Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized ...that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers.
In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency-approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks).
Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup.
Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer.
Transthoracic minimally invasive esophagectomy (MIE) is increasingly performed as part of curative multimodality treatment. There appears to be no robust evidence on the preferred location of the ...anastomosis after transthoracic MIE.
To compare an intrathoracic with a cervical anastomosis in a randomized clinical trial.
This open, multicenter randomized clinical superiority trial was performed at 9 Dutch high-volume hospitals. Patients with midesophageal to distal esophageal or gastroesophageal junction cancer planned for curative resection were included. Data collection occurred from April 2016 through February 2020.
Patients were randomly assigned (1:1) to transthoracic MIE with intrathoracic or cervical anastomosis.
The primary end point was anastomotic leakage requiring endoscopic, radiologic, or surgical intervention. Secondary outcomes were overall anastomotic leak rate, other postoperative complications, length of stay, mortality, and quality of life.
Two hundred sixty-two patients were randomized, and 245 were eligible for analysis. Anastomotic leakage necessitating reintervention occurred in 15 of 122 patients with intrathoracic anastomosis (12.3%) and in 39 of 123 patients with cervical anastomosis (31.7%; risk difference, -19.4% 95% CI, -29.5% to -9.3%). Overall anastomotic leak rate was 12.3% in the intrathoracic anastomosis group and 34.1% in the cervical anastomosis group (risk difference, -21.9% 95% CI, -32.1% to -11.6%). Intensive care unit length of stay, mortality rates, and overall quality of life were comparable between groups, but intrathoracic anastomosis was associated with fewer severe complications (risk difference, -11.3% -20.4% to -2.2%), lower incidence of recurrent laryngeal nerve palsy (risk difference, -7.3% 95% CI, -12.1% to -2.5%), and better quality of life in 3 subdomains (mean differences: dysphagia, -12.2 95% CI, -19.6 to -4.7; problems of choking when swallowing, -10.3 95% CI, -16.4 to 4.2; trouble with talking, -15.3 95% CI, -22.9 to -7.7).
In this randomized clinical trial, intrathoracic anastomosis resulted in better outcome for patients treated with transthoracic MIE for midesophageal to distal esophageal or gastroesophageal junction cancer.
Trialregister.nl Identifier: NL4183 (NTR4333).
•We provide a review of studies carried out during the Arctic polar night.•Ecologically relevant light during the polar night changes with latitude.•Ecologically, “polar night” and “winter” are not ...synonymous.•The polar night represent a major gap in knowledge concerning Arctic ecosystem understanding.
Several recent lines of evidence indicate that the polar night is key to understanding Arctic marine ecosystems. First, the polar night is not a period void of biological activity even though primary production is close to zero, but is rather characterized by a number of processes and interactions yet to be fully understood, including unanticipated high levels of feeding and reproduction in a wide range of taxa and habitats. Second, as more knowledge emerges, it is evident that a coupled physical and biological perspective of the ecosystem will redefine seasonality beyond the “calendar perspective”. Third, it appears that many organisms may exhibit endogenous rhythms that trigger fitness-maximizing activities in the absence of light-based cues. Indeed a common adaptation appears to be the ability to utilize the dark season for reproduction. This and other processes are most likely adaptations to current environmental conditions and community and trophic structures of the ecosystem, and may have implications for how Arctic ecosystems can change under continued climatic warming.
The authors conducted a systematic review of cone-beam computed tomography (CBCT) applications in orthodontics and evaluated the level of evidence to determine whether the use of CBCT is justified in ...orthodontics.
The authors identified articles by searching the Cochrane Library, PubMed, MEDLINE, Embase, Scopus and Cumulative Index to Nursing and Allied Health Literature databases. They searched the articles' reference lists manually for additional articles and had no language limitations. They did not search the gray literature. Inclusion criteria were CBCT use in orthodontics and that the participants be human. The lowest level of evidence accepted for inclusion was a case series with five or more participants. The authors evaluated the studies' methodological quality according to 13 criteria related to study design, measurements and statistical analysis.
The authors identified 550 articles, and 50 met the inclusion criteria. Study topics included temporary anchorage devices, cephalometry, combined orthodontic and surgical treatment, airway measurements, root resorption and tooth impactions, and cleft lip and palate. The methodological quality averaged 53 percent (range, 15-77 percent) of the maximum score.
The authors found no high-quality evidence regarding the benefits of CBCT use in orthodontics. Limited evidence shows that CBCT offers better diagnostic potential, leads to better treatment planning or results in better treatment outcome than do conventional imaging modalities. Only the results of studies on airway diagnostics provided sound scientific data suggesting that CBCT use has added value. The additional radiation exposure should be weighed against possible benefits of CBCT, which have not been supported in the literature. In future studies, investigators should evaluate the effects of CBCT on treatment procedures, progression and outcome quantitatively.
The true influence of body mass index on the outcome of esophageal cancer surgery is unclear. The aim of this study was to determine the relation between preoperative body mass index and clinical and ...oncological outcomes of esophagectomy for cancer in a patient cohort from the Dutch nationwide audit.
All patients who underwent esophagectomy for cancer between January 2011 and 2016 were identified in the Dutch Upper Gastrointestinal Cancer Audit. Patients were divided into 4 body mass index categories (<18.5 kg/m2 underweight, 18.5 to 25 kg/m2 normal weight, 25 to 30 kg/m2 overweight, and >30 kg/m2 obese) and were compared for clinical and oncological outcomes with the use of propensity score–matched analysis.
Of the patients, 2,598 were included (underweight = 70, normal weight = 1,097, overweight = 1,007, and obese = 424). Before propensity score–matched analysis, underweight patients had a significantly longer hospital stay, more chyle leakage, underwent more re-operations, and had a higher in-hospital/30-day mortality compared to the other weight groups. After propensity score–matched analysis, 560 patients were included: 62 were underweight, 180 were normal weight, 165 were overweight, and 153 were obese. Length of hospital stay, chyle leakage, necrosis of the reconstruction, re-interventions, re-operations, re-admittance to the intensive care unit/medium care unit, and in-hospital/30-day mortality were seen most in the underweight group. No differences were seen in intraoperative complications and oncological outcomes.
Underweight patients are more prone for the development of postoperative complications after esophagectomy. Physicians and dieticians should be aware of the impact of underweight on postoperative outcome. Future studies should focus on nutritional status and the effect of preoperative correction of body weight.
The optimal staging for gastric cancer remains a matter of debate.
To evaluate the value of 18F-fludeoxyglucose-positron emission tomography with computed tomography (FDG-PET/CT) and staging ...laparoscopy (SL) in addition to initial staging by means of gastroscopy and CT in patients with locally advanced gastric cancer.
This multicenter prospective, observational cohort study included 394 patients with locally advanced, clinically curable gastric adenocarcinoma (≥cT3 and/or N+, M0 category based on CT) between August 1, 2017, and February 1, 2020.
All patients underwent an FDG-PET/CT and/or SL in addition to initial staging.
The primary outcome was the number of patients in whom the intent of treatment changed based on the results of these 2 investigations. Secondary outcomes included diagnostic performance, number of incidental findings on FDG-PET/CT, morbidity and mortality after SL, and diagnostic delay.
Of the 394 patients included, 256 (65%) were men and mean (SD) age was 67.6 (10.7) years. A total of 382 patients underwent FDG-PET/CT and 357 underwent SL. Treatment intent changed from curative to palliative in 65 patients (16%) based on the additional FDG-PET/CT and SL findings. FDG-PET/CT detected distant metastases in 12 patients (3%), and SL detected peritoneal or locally nonresectable disease in 73 patients (19%), with an overlap of 7 patients (2%). FDG-PET/CT had a sensitivity of 33% (95% CI, 17%-53%) and specificity of 97% (95% CI, 94%-99%) in detecting distant metastases. Secondary findings on FDG/PET were found in 83 of 382 patients (22%), which led to additional examinations in 65 of 394 patients (16%). Staging laparoscopy resulted in a complication requiring reintervention in 3 patients (0.8%) without postoperative mortality. The mean (SD) diagnostic delay was 19 (14) days.
This study's findings suggest an apparently limited additional value of FDG-PET/CT; however, SL added considerably to the staging process of locally advanced gastric cancer by detection of peritoneal and nonresectable disease. Therefore, it may be useful to include SL in guidelines for staging advanced gastric cancer, but not FDG-PET/CT.
For gastric cancer patients, surgical resection with en-bloc lymphadenectomy is the cornerstone of curative treatment. Open gastrectomy has long been the preferred surgical approach worldwide. ...However, this procedure is associated with considerable morbidity. Several meta-analyses have shown an advantage in short-term outcomes of laparoscopic gastrectomy compared to open procedures, with similar oncologic outcomes. However, it remains unclear whether the results of these Asian studies can be extrapolated to the Western population. In this trial from the Netherlands, patients with resectable gastric cancer will be randomized to laparoscopic or open gastrectomy.
The study is a non-blinded, multicenter, prospectively randomized controlled superiority trial. Patients (≥18 years) with histologically proven, surgically resectable (cT1-4a, N0-3b, M0) gastric adenocarcinoma and European Clinical Oncology Group performance status 0, 1 or 2 are eligible to participate in the study after obtaining informed consent. Patients (n = 210) will be included in one of the ten participating Dutch centers and are randomized to either laparoscopic or open gastrectomy. The primary outcome is postoperative hospital stay (days). Secondary outcome parameters include postoperative morbidity and mortality, oncologic outcomes, readmissions, quality of life and cost-effectiveness.
In this randomized controlled trial laparoscopic and open gastrectomy are compared in patients with resectable gastric cancer. It is expected that laparoscopic gastrectomy will result in a faster recovery of the patient and a shorter hospital stay. Secondly, it is expected that laparoscopic gastrectomy will be associated with a lower postoperative morbidity, less readmissions, higher cost-effectiveness, better postoperative quality of life, but with similar mortality and oncologic outcomes, compared to open gastrectomy. The study started on 1 December 2014. Inclusion and follow-up will take 3 and 5 years respectively. Short-term results will be analyzed and published after discharge of the last randomized patient.
NCT02248519.
Fish consumption is considered health beneficial as it decreases cardiovascular disease (CVD)-risk through effects on plasma lipids and inflammation. We investigated a salmon protein hydrolysate ...(SPH) that is hypothesized to influence lipid metabolism and to have anti-atherosclerotic and anti-inflammatory properties. 24 female apolipoprotein (apo) E(-/-) mice were divided into two groups and fed a high-fat diet with or without 5% (w/w) SPH for 12 weeks. The atherosclerotic plaque area in aortic sinus and arch, plasma lipid profile, fatty acid composition, hepatic enzyme activities and gene expression were determined. A significantly reduced atherosclerotic plaque area in the aortic arch and aortic sinus was found in the 12 apoE(-/)- mice fed 5% SPH for 12 weeks compared to the 12 casein-fed control mice. Immunohistochemical characterization of atherosclerotic lesions in aortic sinus displayed no differences in plaque composition between mice fed SPH compared to controls. However, reduced mRNA level of Icam1 in the aortic arch was found. The plasma content of arachidonic acid (C20:4n-6) and oleic acid (C18:1n-9) were increased and decreased, respectively. SPH-feeding decreased the plasma concentration of IL-1β, IL-6, TNF-α and GM-CSF, whereas plasma cholesterol and triacylglycerols (TAG) were unchanged, accompanied by unchanged mitochondrial fatty acid oxidation and acyl-CoA:cholesterol acyltransferase (ACAT)-activity. These data show that a 5% (w/w) SPH diet reduces atherosclerosis in apoE(-/-) mice and attenuate risk factors related to atherosclerotic disorders by acting both at vascular and systemic levels, and not directly related to changes in plasma lipids or fatty acids.
To compare overall survival in patients with esophageal adenocarcinoma who underwent transhiatal esophagectomy (THE) with limited lymphadenectomy or transthoracic esophagectomy (TTE) with extended ...lymphadenectomy with or without neoadjuvant chemoradiotherapy (nCRT).
The application of neoadjuvant therapy might change the association between the extent of lymphadenectomy and survival in patients with esophageal adenocarcinoma. This may influence the choice of surgical approach in patients treated with nCRT.
Patients with potentially curable subcarinal esophageal adenocarcinoma treated with surgery alone or nCRT followed by surgery in 7 centers were included. The effect of surgical approach on overall survival, differentiated by the addition or omission of nCRT, was analyzed using a multivariable Cox regression model that included well-known prognostic factors and factors that might have influenced the choice of surgical approach.
In total, 701 patients were included, of whom 318 had TTE with extended lymphadenectomy and 383 had THE with limited lymphadenectomy. TTE had differential effects on survival (P for interaction = 0.02), with a more favorable prognostic effect in patients who were treated with surgery alone hazard ratio (HR) = 0.77, 95% confidence interval (CI) 0.58-1.03. This association was statistically significant in a subgroup of patients with 1 to 8 positive lymph nodes in the resection specimen (HR = 0.62, 95% CI 0.43-0.90). The favorable prognostic effect of TTE over THE was absent in the nCRT and surgery group (HR = 1.16, 95% CI 0.80-1.66) and in the subgroup of nCRT patients with 1 to 8 positive lymph nodes in the resection specimen (HR = 1.00, 95% CI 0.61-1.68).
Compared to surgery alone, the addition of nCRT may reduce the need for TTE with extended lymphadenectomy to improve long-term survival in patients with esophageal adenocarcinoma.
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