylation clock exhibited increased DNA damage in urinary shedding cells, along with a higher rate of eGFR decline. Moreover, in cases of advanced CKD (G4-5), the DNA damage in urinary shedding cells was significantly increased, highlighting the interplay between elevated DNA damage and eGFR decline. This study suggests the potential role of the DNA methylation clock and urinary DNA damage as predictive markers for the progression of chronic kidney disease.

Longitudinal changes in pancreatic volume and pancreatic fat with weight gain in Japanese without diabetes: An analysis using health check-up data.

Aims/introduction: There have been few reports about the longitudinal changes in pancreas volume (PV) or pancreatic steatosis (PS) in response to obesity. In this longitudinal analysis using health check-up data, we explored changes in PV, PS and glucose metabolic indices that occurred after weight gain in Japanese without diabetes. Materials/methods: Clinical data on 37 Japanese subjects with a ≥1 kg/m2 increase in body mass index between two health check-ups and without diabetes were collected. PV, pancreas attenuation (PA) and splenic attenuation (SA) were evaluated using computed tomography (CT) images. The pancreas area was outlined by hand in multiple images with slice thickness of 2 mm, and the PV was computed by summing these areas. PS was defined as the difference between SA and PA (SA-PA). Medical records were collected, including findings on immunoreactive insulin (IRI), homeostasis model assessment of insulin resistance (HOMA-R) and beta cell function (HOMA-ß). Paired t-test and Spearman's correlation coefficient were used in the analyses. Results: The median follow-up period was 21.1 months and the mean BMI was increased from 25.5 ± 3.3 kg/m2 to 27.0 ± 3.3 kg/m2. PV (53.5 ± 15.9 cm3 vs. 56.2 ± 16.4 cm3) and SA-PA (8.7 ± 9.1 HU vs. 13.6 ± 10.9 HU) increased significantly after weight gain (both, P < 0.001). There were significant increases of IRI and HOMA-R with the weight gain (both, P < 0.05), whereas HOMA-ß exhibited only a nonsignificant trend of increase (55.4％ (41.5-65.5) vs. 56.8％ (46.2-83.7), P = 0.07). Conclusions: Both PV and PS were increased longitudinally with weight gain in Japanese without diabetes.

WJOG13219G: The Efficacy and Safety of FOLFOXIRI or Doublet plus Anti-VEGF Therapy in Previously Untreated BRAFV600E Mutant Metastatic Colorectal Cancer: A Multi-Institutional Registry-Based Study (BRACELET Study).

BACKGROUND: The real-world survival benefit of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus anti-VEGF therapy (Triplet) over doublet chemotherapy (Doublet) remains controversial in patients with BRAFV600E mutant metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: WJOG13219G was a multicenter, retrospective, registry-based study of patients with BRAFV600E mutant mCRC who received first-line triplet or doublet chemotherapy from January 2014 to December 2019 in Japan. Inverse probability of treatment weighting (IPTW) was used to adjust for patient background. RESULTS: The analysis included 79 and 91 patients in the Triplet and Doublet groups, respectively. The Triplet group was significantly younger and had better performance status. No statistical difference was noted in progression-free survival (PFS; HR, 0.82; 95% CI, 0.60-1.13; P = .22) and overall survival (OS; HR, 0.88; 95% CI, 0.62-1.25; P = .48) between both groups. IPTW analysis also showed no difference between the 2 groups in PFS (HR, 0.86; 95% CI, 0.69-1.08; P = .20) and OS (HR, 0.93; 95% CI, 0.73-1.20; P = .59). The Triplet and Doublet groups had an objective response rate of 53% and 41%, respectively (P = .10). At least one grade 3 or 4 adverse event was seen in 51 (65%) and 43 (47%) patients in the Triplet and Doublet groups, respectively, with the incidence of neutropenia being significantly higher in the former. CONCLUSION: Triplet therapy had no survival benefit versus doublet therapy in the overall and IPTW cohorts or specific subgroups for real-world patients with BRAFV600E mutant mCRC.

A significant risk of metabolic dysfunction-associated fatty liver disease plus diabetes on subclinical atherosclerosis.

BACKGROUND: This cross-sectional study aims to investigate the association between subclinical atherosclerosis and metabolic dysfunction-associated fatty liver disease (MAFLD) or non-alcoholic fatty liver disease (NAFLD), and a synergistic effect of diabetes mellitus (DM) and MAFLD on subclinical atherosclerosis. METHODS: Of 977 subjects who underwent health checkups with coronary artery calcification (CAC), carotid intima-media thickness, and brachial-ankle pulse wave velocity (ba-PWV), 890 were included in this study. They were classified as MAFLD, NAFLD, or Neither-FLD, and MAFLD was further categorized into three groups by three metabolic disorders (obesity, lean with metabolic dysregulation, DM), according to its new definition: Obesity-MAFLD, Lean-MAFLD and DM-MAFLD. RESULTS: In a multivariable analysis, MAFLD and NAFLD were significantly associated with subclinical atherosclerosis, except for an association between ba-PWV and NAFLD. MAFLD had higher odds for CAC than NAFLD (for CAC score > 100, odds ratio (OR) = 2.599, 95% confidence interval (CI) = 1.625-4.157; OR = 1.795, 95%CI = 1.145-2.814, respectively). In a sub-analysis, DM-MAFLD had higher odds for CAC (for CAC score > 100, OR = 5.833, 95%CI = 3.047-11.164) than the other groups of MAFLD, when compared to Neither FLD as a reference. Moreover, DM-MAFLD had a higher level of homeostasis model assessment of insulin resistance and high sensitive C-reactive protein, compared to the other groups of MAFLD. CONCLUSIONS: MAFLD was significantly associated with subclinical atherosclerosis in the general population. Additionally, DM-MAFLD could be a significant risk factor for cardiovascular disease through insulin resistance and low-grade inflammation and requires careful follow-up or appropriate intervention.

Unbiased, comprehensive analysis of Japanese health checkup data reveals a protective effect of light to moderate alcohol consumption on lung function.

The overall effect of lifestyle habits, such as alcohol consumption, on general health remains controversial and it is important to clarify how such habits affect aging-related health impairments. To discover novel impacts of lifestyle on general health, we employed a mathematical approach to perform a comprehensive, unbiased, cross-sectional analysis of data from 6036 subjects who participated in a Japanese health checkup. Notably, we found that moderate alcohol consumption was positively correlated with lung function, muscle mass, and strength. Health checkup data were collected periodically from the same subjects. These people were light to moderate drinkers who had high health awareness and were basically free of major underlying diseases. We next analyzed 5 years of data from 1765 of these subjects. We found that higher baseline alcohol consumption, as well as increased alcohol intake over 5 years attenuated time-related deterioration of forced vital capacity without affecting total lung volume. This effect was independent of smoking. Our study suggests a possible protective effect of moderate amounts of alcohol on lung function, due to increased muscle mass/strength and forced vital capacity.

Estimating copy number using next-generation sequencing to determine ERBB2 amplification status.

Assessing Erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification status in breast and gastric cancer is necessary for deciding the best therapeutic strategy. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are currently used for assessing protein levels and gene copy number (CN), respectively. The use of next-generation sequencing (NGS) to measure ERBB2 CN in breast cancer is approved by the United States Federal Drug Administration as a companion diagnostic. However, a CN of less than 8 is evaluated as "equivocal", which means that some ERBB2 amplification cases diagnosed as "HER2 negative" might be false-negative cases. We reviewed the results of gene profiling targeting 160 cancer-related genes in breast (N = 90) and non-breast (N = 19) cancer tissue, and compared the ERBB2 CN results with the IHC/FISH scores. We obtained an estimated CN from the measured CN by factoring in the histological proportion of tumor cells and found that an ERBB2-estimated CN of 3.2 or higher was concordant with the combined IHC/FISH outcome in 98.4% (88/90) of breast cancer cases, while this was not always evident among non-breast cancer cases. Therefore, NGS-estimated ERBB2 CN could be considered a diagnostic test for anti-HER2 therapy after the completion of adequate prospective clinical trials.

A significant association of non-obese non-alcoholic fatty liver disease with osteosarcopenic obesity in females 50 years and older.

BACKGROUND & AIMS: Osteosarcopenic obesity (OSO) encompassing obesity, sarcopenia and osteopenia, is due to redistribution or infiltration of fat into muscle and bone. This cross-sectional study evaluated the association between OSO and non-alcoholic fatty liver disease (NAFLD). METHODS: Obesity, sarcopenia and osteopenia was defined using the percentage of body fat mass, reduced muscle mass, and the percentage of young adult mean < 80%, measured by dual-energy x-ray absorptiometry, respectively. Non-obese and obese NAFLD was diagnosed by ultrasound and body mass index cut-off point (25 kg/m2). A total of 619 subjects ≥ 50 years who completed health checkups were divided into obesity group including OSO and sarcopenic obesity (SO) alone phenotype, and non-obesity group that did not belong to any phenotype, including standard (St). RESULTS: Overall osteopenia and OSO were detected in only 10% and 1% in males, compared with 45% and 9% in females, respectively. Multivariate analysis for females demonstrated a significant association of OSO with non-obese NAFLD (odds ratio = 3.737, 95% confidence interval = 1.365-10.233, P = 0.010), while the association between SO alone and non-obese NAFLD was equivocal. The OSO phenotype had a significantly higher proportion of slower walking speed and weaker grip strength, compared to the St phenotype. The proportion of OSO increased with age in contrast to constant prevalence of non-obese NAFLD. CONCLUSION: Non-obese NAFLD had a significant association with OSO in females, independent of plausible confounders. These results suggest that non-obese NAFLD might be an independent risk factor for OSO.

RT-PCR Screening Tests for SARS-CoV-2 with Saliva Samples in Asymptomatic People: Strategy to Maintain Social and Economic Activities while Reducing the Risk of Spreading the Virus.

The year 2020 will be remembered for the coronavirus disease 2019 (COVID-19) pandemic, which continues to affect the whole world. Early and accurate identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is fundamental to combat the disease. Among the current diagnostic tests, real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) is the most reliable and frequently used method. Herein, we discuss the interpretation of RT-qPCR results relative to viral infectivity. Although nasopharyngeal swab samples are often used for RT-qPCR testing, they require collection by trained medical staff. Saliva samples are emerging as an inexpensive and efficient alternative for large-scale screening. Pooled-sample testing of saliva has been applied for mass screening of SARS-CoV-2 infection. Current policies recommend isolating people with borderline cycle threshold (Ct) values (35

Oncogenic KRAS-expressing organoids with biliary epithelial stem cell properties give rise to biliary tract cancer in mice.

Biliary tract cancer (BTC) arises from biliary epithelial cells (BECs) and includes intrahepatic cholangiocarcinoma (IHCC), gallbladder cancer (GC), and extrahepatic cholangiocarcinoma (EHCC). Although frequent KRAS mutations and epigenetic changes at the INK4A/ARF locus have been identified, the molecular pathogenesis of BTC is unclear and the development of corresponding anticancer agents remains inadequate. We isolated epithelial cell adhesion molecule (EpCAM)-positive BECs from the mouse intrahepatic bile duct, gallbladder, and extrahepatic bile duct, and established organoids derived from these cells. Introduction of activated KRAS and homozygous deletion of Ink4a/Arf in the cells of each organoid type conferred the ability to form lethal metastatic adenocarcinoma with differentiated components and a pronounced desmoplastic reaction on cell transplantation into syngeneic mice, indicating that the manipulated cells correspond to BTC-initiating cells. The syngeneic mouse models recapitulate the pathological features of human IHCC, GC, and EHCC, and they should therefore prove useful for the investigation of BTC carcinogenesis and the development of new therapeutic strategies. Tumor cells isolated from primary tumors formed organoids in three-dimensional culture, and serial syngeneic transplantation of these cells revealed that their cancer stem cell properties were supported by organoid culture, but not by adherent culture. Adherent culture thus attenuated tumorigenic activity as well as the expression of both epithelial and stem cell markers, whereas the expression of epithelial-mesenchymal transition (EMT)-related transcription factor genes and mesenchymal cell markers was induced. Our data show that organoid culture is important for maintenance of epithelial cell characteristics, stemness, and tumorigenic activity of BTC-initiating cells.

Moderate alcohol consumption is not associated with subclinical cardiovascular damage but with hepatic fibrosis in non-alcoholic fatty liver disease.

BACKGROUND: Moderate alcohol consumption is believed to be associated with reduced mortality from cardiovascular disease (CVD) in the general population. This cross-sectional study aimed to comprehensively examine the association between alcohol consumption and subclinical cardiovascular damage or hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). METHODS: Subjects with NAFLD without a history of heart disease were extracted from 977 consecutive examinees who completed health checkups and optional cardiovascular examinations. Subclinical cardiovascular damage was assessed by coronary artery calcification (CAC), carotid artery ultrasound, and brachial-ankle pulse wave velocity (ba-PWV). CAC scores were classified into three grades (0, ≤100, and >100) by Agatston's method. Alcohol consumption was divided into three groups [Non-drinking (G0); Light (G1), 0.1-6.9 drinks/week; Moderate (G2), 7-20.9 drinks/week for men and 7-13.9 drinks/week for women]. Noninvasive markers (FIB-4, Fibrosis-4; NFS, NAFLD fibrosis score) were calculated for assessment of hepatic fibrosis and classified into low and intermediate-high grade. RESULTS: The overall mean age was 60.2 years and males were 200 (74.6%) among 268 subjects with NAFLD. Number (%) of G0, G1, and G2 were 102 (38.1%), 103 (38.4%), and 63 (23.5%). Binary logistic regression analysis showed no significant difference between G0 and G1, or G0 and G2 in any of the above subclinical cardiovascular damages (CAC score >0, or CAC score >100, carotid plaque +, intima-media thickness ≥1.1 mm, and ba-PWV >1400 cm/s). However, only G2 had a significant association with intermediate-high grade of FIB-4 or NFS [odds ratio (95% confidence intervals), p value: 1.871 (1.209-2.893), p = 0.005; 2.910 (1.715-4.939), p = 0.000], compared to G0. CONCLUSIONS: Non-heavy drinking might not reduce the risk of CVD in NAFLD subjects. On the contrary, even moderate drinking could promote hepatic fibrosis. Thus, NAFLD drinkers should not be recommended for even a moderate amount of alcohol.

Multiple Immune-Related Adverse Events and Anti-Tumor Efficacy: Real-World Data on Various Solid Tumors.

PURPOSE: Immune checkpoint inhibitors (ICIs) have been approved for various types of cancer; however, they cause a broad spectrum of immune-related adverse events (irAEs). The association between the development of irAEs and the clinical benefit remains uncertain. We aimed to evaluate the association of irAEs and the treatment efficacy in real-world practice. PATIENTS AND METHODS: We conducted a retrospective study on patients with recurrent or metastatic non-small-cell lung cancer, malignant melanoma, renal cell carcinoma, or gastric cancer who received anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, or atezolizumab) at the Keio University Hospital between September 2014 and January 2019. We recorded treatment-related AEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 4. We performed an overall survival (OS) analysis using a Cox proportional hazards model and the shared frailty model. RESULTS: Of 212 patients eligible for this study, 108 experienced irAEs and 42 developed multiple irAEs. The median OS was significantly longer in the irAEs than in the no-irAE group (28.1 months vs 12.7 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.33-0.73; P = 0.0004). Moreover, the OS of patients with multiple irAEs was significantly longer than that of patients with a single irAE (42.3 months vs 18.8 months; HR, 0.473; 95% CI, 0.346-0.647; P < 0.0001). CONCLUSION: Our single-center retrospective study revealed a significant tendency associating the development of multiple irAEs with favorable prognoses.

A Phase II Study of Regorafenib With a Lower Starting Dose in Patients With Metastatic Colorectal Cancer: Exposure-Toxicity Analysis of Unbound Regorafenib and Its Active Metabolites (RESET Trial).

BACKGROUND: Regorafenib demonstrated survival benefits as salvage therapy for patients with metastatic colorectal cancer. However, severe toxicities frequently occurred early in the treatment with the standard dose (160 mg/day), resulting in a dose reduction or interruption. To improve the tolerability and maintain sufficient efficacy, we conducted a phase II study of regorafenib with a lower starting dose (120 mg/day). PATIENTS AND METHODS: Regorafenib was initiated at 120 mg/day, and the dosage was increased to 160 mg/day on day 15 of the first cycle for patients who had met the dose escalation criteria. The primary endpoint was the disease control rate (DCR). The pharmacokinetics of the total and unbound regorafenib and its active metabolites (M2, M5) were assessed. RESULTS: A total of 70 patients were enrolled from September 2016 to December 2017. Only 6 patients achieved dose escalation to 160 mg on day 15 as planned. For the 68 evaluable patients, the DCR was 32.4% (95% confidence interval, 21.5%-44.8%), which was less than the threshold (30%) of our statistical hypothesis. The serum concentrations of total regorafenib for patients whose dose was escalated to 160 mg/day were significantly lower than those of the patients whose dose was not escalated (median, 3978 vs. 7244 nM; P = .027). The serum unbound concentrations of the sum of regorafenib and the active metabolites correlated significantly with the maximum grade of regorafenib-related symptomatic adverse events in the first cycle (11,138 vs. 19,096 pM; P = .035). CONCLUSION: Regorafenib with a low starting dose of 120 mg/day did not achieve the expected DCR. A relationship of unbound exposure with toxicity was found.

Early administration of systemic chemotherapy should be considered for scirrhous gastric cancer: A case report.

Scirrhous gastric cancer tends to disseminate to the peritoneum and retroperitoneum, where it induces fibrosis. Retroperitoneal fibrosis (RPF) frequently causes acute renal failure due to ureteral obstruction and it tends to make many of physicians hesitate to initiate systemic chemotherapy. The present study reported the case of a 68-year-old man who was diagnosed with scirrhous gastric cancer with peritoneal and retroperitoneal dissemination, causing acute renal failure due to RPF. Before initiating systemic chemotherapy, the patient became anuric and introduced hemodialysis (HD). Although the patient's performance status was poor, there were no contraindications, such as active infection or severe complications, for systemic chemotherapy. Weekly 5-FU/l LV (5-FU 600 mg/m2, l-LV 250 mg/m2 on days 1, 8, 15, 22, 29 and 36; 8 weeks/cycle) was selected as the feasible treatment for the patient. After chemotherapy the patient opted to withdraw from HD and suffered from no severe toxicity. This indicates, retrospectively, that earlier systemic chemotherapy administration prior to HD introduction may result in improvement of renal function and avoidance of HD.

Clinical efficacy of immune checkpoint inhibitors in the treatment of unresectable advanced or recurrent gastric cancer: an evidence-based review of therapies.

Standard treatment options for patients with advanced gastric cancer (GC) offer limited efficacy and are associated with some toxicity, which necessitates the development of more effective therapies for improving the treatment outcomes for this disease. Immunotherapy involving immune checkpoint inhibitors (ICIs) which inhibit the programmed death 1 (PD-1)/programmed death ligand 1 interaction has emerged as a new treatment option. Nivolumab, a human IgG4 monoclonal antibody inhibitor of PD-1, has demonstrated promising clinical activity and induced durable responses in patients with advanced GC. Nivolumab has recently been approved for treating patients with pretreated advanced GC in Japan. In the present review, we summarized current evidence of the clinical efficacy of ICIs in a variety of solid tumors and reported our experience in patients with GC who were treated with nivolumab and the interesting features that were observed in these cases. Certain ICI-specific clinical features such as pseudo- and hyper-progression of tumor and hyper-response to subsequent chemotherapy have been reported in several cancer types. Lastly, we discussed the present scenario regarding research on biomarkers for assessing the clinical benefits of ICI therapies.

Pancreatic Fat Content Detected by Computed Tomography and Its Significant Relationship With Intraductal Papillary Mucinous Neoplasm.

OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are premalignant lesions of pancreatic ductal adenocarcinomas (PDACs). Fat accumulation in the pancreas is increasingly recognized as a cause of PDAC. We aimed to identify factors that are relevant between IPMN and metabolic-related factors, including pancreatic fat. METHODS: The database for 781 subjects who underwent a health checkup and upper abdominal magnetic resonance imaging was searched and computed tomography attenuation indexes (pancreatic and spleen attenuation, pancreas-to-spleen attenuation ratio) were decided by measuring the regions of interest in the pancreas and spleen on nonenhanced images, using Hounsfield units. Eighty-five subjects from each of the IPMN and noncyst groups were matched for age, sex, and glycemic status and statistically compared in clinical characteristics. RESULTS: There was no difference in metabolic-related factors except for apolipoprotein A1 and high-density lipoprotein cholesterol between the 2 groups in univariate analysis. Multivariate logistic regression analysis showed that both indexes were significantly associated with IPMN (odds ratio, 0.905 [95% confidence intervals, 0.851-0.963; P = 0.002]; odds ratio, 0.006 [95% confidence intervals, 0.000-0.152; P = 0.002]). CONCLUSIONS: Pancreatic fat content measured by computed tomography was significantly associated with IPMN. These results suggest that IPMN may develop secondary to pancreatic steatosis that could be an overlapping risk factor for PDAC and IPMN.

Pilot study of WT1 peptide-pulsed dendritic cell vaccination with docetaxel in esophageal cancer.

In the present study, the immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell (DC) vaccination combined with docetaxel (DCDOC) in advanced esophageal cancer patients who had already received first-line chemotherapy was investigated. Ten HLA-A*2402 patients were treated with docetaxel (50 mg/m2) on day 1 and WT1 peptide-pulsed DC vaccination (1×107 cells) on days 15 and 22 (repeated every 4 weeks for 3 cycles). The delayed-type hypersensitivity skin test, HLA tetramer assay and interferon-γ enzyme-linked immunospot (ELISPOT) assay were used to evaluate the induction of a WT1-specific immune response. Median overall survival was 5 months (range, 1.1-11.6). The clinical effect of DCDOC therapy was not observed and only 1 patient could complete the protocol therapy. Disease progression was observed in 9 patients and 1 patient succumbed to fatality during the second cycle of therapy. As a pilot study, it was not possible to evaluate the safety of WT1 peptide-pulsed DCDOC therapy for esophageal squamous cell cancer. However, a WT1-specific response in 6 patients, as indicated by the ELISPOT or HLA/WT1-tetramer assay, was demonstrated. The results suggested that the positive immune response had significant relevance on the low percentage of CD11b+ and CD66b+ granulocytic myeloid-derived suppressor cells in CD15+ cells. Furthermore, DCDOC elicited a WT1-specific immune response regardless of the myelosuppression associated with docetaxel. The present findings support future studies and further work to assess DCDOC as an adjuvant therapy for esophageal cancer will be performed. The present clinical trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry on November 11th, 2011, no. UMIN000006704.

Post-progression survival following second-line chemotherapy in patients with advanced pancreatic cancer previously treated with gemcitabine: a meta-analysis.

Background Post-progression survival (PPS) could be a confounding element in interpreting data from clinical trials of second-line chemotherapy in patients with advanced pancreatic cancer (PC) previously treated with gemcitabine (GEM) because a recent meta-analysis of oxaliplatin combination therapy showed statistical heterogeneity for overall survival (OS) but not for progression-free survival (PFS). This study aimed to improve the understanding of the impact of PPS on OS in this setting. Methods Databases were searched to identify randomized controlled trials (RCTs) in the salvage setting. We evaluated relationships between OS and PFS, PPS, and other variables. Results Totally, 17 RCTs with 3253 patients were identified. Median OS was strongly and moderately associated with median PPS and PFS, respectively (r = 0.913; p < 0.001 and 0.780; p < 0.001, respectively). The proportion of patients with good performance status was significantly associated with both PPS and PFS (r = 0.574, p < 0.001 and 0.492, p < 0.001, respectively). The induction rate of subsequent chemotherapy was related to the duration of PPS and OS (r = 0.640, p < 0.001 and 0.647, p < 0.001, respectively). Median PPS and OS were significantly longer in recent trials than those in older trials (3.55 versus 2.78 months, p < 0.001 and 6.29 versus 5.02 months, p < 0.001). Conclusions Median PPS was strongly correlated with median OS. Given the recently increased opportunity for subsequent chemotherapy and supportive care, PPS may serve as an important element to clarify problems in this setting.

Comprehensive genomic sequencing detects important genetic differences between right-sided and left-sided colorectal cancer.

OBJECTIVES: Anti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than right-sided colorectal cancer (RCRC). We hypothesized that RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy and tested this using comprehensive genomic sequencing. MATERIALS AND METHODS: A total of 201 patients with either primary RCRC or LCRC were analyzed. We investigated tumors for genetic alterations using a 415-gene panel, which included alterations associated with resistance to anti-EGFR therapy: TK receptors (ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway (KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway (PTEN and PIK3CA). Patients whose tumors had no alterations in these 12 genes, theoretically considered to respond to anti-EGFR therapy, were defined as "all wild-type", while remaining patients were defined as "mutant-type". RESULTS: Fifty-six patients (28%) and 145 patients (72%) had RCRC and LCRC, respectively. Regarding genetic alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) with RCRC were "all wild-type" compared with 41 of 145 patients (28%) with LCRC (P = 0.009). Among the 49 patients who received anti-EGFR therapy, RCRC showed significantly worse progression-free survival (PFS) than LCRC (P = 0.022), and "mutant-type" RCRC showed significantly worse PFS compared with "all wild-type" LCRC (P = 0.004). CONCLUSIONS: RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC. Furthermore, our data shows primary tumor sidedness is a surrogate for the non-random distribution of genetic alterations in CRC.