Multifocal lung cancer is an increasingly common clinical scenario, but there is lack of high-level evidence for its optimal treatment. Thus, we surveyed members of the interdisciplinary ...International Association for the Study of Lung Cancer on their therapeutic approaches and analyzed the resultant practice patterns.
We described the clinical scenario of an otherwise healthy 60-year-old man with bilateral pulmonary nodules and asked the 6373 members of the International Association for the Study of Lung Cancer whether they would recommend surgery, and if so, the extent of surgery. We also asked what other measures would be recommended to complete the staging and whether radiation therapy or chemotherapy would be suggested.
We received 221 responses (response rate 3.5%) from multiple specialists. Most respondents (140 63%) recommended surgery for this scenario. Surgeons were significantly more likely to recommend surgery than were those in other specialties. Of those who recommended surgery, most would obtain a PET/CT scan to rule out distant metastases and a magnetic resonance imaging scan to rule out brain metastases; but in the absence of radiographic lymph node involvement, most would not stage the mediastinum by bronchoscopy or mediastinoscopy before resection. When surgery was not recommended or declined, respondents commonly recommended radiation.
This survey suggests that therapeutic recommendations for multifocal lung cancer are influenced to a large extent by physicians’ specialty training, probably because of the lack of high-level evidence for its standard treatment. Ongoing systematic and multidisciplinary approaches with robust short-term and long-term patient outcomes may improve the quality of evidence for the optimal management of this clinical entity.
Chronic kidney disease (CKD) is associated with reduced insulin sensitivity, through mechanisms that are not well understood. Low vitamin K intake and incomplete carboxylation of the vitamin ...K-dependent protein osteocalcin may promote insulin resistance. We assessed relationships of osteocalcin concentration, carboxylation, and fragmentation with CKD and glucose homeostasis in a cross-sectional study.
We included 87 participants without diabetes: 50 (27 female) with moderate to severe CKD (estimated glomerular filtration rate <60 mL/min/1.73 m
not treated with dialysis) and 37 (17 female) healthy controls. Total osteocalcin was measured by immunoassay, and osteocalcin carboxylation and fragmentation status by liquid chromatography-electrospray ionization-based mass spectrometric immunoassay. Endpoints included glucose tolerance (based on 2-hour oral glucose tolerance test), insulin sensitivity (hyperinsulinemic-euglycemic clamp), and pancreatic beta-cell function (intravenous glucose tolerance test).
The total plasma osteocalcin concentration was higher in the CKD group (mean standard deviation 102.9 147.5) than that in the control group (53.6 51.1 ng/mL, P = .03), and more osteocalcin was circulating as fragments. The extent of osteocalcin carbocylation did not differ between individuals with and without CKD. Osteocalcin concentration, carboxylation, and fragmentation were not associated with any measure of glucose homeostasis in multivariable-adjusted analyses.
In CKD, circulating osteocalcin concentrations are elevated, in part due to larger proportions of fragmented forms. However, osteocalcin carboxylation status is not significantly different between individuals with and without CKD. Our data also do not provide support for the hypothesis that differences in osteocalcin carboxylation may explain reduced insulin sensitivity in individuals with CKD.
Ollier disease (OD) and Maffucci Syndrome (MS) are rare disorders characterized by multiple enchondromas, commonly causing bone deformities, limb length discrepancies, and pathological fractures. MS ...is distinguished from OD by the development of vascular anomalies. Both disorders are cancer predisposition syndromes with malignancies developing in ~50% of the individuals with OD or MS. Somatic gain-of-function variants in IDH1 and IDH2 have been described in the enchondromas, vascular anomalies and chondrosarcomas of approximately 80% of the individuals with OD and MS. To date, however, no investigation of germline causative variants for these diseases has been comprehensively performed. To search for germline causative variants, we performed whole exome sequencing or whole genome sequencing of blood or saliva DNA in 94 unrelated probands (68 trios). We found that 7 had rare germline missense variants in HIF1A, 6 had rare germline missense variants in VHL, and 3 had IDH1 variants including 2 with mosaic IDH1-p.Arg132His variant. A burden analysis using 94 probands assigned as cases and 2,054 unrelated individuals presenting no OD- or MS-related features as controls, found that variants in HIF1A, VHL, and IDH1 were all significantly enriched in cases compared to controls. To further investigate the role of HIF-1 pathway in the pathogenesis of OD and MS, we performed RNA sequencing of fibroblasts from 4 probands with OD or MS at normoxia and at hypoxia. When cultured in hypoxic conditions, both proband and control cells showed altered expression of a subset of HIF-1 regulated genes. However, the set of differentially expressed genes in proband fibroblasts included a significantly reduced number of HIF-1 regulated genes compared to controls. Our findings suggest that germline or early post-zygotic variants identified in HIF1A, VHL, and IDH1 in probands with OD and MS underlie the development of the phenotypic abnormalities in a subset of individuals with OD and MS, but extensive functional studies are needed to further confirm it.
Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October ...2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types. These disorders include adenomatous polyposis syndromes (
and
), juvenile polyposis coli (
and
), Peutz-Jeghers Syndrome (
/
), and PTEN hamartoma tumor syndrome (PHTS;
), which can present with a more limited juvenile polyposis phenotype. Herein, the panel of experts provides recommendations for clinical diagnosis, approach to genetic testing, and focus on cancer surveillance recommendations when appropriate during the pediatric period. We also review current controversies on genetic evaluation of patients with hepatoblastoma and indications for surveillance for this tumor. Childhood cancer risks and surveillance associated with disorders involving the mismatch repair genes, including Lynch syndrome and constitutional mismatch repair deficiency (CMMRD), are discussed elsewhere in this series.
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The Laparoscopic Approach to Cervical Cancer (LACC) trial found that minimally invasive radical hysterectomy compared to open radical hysterectomy compromised oncologic outcomes and was associated ...with worse progression-free survival (PFS) and overall survival (OS) in early-stage cervical carcinoma. We sought to assess oncologic outcomes at multiple centers between minimally invasive (MIS) radical hysterectomy and OPEN radical hysterectomy.
This is a multi-institutional, retrospective cohort study of patients with 2009 FIGO stage IA1 (with lymphovascular space invasion) to IB1 cervical carcinoma from 1/2007–12/2016. Patients who underwent preoperative therapy were excluded. Squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinomas were included. Appropriate statistical tests were used.
We identified 1093 cases for analysis—715 MIS (558 robotic 78%) and 378. OPEN procedures. The OPEN cohort had more patients with tumors >2 cm, residual disease in the hysterectomy specimen, and more likely to have had adjuvant therapy. Median follow-up for the MIS and OPEN cohorts were 38.5 months (range, 0.03–149.51) and 54.98 months (range, 0.03–145.20), respectively. Three-year PFS rates were 87.9% (95% CI: 84.9–90.4%) and 89% (95% CI: 84.9–92%), respectively (P = 0.6). On multivariate analysis, the adjusted HR for recurrence/death was 0.70 (95% CI: 0.47–1.03; P = 0.07). Three-year OS rates were 95.8% (95% CI: 93.6–97.2%) and 96.6% (95% CI: 93.8–98.2%), respectively (P = 0.8). On multivariate analysis, the adjusted HR for death was 0.81 (95% CI: 0.43–1.52; P = 0.5).
This multi-institutional analysis showed that an MIS compared to OPEN radical hysterectomy for cervical cancer did not appear to compromise oncologic outcomes, with similar PFS and OS.
•Minimally invasive (MIS) compared to open radical hysterectomy did not compromise outcomes in early-stage cervical cancer•Our findings are contrary to those of the Laparoscopic Approach to Cervical Cancer (LACC) trial favoring laparotomy•As the NCCN has changed guidelines in accordance with LACC, women may miss out on the benefits of MIS radical hysterectomy
Sugar-sweetened beverage (SSB) consumption and low-grade chronic inflammation are both independently associated with type 2 diabetes and cardiovascular disease. Fructose, a major component of SSBs, ...may acutely trigger inflammation, which may be one link between SSB consumption and cardiometabolic disease.
We sought to determine whether beverages sweetened with fructose, high-fructose corn syrup (HFCS), and glucose differentially influence systemic inflammation fasting plasma C-reactive protein and interleukin-6 (IL-6) as primary endpoints acutely and before major changes in body weight. Secondary endpoints included adipose tissue inflammation, intestinal permeability, and plasma fetuin-A as potential mechanistic links between fructose intake and low-grade inflammation.
We conducted a randomized, controlled, double-blind, crossover design dietary intervention (the Diet and Systemic Inflammation Study) in 24 normal-weight to obese adults without fructose malabsorption. Participants drank 4 servings/d of fructose-, glucose-, or HFCS-sweetened beverages accounting for 25% of estimated calorie requirements while consuming a standardized diet ad libitum for three 8-d periods.
Subjects consumed 116% of their estimated calorie requirement while drinking the beverages with no difference in total energy intake or body weight between groups as reported previously. Fasting plasma concentrations of C-reactive protein and IL-6 did not differ significantly at the end of the 3 diet periods. We did not detect a consistent differential effect of the diets on measures of adipose tissue inflammation except for adiponectin gene expression in adipose tissue (P = 0.005), which was lowest after the glucose phase. We also did not detect consistent evidence of a differential impact of these sugars on measures of intestinal permeability (lactulose:mannitol test, plasma zonulin, and plasma lipopolysaccharide-binding protein).
Excessive amounts of fructose, HFCS, and glucose from SSBs consumed over 8 d did not differentially affect low-grade chronic systemic inflammation in normal-weight to obese adults. This trial was registered at clinicaltrials.gov as NCT01424306.
Intestinal permeability and adipose tissue inflammation are considered mechanistic links in the relationship between diet, obesity, and chronic disease. However, methods to measure both are not well ...standardized, and the reliability of commonly used measures is not known.
We calculated the intraclass correlation coefficient (ICC) for several common measures of intestinal permeability and adipose tissue inflammation from a randomized clinical trial of cross-over design in which normal-weight (
= 12) or overweight/obese (
= 12) individuals each completed three 8-day dietary intervention periods.
For biomarkers of intestinal permeability, plasma zonulin, and lipopolysaccharide-binding protein, ICCs were "excellent" (i.e., >0.9). The direct measure of intestinal permeability, the lactulose/mannitol test, exhibited "fair" reliability (ICC = 0.53). A wider range of ICCs (0.6-0.9), suggesting "good" to "excellent" reliability, were obtained for measures of adipose tissue expression of genes encoding major mediators of inflammation. Similarly, individual immune cell populations isolated from adipose tissue, expressed as a percentage of all CD45
cells, also had "good" to "excellent" ICCs. However, when these populations were expressed as number of cells per gram of tissue, ICC values were "fair," falling below 0.6.
Due to the repeated measures design, our study offered a unique opportunity to assess reliability of commonly used biomarkers of intestinal permeability and adipose tissue inflammation. Our findings suggest that these measures were generally highly reliable in the short-term.
Along with other factors, particularly validity, the demonstrated reliabilities can help inform the choice of endpoints in studies of intestinal permeability and adipose tissue inflammation.
Plasma phospholipid pentadecanoic acid (C15:0), heptadecanoic acid (C17:0), and trans–palmitoleic acid (trans-C16:1n–7) are correlates of dairy fat intake. However, their relative concentrations may ...be influenced by other endogenous factors, such as liver fat content, and their validity as biomarkers of dairy fat intake has yet to be established.
We investigated whether liver fat content modifies relations between concentrations of C15:0, C17:0, and trans-C16:1n–7 (alone and in combination with iso-C17:0) and known dairy fat intake in the context of a randomized controlled intervention study. We further examined the proportion of dairy fat intake explained by these fatty acids on their own and when considering liver fat content.
We used data from a 12-wk intervention trial in which participants (n = 62) consumed diets limited in dairy (0.3 g/d of dairy fat), rich in low-fat dairy (8.7 g/d of dairy fat), or rich in full-fat dairy (28.5 g/d of dairy fat). We used linear regression models to examine relations between relative fatty acid concentrations and grams per day of dairy fat intake, liver fat percentage, and their interaction.
Only trans-C16:1n–7 in isolation (β: 0.0004 ± 0.0002, P = 0.03) and combined with iso-C17:0 (β: 0.002 ± 0.0005, P < 0.0001) were consistently positively associated with dairy fat intake regardless of liver fat content. Trans-C16:1n–7 combined with iso-C17:0 also explained the greatest proportion of variation (35.4%) in dairy fat intake. C15:0 and C17:0 were not associated with dairy fat intake after adjusting for liver fat and were predicted to be higher in relation to increased dairy fat intake only among individuals with elevated liver fat.
The potential for liver fat to affect relative plasma phospholipid concentrations of C15:0 and C17:0 raises questions about their validity as biomarkers of dairy fat intake. Of the fatty acid measures tested, trans-C16:1n–7 combined with iso-C17:0, especially with adjustment of liver fat, age, and sex, may provide the most robust estimate of dairy fat consumption.
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Increased energy intake is consistently observed in individuals consuming sugar-sweetened beverages (SSBs), likely mainly because of an inadequate satiety response to liquid calories. However, SSBs ...have a high content of fructose, the consumption of which acutely fails to trigger responses in key signals involved in energy homeostasis. It is unclear whether the fructose content of SSBs contributes to the increased energy intake in individuals drinking SSBs.
We investigated whether the relative amounts of fructose and glucose in SSBs modifies ad libitum energy intake over 8 d in healthy adults without fructose malabsorption.
We conducted 2 randomized, controlled, double-blind crossover studies to compare the effects of consuming 4 servings/d of a fructose-, glucose-, or aspartame-sweetened beverage (study A; n = 9) or a fructose-, glucose-, or high-fructose corn syrup (HFCS)-sweetened beverage (study B; n = 24) for 8 d on overall energy intake. SSBs were provided at 25% of estimated energy requirement, or an equivalent volume of the aspartame-sweetened beverage, and consumption was mandatory. All solid foods were provided at 125% of estimated energy requirements and were consumed ad libitum.
In study A, ad libitum energy intake was 120% ± 10%, 117% ± 12%, and 102% ± 15% of estimated energy requirements when subjects consumed the fructose-, glucose-, and aspartame-sweetened beverages. Energy intake was significantly higher in the fructose and glucose phases than in the aspartame phase (P < 0.003 for each), with no difference between the fructose and glucose phases (P = 0.462). In study B, total energy intake during the fructose, HFCS, and glucose phases was 116% ± 14%, 116% ± 16%, and 116% ± 16% of the subject's estimated total energy requirements (P = 0.880).
In healthy adults, total 8-d ad libitum energy intake was increased in individuals consuming SSBs compared with aspartame-sweetened beverages. The energy overconsumption observed in individuals consuming SSBs occurred independently of the relative amounts of fructose and glucose in the beverages. These trials were registered at clinicaltrials.gov as NCT00475475 and NCT01424306.
Fructose-, compared to glucose-, sweetened beverages increase liver triglyceride content in the short-term, prior to weight gain. In secondary analyses of a randomized cross-over design study during ...which 24 healthy adults consumed 25% of their estimated energy requirement in the form of glucose-, fructose-, and high-fructose corn syrup-sweetened beverages in addition to an identical ad libitum diet for three periods of 8 days each, we investigated the hypothesis that fructose in sweetened beverages also triggers insulin resistance in the short term. Total energy intake, body weight, and fasting glucose did not differ among diet phases. However, there was a significant trend for higher fasting insulin (p = 0.042 for trend) and, among normal-weight participants, homeostasis model assessment index of insulin resistance (p = 0.034 for diet × adiposity interaction) according to the glucose content of the beverages. In conclusion, in contrast to our hypothesis, insulin resistance was increased with higher glucose vs. fructose content of the beverages in this short-term trial.
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