Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAF^V600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety-three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAF^V600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAF^V600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.     

First-in-human,phase I study of PF-06647263, an anti-EFNA4 calicheamicin antibody–drug conjugate,in patients with advanced solid tumors

PF-06647263, a novel antibody–drug conjugate consisting of an anti-EFNA4 antibody linked to a calicheamicin payload, has shown potent antitumor activity in human xenograft tumor models, including triple-negative breast cancer (TNBC). In the dose-escalation part 1 of this multicenter, open-label, phase I study (NCT02078752), successive cohorts of patients (n, 48) with advanced solid tumors and no available standard therapy received PF-06647263 every 3 weeks (Q3W) or every week (QW), following a modified toxicity probability interval (mTPI) method (initial dosing: 0.015 mg/kg Q3W). Primary objective in part 1 was to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D). In part 2 (dose-expansion cohort), 12 patients with pretreated, metastatic TNBC received PF-06647263 at the RP2D to further evaluate tumor response and overall safety. PF-06647263 QW administration (n, 23) was better tolerated than the Q3W regimen (n, 25) with only 1 DLT reported (thrombocytopenia). The most common AEs with the QW regimen (fatigue, nausea, vomiting, mucosal inflammation, thrombocytopenia, and diarrhea) were mostly mild to moderate in severity. The MTD was not estimated. PF-06647263 exposures increased in a dose-related manner across the doses evaluated. The RP2D was determined to be 0.015 mg/kg QW. Six (10%) patients achieved a confirmed partial response and 22 (36.7%) patients had stable disease. No correlations were observed between tumor responses and EFNA4 expression levels. Study findings showed manageable safety and favorable PK for PF-06647263 administered QW at the RP2D, with preliminary evidence of limited antitumor activity in patients with TNBC and ovarian cancer.     

Use of Checklists in Reviews of Health Economic Evaluations, 2010 to 2018

Objective

It is useful for reviewers of economic evaluations to assess quality in a manner that is consistent and comprehensive. Checklists can allow this, but there are concerns about their reliability and how they are used in practice. We aimed to describe how checklists have been used in systematic reviews of health economic evaluations.

Traumatic Event Exposure,Posttraumatic Stress Disorder,and Sleep Disturbances in a National Sample of U.S. Adults

Posttraumatic stress disorder (PTSD) is a highly prevalent, debilitating disorder found to develop after exposure to a potentially traumatic event (PTE). Individuals with PTSD often report sleep disturbances, specifically nightmares and insomnia, which are listed within the criteria for PTSD. This research examined prevalence of insomnia and nightmares within a national sample of 2,647 adults (data weighted by age and sex to correct for differences in sample distribution) who had been exposed to one or more PTEs. Prevalence of self‐reported sleep disturbance, sleep disturbances by PTE type, and gender differences were examined. All participants completed a self‐administered, structured online interview that assessed exposure to stressful events and PTSD symptoms. Among individuals who met DSM‐5 criteria for PTSD, a large majority (more than 92%) reported at least one sleep disturbance. Insomnia was relatively more prevalent than PTE‐related nightmares among individuals with PTSD and among all PTE‐exposed individuals. A higher number of PTEs experienced significantly increased the likelihood of both trauma‐related nightmares and insomnia, McFadden's pseudo R² = .07, p < .001. Women exposed to PTEs were more likely to endorse experience of insomnia, χ²(1, N = 2,647) = 99.13, p < .001, φ = .194, and nightmares compared to men, χ²(1, N = 2,648) = 82.98, p < .001, φ = .177, but this gender difference was not significant among individuals with PTSD, ps = .130 and .050, respectively. Differences in sleep disturbance prevalence by PTE type were also examined. Implications for treatment and intervention and future directions are discussed.     

Better Defining the Role of Total Neoadjuvant Radiation: Changing Paradigms in Locally Advanced Pancreatic Cancer

Annals of Surgical Oncology - This study was designed to better define the role of radiation (Neo-Rad) in addition to neoadjuvant multiagent chemotherapy (NAT) for the treatment of locally advanced...