Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging. However, immunotherapy responses are uniquely challenging to ...interpret because tumors often shrink slowly or can appear transiently enlarged due to inflammation. We hypothesized that monitoring tumor cell death in real time by quantifying changes in circulating tumor DNA (ctDNA) levels could enable early assessment of immunotherapy efficacy.
We compared longitudinal changes in ctDNA levels with changes in radiographic tumor size and with survival outcomes in 28 patients with metastatic non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitor therapy. CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using a multigene next-generation sequencing assay. We defined a ctDNA response as a >50% decrease in mutant allele fraction from baseline, with a second confirmatory measurement.
Strong agreement was observed between ctDNA response and radiographic response (Cohen's kappa, 0.753). Median time to initial response among patients who achieved responses in both categories was 24.5 days by ctDNA versus 72.5 days by imaging. Time on treatment was significantly longer for ctDNA responders versus nonresponders (median, 205.5 vs. 69 days;
< 0.001). A ctDNA response was associated with superior progression-free survival hazard ratio (HR), 0.29; 95% CI, 0.09-0.89;
= 0.03, and superior overall survival (HR, 0.17; 95% CI, 0.05-0.62;
= 0.007).
A drop in ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with immune checkpoint inhibitors for NSCLC.
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Listeria monocytogenes (L. monocytogenes), an important food-borne pathogenic microorganism, has resistance immune function to many commonly used drugs. Myristic acid is a traditional Chinese herbal ...medicine, but it has been rarely used as a food additive, limiting the development of natural food preservatives. In this study, the antibacterial activity and mechanism of myristic acid against L. monocytogenes were studied. The minimum inhibitory concentration (MIC) of myristic acid against 13 L. monocytogenes strains ranged from 64 to 256 μg ml
. The time-kill assay demonstrated that when myristic acid was added to dairy products, flow cytometry confirmed that myristic acid influenced cell death and inhibited the growth of L. monocytogenes. Transmission electron microscopy (TEM), scanning electron microscopy (SEM), and NPN uptake studies illustrated that myristic acid changed the bacterial morphology and membrane structure of L. monocytogenes, which led to rapid cell death. Myristic acid could bind to DNA and lead to changes in DNA conformation and structure, as identified by fluorescence spectroscopy. Our studies provide additional evidence to support myristic acid being used as a natural antibacterial agent and also further fundamental understanding of the modes of antibacterial action.
: PD-1 inhibitors have been approved for the treatment of dMMR patients with metastatic colorectal cancer, but the efficacy of neoadjuvant treatment with PD-1 in dMMR locally advanced rectal cancer ...(LARC) patients has not yet been defined.
: Two patients with LARC received Nivolumab as neoadjuvant treatment in July 2017. Whole-exome sequencing (WES) and multiplex immunofluorescence analysis were performed.
: Of the two patients, one achieved pathological complete response after six cycles of nivolumab followed by surgery. The other patient was confirmed to be clinical complete response after six cycles of nivolumab. "Watch and wait" strategy was performed for anal preservation. WES showed high tumor mutation burden. Multiplex immunofluorescence analysis showed immune microenvironment alternation between pretreatment specimen and post-treatment specimen.
: Neoadjuvant nivolumab induced complete response in both of the two patients with LARC. Immunotherapy might be an alternative strategy for neoadjuvant treatment for dMMR/MSI rectal cancer.
Background & Aims Bowel preparation is defined as adequate if it is sufficient for identification of polyps greater than 5 mm. However, adequate preparation has not been quantified. We performed a ...prospective observational study to provide an objective definition of adequate preparation, based on the Boston Bowel Prep Scale (BBPS, which consists of 0–3 points for each of 3 colon segments). Methods We collected data from 438 men who underwent screening or surveillance colonoscopies and then repeat colonoscopy examinations within 60 days by a different blinded endoscopist (1161 colon segments total) at the West Haven Veterans Affairs Medical Center from January 2014 to February 2015. Missed polyps were defined as those detected on the second examination of patients with the best possible bowel preparation (colon segment BBPS score of 3) on the second examination. The primary outcome was the proportion of colon segments with adenomas larger than 5 mm that were missed in the first examination. We postulated that the miss rate was noninferior for segments with BBPS scores of 2 vs those with BBPS scores of 3 (noninferiority margin, <5%). Our secondary hypotheses were that miss rates were higher in segments with BBPS scores of 1 vs those with scores of 3 or of 2. Results The adjusted proportion with missed adenomas greater than 5 mm was noninferior for segments with BBPS scores of 2 (5.2%) vs those with BBPS scores of 3 (5.6%) (a difference of -0.4%; 95% confidence interval CI, -2.9% to 2.2%). Of study subjects, 347 (79.2%) had BBPS scores of 2 or greater in all segments on the initial examination. A higher proportion of segments with BBPS scores of 1 had missed adenomas larger than 5 mm (15.9%) than segments with BBPS scores of 3 (5.6%) (a difference of 10.3%; 95% CI, 2.7%–17.9%) or 2 (5.2%) (a difference of 10.7%; 95% CI, 3.2%–18.1%). Screening and surveillance intervals based solely on the findings at the first examination would have been incorrect for 16.3% of patients with BBPS scores of 3 in all segments, for 15.3% with BBPS scores of 2 or 3 in all segments, and for 43.5% of patients with a BBPS score of 1 in 1 or more segments. Conclusions Patients with BBPS scores of 2 or 3 for all colon segments have adequate bowel preparation for the detection of adenomas larger than 5 mm and should return for screening or surveillance colonoscopy at standard guideline-recommended intervals. Colon segments with a BBPS score of 1 have a significantly higher rate of missed adenomas larger than 5 mm than segments with scores of 2 or 3. This finding supports a recommendation for early repeat colonoscopic evaluation in patients with a BBPS score of 0 or 1 in any colon segment.
Opinion statement
Intravenous administration of fluoropyrimidine-based chemotherapy has been the backbone of treatment in colorectal cancer (CRC) for decades. The availability of oral capecitabine ...has improved the tolerability and simplified combination schedules. In addition to capecitabine, several other oral drugs have proven efficacy, particularly in palliative treatment lines. Clinical guidelines describe several available third-line treatment options for metastatic CRC (mCRC), but few insights are provided to guide the selection and sequence. In this review, we describe the available evidence and most recent data concerning oral drugs with proven efficacy in CRC, including antiangiogenetic tyrosine kinase inhibitors (VEGFR TKIs), inhibitors blocking EGFR/Raf/MEK/ERK signaling pathway and modified fluoropyrimidine, and share recommendations and insights on selecting third-line oral therapies for mCRC in China. In general, third-line treatment options for mCRC are mainly regorafenib, fruquintinib, and chemo/targeted therapy reintroduction, while FTD/TPI was rarely used in China probably due to poor accessibility. Fruquintinib is preferred in patients with poor performance status (PS), elder age, and severe organ dysfunction, compared to regorafenib. New drugs of clinical trials were more recommended for the patients with BRAF mutant tumor, and those with good previous treatment efficacy tended to be recommended for chemo/targeted therapy reintroduction. The management of mCRC is evolving, and it must be emphasized that the consideration and recommendations presented here reflect current treatment practices in China and thus might change according to new clinical data as well as the availability of new oral drugs.
BACKGROUND:Evidence regarding the effect of preoperative radiotherapy on anastomotic integrity remains conflicting in rectal cancer surgery. Prospective comparisons with appropriate controls are ...needed.
OBJECTIVE:This study aimed to assess the impact of preoperative radiotherapy on anastomotic leakage and stenosis after rectal cancer resection.
DESIGN:This was a post hoc analysis of a randomized controlled trial (NCT01211210).
SETTINGS:Data were retrieved from the leading center of the trial, which is a tertiary hospital.
PATIENTS:The full analysis population of 318 patients was included.
INTERVENTIONS:Patients were randomly assigned to receive preoperative radiation (50 Gy per 25 fractions) and 5-fluorouracil infusion, alone (arm A) or combined with oxaliplatin (arm B), or preoperative chemotherapy with 5-fluorouracil and oxaliplatin without radiation (arm C).
MAIN OUTCOME MEASURES:The rates of anastomotic leakage and stenosis were calculated for each treatment arm. Multivariate analysis was used to verify the effect of preoperative radiotherapy.
RESULTS:The treatment arms were comparable in terms of most baseline characteristics, but more diversions were used in the chemoradiotherapy arms. Anastomotic leakage occurred in 20.2% of patients in arm A, 23.6% of patients in arm B, and 8.5% of patients in arm C (p = 0.007). The corresponding rates of stenosis were 17.0%, 18.9%, and 6.8% (p = 0.02). Multivariate analysis confirmed the correlation between preoperative radiotherapy and clinical leakage (p = 0.02), which was associated with delayed stenosis (p < 0.001). For patients undergoing chemoradiotherapy, radiation proctitis was identified as an independent risk factor for clinical leakage (p = 0.01) and stenosis (p < 0.001).
LIMITATIONS:The main limitations were discrepancies in stoma creation and chemotherapy regimen among the treatment arms.
CONCLUSIONS:Preoperative radiotherapy increases the risk of anastomotic leakage and stenosis after rectal cancer resection. Clinical leakage independently contributes to the development of stenosis.
IMPORTANCE: Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options. OBJECTIVE: To evaluate the efficacy and safety of oral fruquintinib, a vascular ...endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. DESIGN, SETTING, AND PARTICIPANTS: FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017. INTERVENTIONS: Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objectiveresponse rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stabledisease recorded ≥8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. RESULTS: Of the 416 randomized patients (mean age, 54.6 years; 161 38.7% women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months 95% CI, 8.2-10.5 vs 6.6 months 95% CI, 5.9-8.1); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months 95% CI, 3.7-4.6 vs 1.8 months 95% CI, 1.8-1.8 months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% (27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization. CONCLUSIONS AND RELEVANCE: Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02314819
Modifications of FOLFIRINOX are widely used despite the absence of prospective data validating efficacy in metastatic disease (metastatic pancreatic cancer (MPC)) or locally advanced pancreatic ...cancer (LAPC). We conducted a multicentre phase II study of modified FOLFIRINOX in advanced pancreatic cancer to assess the impact of dose attenuation in MPC and efficacy in LAPC.
Patients with untreated MPC or LAPC received modified FOLFIRINOX (irinotecan and bolus 5-fluorouracil reduced by 25%). Adverse events (AEs) were compared with full-dose FOLFIRINOX. Response rate (RR), median progression-free survival (PFS) and median overall survival (OS) were determined.
In total, 31 and 44 patients with LAPC and MPC were enrolled, respectively. In MPC, efficacy of modified FOLFIRINOX was comparable with FOLFIRINOX with RR 35.1%, OS 10.2 months (95% CI 7.65-14.32) and PFS 6.1 months (95% CI 5.19-8.31). In LAPC, efficacy was notable with RR 17.2%, resection rate 41.9%, PFS 17.8 months (95% CI 11.0-23.9) and OS 26.6 months (95% CI 16.7, NA). Neutropenia (P<0.0001), vomiting (P<0.001) and fatigue (P=0.01) were significantly decreased. (18)F-Fluorodeoxyglucose positron emission tomography imaging response did not correlate with PFS or OS.
In this first prospective study of modified FOLFIRINOX in MPC and LAPC, we observed decreased AEs compared with historical control patients. In MPC, the efficacy appears comparable with FOLFIRINOX. In LAPC, PFS and OS were prolonged and support the continued use of FOLFIRINOX in this setting.
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