Esophageal adenocarcinoma (EAC) has a dismal prognosis, and survival benefits of recent multimodality treatments remain small. Cancer-associated fibroblasts (CAFs) are known to contribute to poor ...outcome by conferring therapy resistance to various cancer types, but this has not been explored in EAC. Importantly, a targeted strategy to circumvent CAF-induced resistance has yet to be identified. By using EAC patient-derived CAFs, organoid cultures, and xenograft models we identified IL-6 as the stromal driver of therapy resistance in EAC. IL-6 activated epithelial-to-mesenchymal transition in cancer cells, which was accompanied by enhanced treatment resistance, migratory capacity, and clonogenicity. Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines. Analysis of patient gene expression profiles identified ADAM12 as a noninflammation-related serum-borne marker for IL-6–producing CAFs, and serum levels of this marker predicted unfavorable responses to neoadjuvant chemoradiation in EAC patients. These results demonstrate a stromal contribution to therapy resistance in EAC. This signaling can be targeted to resensitize EAC to therapy, and its activity can be measured using serum-borne markers.
Mineral carbonation of basic silicate minerals regulates atmospheric CO(2) on geological time scales by locking up carbon. Mining and spreading onto the earth's surface of fast-weathering silicates, ...such as olivine, has been proposed to speed up this natural CO(2) sequestration ('enhanced weathering'). While agriculture may offer an existing infrastructure, weathering rate and impacts on soil and plant are largely unknown. Our objectives were to assess weathering of olivine in soil, and its effects on plant growth and nutrient uptake. In a pot experiment with perennial ryegrass (Lolium perenne L.), weathering during 32 weeks was inferred from bioavailability of magnesium (Mg) in soil and plant. Olivine doses were equivalent to 1630 (OLIV1), 8150, 40700 and 204000 (OLIV4) kg ha(-1). Alternatively, the soluble Mg salt kieserite was applied for reference. Olivine increased plant growth (+15.6%) and plant K concentration (+16.5%) in OLIV4. At all doses, olivine increased bioavailability of Mg and Ni in soil, as well as uptake of Mg, Si and Ni in plants. Olivine suppressed Ca uptake. Weathering estimated from a Mg balance was equivalent to 240 kg ha(-1) (14.8% of dose, OLIV1) to 2240 kg ha(-1) (1.1%, OLIV4). This corresponds to gross CO(2) sequestration of 290 to 2690 kg ha(-1) (29 10(3) to 269 10(3) kg km(-2).) Alternatively, weathering estimated from similarity with kieserite treatments ranged from 13% to 58% for OLIV1. The Olsen model for olivine carbonation predicted 4.0% to 9.0% weathering for our case, independent of olivine dose. Our % values observed at high doses were smaller than this, suggesting negative feedbacks in soil. Yet, weathering appears fast enough to support the 'enhanced weathering' concept. In agriculture, olivine doses must remain within limits to avoid imbalances in plant nutrition, notably at low Ca availability; and to avoid Ni accumulation in soil and crop.
Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable ...esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen.
From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses.
The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio HR, 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent (
value for interaction,
= .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38%
25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13).
The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years.
To identify independent risk factors for development of benign cervical anastomotic strictures in general and specifically for refractory strictures after esophagectomy in a large series of patients.
...Benign strictures develop frequently when a cervical anastomosis is performed after esophagectomy, causing burdensome symptoms and poor quality of life.
From 1996 to 2006, all patients in the Academic Medical Center prospective database undergoing esophagectomy with a cervical anastomosis were included. Stricture was defined as dysphagia requiring endoscopic dilation of the anastomosis. Prediction of stricture was assessed using uni- and multivariate logistic regression analysis. Evaluation of risk factors was also performed for refractory strictures (>2 times the median number of dilations in all patients with stricture) in a similar fashion.
A total of 607 patients underwent potentially curative esophagectomy, with an in-hospital mortality of 2.5%. During follow-up, 253 (41.7%) patients developed a stricture after a median time of 74 days, requiring a median number of 5 dilations. Cardiovascular disease (P = 0.002), gastric tube compared with colonic interposition (P = 0.03), and anastomotic leakage (P = 0.002) were predictive for development of stricture in multivariate analysis. Development of stricture within 90 days after surgery (P = 0.001), chemoradiotherapy (P = 0.02), and anastomotic leakage (P = 0.03) were independent predictors for refractory strictures requiring over 10 dilations.
The benign cervical stricture rate after esophagectomy was relatively high. Cardiovascular disease, gastric tube compared with colonic interposition and postoperative anastomotic leakage were independent predictors for development of benign anastomotic stricture. Anastomotic leakage, chemoradiotherapy and early development of stricture were independently associated with the development of refractory strictures, requiring a higher number of dilations. Prevention of anastomotic stricture formation should be focused on prevention of anastomotic leakage.
Goal-directed therapy (GDT) can reduce postoperative complications in high-risk surgery patients. It is uncertain whether GDT has the same benefits in patients undergoing esophageal surgery. Goal of ...this Quality Improvement study was to evaluate the effects of a stroke volume guided GDT on post-operative outcome.
We compared the postoperative outcome of patients undergoing esophagectomy before (99 patients) and after (100 patients) implementation of GDT. There was no difference in the proportion of patients with a complication (56% vs. 54%, p = 0.82), hospital stay and mortality. The incidence of prolonged ICU stay (>48 hours) was reduced (28% vs. 12, p = .005) in patients treated with GDT. Secondary analysis of complication rate showed a decrease in pneumonia (29 vs. 15%, p = .02), mediastinal abscesses (12 vs. 3%, p = .02), and gastric tube necrosis (5% vs. 0%, p = .03) in patients treated with GDT. Patients in the GDT group received significantly less fluids but received more colloids.
The implementation of GDT during esophagectomy was not associated with reductions in overall morbidity, mortality and hospital length of stay. However, we observed a decrease in pneumonia, mediastinal abscesses, gastric tube necrosis, and ICU length of stay.
This is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting ...of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed.
This trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test.
There were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio HR 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the log-rank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms.
Preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC.
This study compared outcomes of patients with esophageal cancer and clinically complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT) undergoing active surveillance or immediate surgery.
...Since nearly one-third of patients with esophageal cancer show pathologically complete response after nCRT according to CROSS regimen, the oncological benefit of immediate surgery in cCR is topic of debate.
Patients with cCR based on endoscopic biopsies and endoscopic ultrasonography with fine-needle aspiration initially declining or accepting immediate surgery after nCRT were identified between 2011 and 2018. Primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), rate and timing of distant dissemination, and postoperative outcomes.
Some 98 patients with cCR were identified: 31 in the active surveillance- and 67 in the immediate surgery group with median followup of survivors of 27.7 and 34.8 months, respectively. Propensity score matching resulted in 2 comparable groups (n = 29 in both groups). Patients undergoing active surveillance or immediate surgery had a 3-year OS of 77% and 55% (HR 0.41; 95% CI 0.14-1.20, P = 0.104), respectively. The 3-year PFS was 60% and 54% (HR 1.08; 95% CI 0.44-2.67, P = 0.871), respectively. Patients undergoing active surveillance or immediate surgery had a comparable distant dissemination rate (both groups 28%), radical resection rate (both groups 100%), and severity of postoperative complications (Clav- ien-Dindo grade ≥ 3: 43% vs 45%, respectively).
In this retrospective study, OS and PFS in patients with cCR undergoing active surveillance or immediate surgery were not significantly different. Active surveillance with postponed surgery for recurrent disease was not associated with a higher distant dissemination rate or more severe adverse postoperative outcomes.
After neoadjuvant chemoradiotherapy for oesophageal cancer, roughly half of the patients with squamous cell carcinoma and a quarter of those with adenocarcinoma have a pathological complete response ...of the primary tumour before surgery. Thus, the necessity of standard oesophagectomy after neoadjuvant chemoradiotherapy should be reconsidered for patients who respond sufficiently to neoadjuvant treatment. In this study, we aimed to establish the accuracy of detection of residual disease after neoadjuvant chemoradiotherapy with different diagnostic approaches, and the optimal combination of diagnostic techniques for clinical response evaluations.
The preSANO trial was a prospective, multicentre, diagnostic cohort study at six centres in the Netherlands. Eligible patients were aged 18 years or older, had histologically proven, resectable, squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction, and were eligible for potential curative therapy with neoadjuvant chemoradiotherapy (five weekly cycles of carboplatin area under the curve 2 mg/mL per min plus paclitaxel 50 mg/m2 of body-surface area combined with 41·4 Gy radiotherapy in 23 fractions) followed by oesophagectomy. 4–6 weeks after completion of neoadjuvant chemoradiotherapy, patients had oesophagogastroduodenoscopy with biopsies and endoscopic ultrasonography with measurement of maximum tumour thickness. Patients with histologically proven locoregional residual disease or no-pass during endoscopy and without distant metastases underwent immediate surgical resection. In the remaining patients a second clinical response evaluation was done (PET–CT, oesophagogastroduodenoscopy with biopsies, endoscopic ultrasonography with measurement of maximum tumour thickness, and fine-needle aspiration of suspicious lymph nodes), followed by surgery 12–14 weeks after completion of neoadjuvant chemoradiotherapy. The primary endpoint was the correlation between clinical response during clinical response evaluations and the final pathological response in resection specimens, as shown by the proportion of tumour regression grade (TRG) 3 or 4 (>10% residual carcinoma in the resection specimen) residual tumours that was missed during clinical response evaluations. This study was registered with the Netherlands Trial Register (NTR4834), and has been completed.
Between July 22, 2013, and Dec 28, 2016, 219 patients were included, 207 of whom were included in the analyses. Eight of 26 TRG3 or TRG4 tumours (31% 95% CI 17–50) were missed by endoscopy with regular biopsies and fine-needle aspiration. Four of 41 TRG3 or TRG4 tumours (10% 95% CI 4–23) were missed with bite-on-bite biopsies and fine-needle aspiration. Endoscopic ultrasonography with maximum tumour thickness measurement missed TRG3 or TRG4 residual tumours in 11 of 39 patients (28% 95% CI 17–44). PET–CT missed six of 41 TRG3 or TRG4 tumours (15% 95% CI 7–28). PET–CT detected interval distant histologically proven metastases in 18 (9%) of 190 patients (one squamous cell carcinoma, 17 adenocarcinomas).
After neoadjuvant chemoradiotherapy for oesophageal cancer, clinical response evaluation with endoscopic ultrasonography, bite-on-bite biopsies, and fine-needle aspiration of suspicious lymph nodes was adequate for detection of locoregional residual disease, with PET–CT for detection of interval metastases. Active surveillance with this combination of diagnostic modalities is now being assessed in a phase 3 randomised controlled trial (SANO trial; Netherlands Trial Register NTR6803).
Dutch Cancer Society.
Fatty acids (FAs) are important regulators of immune responses and innate defense mechanisms. We hypothesized that disturbed FA metabolism could contribute to the progression of HIV infection. Plasma ...levels of 45 FAs were analyzed with gas chromatography in healthy controls and HIV-infected patients with regard to Mycobacterium avium complex (MAC) infection. In vitro, we assessed MAC-PPD-induced release of inflammatory cytokines in peripheral and bone marrow mononuclear cells (PBMC and BMMC) according to levels of n-6 polyunsaturated fatty acids (PUFAs). While plasma saturated FAs were higher in HIV infection, PUFAs, and in particular the n-6 PUFA arachidonic acid (AA), were lower in patients with advanced disease. The ratio between AA and precursor dihomo-γ-linolenic acid, reflecting Δ5-desaturase activity, was markedly lower and inversely correlated with plasma HIV RNA levels in these patients. Depletion of AA was observed prior to MAC infection, and MAC-PPD-induced release of TNF and IL-6 in PBMC and BMMC was lower in patients with low plasma AA. Our findings suggest that dysregulated metabolism of n-6 PUFAs may play a role in the progression of HIV infection. While high AA may contribute to chronic inflammation in asymptomatic HIV-infected patients, low AA seems to increase the susceptibility to MAC infection in patients with advanced disease.
The basic principle of hot-tapping is to establish a new branch pipeline connection to an existing (mother) pipeline while under full pressure. This involves connecting the branch pipe, including a ...valve, to the mother pipeline, usually by means of welding or mechanical clamp connections, cutting a hole in the pipe wall by a machine attached to the valve, retracting the cutting head, closing the valve, and disconnecting and recovering the cutting machine.
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