Real-world evidence of adjuvant gemcitabine plus capecitabine vs gemcitabine monotherapy for pancreatic ductal adenocarcinoma

The added value of capecitabine to adjuvant gemcitabine monotherapy (GEM) in pancreatic ductal adenocarcinoma (PDAC) was shown by the ESPAC-4 trial. Real-world data on the effectiveness of gemcitabine plus capecitabine (GEMCAP), in patients ineligible for mFOLFIRINOX, are lacking. Our study assessed whether adjuvant GEMCAP is superior to GEM in a nationwide cohort. Patients treated with adjuvant GEMCAP or GEM after resection of PDAC without preoperative treatment were identified from The Netherlands Cancer Registry (2015-2019). The primary outcome was overall survival (OS), measured from start of chemotherapy. The treatment effect of GEMCAP vs GEM was adjusted for sex, age, performance status, tumor size, lymph node involvement, resection margin and tumor differentiation in a multivariable Cox regression analysis. Secondary outcome was the percentage of patients who completed the planned six adjuvant treatment cycles. Overall, 778 patients were included, of whom 21.1% received GEMCAP and 78.9% received GEM. The median OS was 31.4 months (95% CI 26.8-40.7) for GEMCAP and 22.1 months (95% CI 20.6-25.0) for GEM (HR: 0.71, 95% CI 0.56-0.90; logrank P =.004). After adjustment for prognostic factors, survival remained superior for patients treated with GEMCAP (HR: 0.73, 95% CI 0.57-0.92, logrank P =.009). Survival with GEMCAP was superior to GEM in most subgroups of prognostic factors. Adjuvant chemotherapy was completed in 69.5% of the patients treated with GEMCAP and 62.7% with GEM (P =.11). In this nationwide cohort of patients with PDAC, adjuvant GEMCAP was associated with superior survival as compared to GEM monotherapy and number of cycles was similar

Nationwide Outcome of Tailored Surgery for Symptomatic Chronic Pancreatitis based on Pancreatic Morphology:Validation of the International guidelines

OBJECTIVE: To determine the nationwide use and outcome of tailored surgical treatment for symptomatic chronic pancreatitis (CP) as advised by recent guidelines.SUMMARY BACKGROUND DATA: Randomized trials have shown that surgery is superior to endoscopy in patients with symptomatic CP, although endoscopy remains popular Recent guidelines advice to "tailor surgery" based on pancreatic morphology meaning that the least extensive procedure should be selected based on pancreatic morphology. However, nationwide, and multicenter studies On tailored surgery for symptomatic CP are lacking.METHODS: Nationwide multicenter retrospective analysis of consecutive patients undergoing surgical treatment for symptomatic CP in all seven Dutch university medical centers (2010-2020). Outcomes included volume trend, major complications, 90-day mortality, postoperative opioid use and clinically relevant pain relief. Surgical treatment was tailored based on the size of the main pancreatic duct and pancreatic head (e.g. surgical drainage for a dilated pancreatic duct, and normal size pancreatic head).RESULTS: Overall, 381 patients underwent surgery for CP: 127 surgical drainage procedures ( 33%; mostly extended lateral pancreaticojejunostomy), 129 duodenum-preserving pancreatic head resections (DPPHR, 34%, mostly Frey), and 125 formal pancreatic resections (33%, mostly distal pancreatectomy). The annual surgical volume increased slightly (Pearson r=0.744). Mortality (90-day) occurred in 6 patients (2%), and was non-significantly lower after surgical drainage (0%, 3%, 2%; P =0.139). Major complications (12%, 24%, 26%; P =0.012), postoperative pancreatic fistula grade B/C (0%, 3%, 22%; P =0.038), surgical reintervention (4%, 16%, 12%; P =0.006), and endocrine insufficiency ( 14%, 21%, 43%; P &lt;0.001) occurred less often after surgical drainage. After a median follow-up of 11 months [IQR 3-23] good rates of clinically relevant pain relief ( 83%, 69%, 80%; P =0.082) were observed and 81% of opioid users had stopped using (83%, 78%, 84%, P =0.496).CONCLUSION: The use of surgery for symptomatic CP increased over the study period. Drainage procedures were associated with the best safety profile and excellent functional outcome, highlighting the importance of tailoring surgery based on pancreatic morphology.</p

Nationwide Outcome of Tailored Surgery for Symptomatic Chronic Pancreatitis based on Pancreatic Morphology:Validation of the International guidelines

OBJECTIVE: To determine the nationwide use and outcome of tailored surgical treatment for symptomatic chronic pancreatitis (CP) as advised by recent guidelines.SUMMARY BACKGROUND DATA: Randomized trials have shown that surgery is superior to endoscopy in patients with symptomatic CP, although endoscopy remains popular Recent guidelines advice to "tailor surgery" based on pancreatic morphology meaning that the least extensive procedure should be selected based on pancreatic morphology. However, nationwide, and multicenter studies On tailored surgery for symptomatic CP are lacking.METHODS: Nationwide multicenter retrospective analysis of consecutive patients undergoing surgical treatment for symptomatic CP in all seven Dutch university medical centers (2010-2020). Outcomes included volume trend, major complications, 90-day mortality, postoperative opioid use and clinically relevant pain relief. Surgical treatment was tailored based on the size of the main pancreatic duct and pancreatic head (e.g. surgical drainage for a dilated pancreatic duct, and normal size pancreatic head).RESULTS: Overall, 381 patients underwent surgery for CP: 127 surgical drainage procedures ( 33%; mostly extended lateral pancreaticojejunostomy), 129 duodenum-preserving pancreatic head resections (DPPHR, 34%, mostly Frey), and 125 formal pancreatic resections (33%, mostly distal pancreatectomy). The annual surgical volume increased slightly (Pearson r=0.744). Mortality (90-day) occurred in 6 patients (2%), and was non-significantly lower after surgical drainage (0%, 3%, 2%; P =0.139). Major complications (12%, 24%, 26%; P =0.012), postoperative pancreatic fistula grade B/C (0%, 3%, 22%; P =0.038), surgical reintervention (4%, 16%, 12%; P =0.006), and endocrine insufficiency ( 14%, 21%, 43%; P &lt;0.001) occurred less often after surgical drainage. After a median follow-up of 11 months [IQR 3-23] good rates of clinically relevant pain relief ( 83%, 69%, 80%; P =0.082) were observed and 81% of opioid users had stopped using (83%, 78%, 84%, P =0.496).CONCLUSION: The use of surgery for symptomatic CP increased over the study period. Drainage procedures were associated with the best safety profile and excellent functional outcome, highlighting the importance of tailoring surgery based on pancreatic morphology.</p

Intrathoracic vs Cervical Anastomosis After Totally or Hybrid Minimally Invasive Esophagectomy for Esophageal Cancer A Randomized Clinical Trial

Background: 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. Objective: To compare an intrathoracic with a cervical anastomosis in a randomized clinical trial. Design, Setting, and Participants: 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. Intervention: Patients were randomly assigned (1:1) to transthoracic MIE with intrathoracic or cervical anastomosis. Main Outcomes and Measures: 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. Results: 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]). Conclusions and Relevance: 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. Trial Registration: Trialregister.nl Identifier: NL4183 (NTR4333)

Intravenous Lidocaine for Refractory Pain in Patients with Pancreatic Ductal Adenocarcinoma and Chronic Pancreatitis:A Multicenter Prospective Nonrandomized Pilot Study

INTRODUCTION:Refractory pain is a major clinical problem in patients with pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). New, effective therapies to reduce pain are urgently needed. Intravenous lidocaine is used in clinical practice in patients with PDAC and CP, but its efficacy has not been studied prospectively.METHODS:Multicenter prospective nonrandomized pilot study included patients with moderate or severe pain (Numeric Rating Scale ≥ 4) associated with PDAC or CP in 5 Dutch centers. An intravenous lidocaine bolus of 1.5 mg/kg was followed by continuous infusion at 1.5 mg/kg/hr. The dose was raised every 15 minutes until treatment response (up to a maximum 2 mg/kg/hr) and consecutively administered for 2 hours. Primary outcome was the mean difference in pain severity, preinfusion, and the first day after (Brief Pain Inventory [BPI] scale 1-10). A BPI decrease ≥1.3 points was considered clinically relevant.RESULTS:Overall, 30 patients were included, 19 with PDAC (63%) and 11 with CP (37%). The mean difference in BPI at day 1 was 1.1 (SD ± 1.3) points for patients with PDAC and 0.5 (SD ± 1.7) for patients with CP. A clinically relevant decrease in BPI on day 1 was reported in 9 of 29 patients (31%), and this response lasted up to 1 month. No serious complications were reported, and only 3 minor complications (vertigo, nausea, and tingling of mouth). Treatment with lidocaine did not impact quality of life.DISCUSSION:Intravenous lidocaine in patients with painful PDAC and CP did not show an overall clinically relevant reduction of pain. However, this pilot study shows that the treatment is feasible in this patient group and had a positive effect in a third of patients which lasted up to a month with only minor side effects. To prove or exclude the efficacy of intravenous lidocaine, the study should be performed in a study with a greater sample size and less heterogeneous patient group.</p

Treatment and overall survival of four types of non-metastatic periampullary cancer:nationwide population-based cohort study

Background: Periampullary adenocarcinoma consists of pancreatic adenocarcinoma (PDAC), distal cholangiocarcinoma (DC), ampullary cancer (AC), and duodenal adenocarcinoma (DA). The aim of this study was to assess treatment modalities and overall survival by tumor origin. Methods: Patients diagnosed with non-metastatic periampullary cancer in 2012–2018 were identified from the Netherlands Cancer Registry. OS was studied with Kaplan–Meier analysis and multivariable Cox regression analyses, stratified by origin. Results: Among the 8758 patients included, 68% had PDAC, 13% DC, 12% AC, and 7% DA. Resection was performed in 35% of PDAC, 56% of DC, 70% of AC, and 59% of DA. Neoadjuvant and/or adjuvant therapy was administered in 22% of PDAC, 7% of DC, 7% of AC, and 12% of DA. Three-year OS was highest for AC (37%) and DA (34%), followed by DC (21%) and PDAC (11%). Adjuvant therapy was associated with improved OS among PDAC (HR = 0.62; 95% CI 0.55–0.69) and DC (HR = 0.69; 95% CI 0.48–0.98), but not AC (HR = 0.87; 95% CI 0.62–1.22) and DA (HR = 0.85; 95% CI 0.48–1.50). Conclusion: This retrospective study identified considerable differences in treatment modalities and OS between the four periampullary cancer origins in daily clinical practice. An improved OS after adjuvant chemotherapy could not be demonstrated in patients with AC and DA

Structural and cellular features in metaphyseal and diaphyseal periosteum of osteoporotic rats

Despite the important physiological role of periosteum in the pathogenesis and treatment of osteoporosis, little is known about the structural and cellular characteristics of periosteum in osteoporosis. To study the structural and cellular differences in both diaphyseal and metaphyseal periosteum of osteoporotic rats, samples from the right femur of osteoporotic and normal female Lewis rats were collected and tissue sections were stained with hematoxylin and eosin, antibodies or staining kit against tartrate resistant acid phosphatase (TRAP), alkaline phosphatase (ALP), vascular endothelial growth factor (VEGF), von Willebrand (vWF), tyrosine hydroxylase (TH) and calcitonin gene-related peptide (CGRP). The results showed that the osteoporotic rats had much thicker and more cellular cambial layer of metaphyseal periosteum compared with other periosteal areas and normal rats (P < 0.001). The number of TRAP+ osteoclasts in bone resorption pits, VEGF+ cells and the degree of vascularization were found to be greater in the cambial layer of metaphyseal periosteum of osteoporotic rats (P < 0.05), while no significant difference was detected in the number of ALP+ cells between the two groups. Sympathetic nerve fibers identified by TH staining were predominantly located in the cambial layer of metaphyseal periosteum of osteoporotic rats. No obvious difference in the expression of CGRP between the two groups was found. In conclusion, periosteum may play an important role in the cortical bone resorption in osteoporotic rats and this pathological process may be regulated by the sympathetic nervous system

Immediate versus postponed intervention for infected necrotizing pancreatitis

BACKGROUND Infected necrotizing pancreatitis is a potentially lethal disease that is treated with the use of a step-up approach, with catheter drainage often delayed until the infected necrosis is encapsulated. Whether outcomes could be improved by earlier catheter drainage is unknown. METHODS We conducted a multicenter, randomized superiority trial involving patients with infected necrotizing pancreatitis, in which we compared immediate drainage within 24 hours after randomization once infected necrosis was diagnosed with drainage that was postponed until the stage of walled-off necrosis was reached. The primary end point was the score on the Comprehensive Complication Index, which incorporates all complications over the course of 6 months of follow-up. RESULTS A total of 104 patients were randomly assigned to immediate drainage (55 patients) or postponed drainage (49 patients). The mean score on the Comprehensive Complication Index (scores range from 0 to 100, with higher scores indicating more severe complications) was 57 in the immediate-drainage group and 58 in the postponed-drainage group (mean difference, −1; 95% confidence interval [CI], −12 to 10; P=0.90). Mortality was 13% in the immediate-drainage group and 10% in the postponed-drainage group (relative risk, 1.25; 95% CI, 0.42 to 3.68). The mean number of interventions (catheter drainage and necrosectomy) was 4.4 in the immediate-drainage group and 2.6 in the postponed-drainage group (mean difference, 1.8; 95% CI, 0.6 to 3.0). In the postponed-drainage group, 19 patients (39%) were treated conservatively with antibiotics and did not require drainage; 17 of these patients survived. The incidence of adverse events was similar in the two groups. CONCLUSIONS This trial did not show the superiority of immediate drainage over postponed drainage with regard to complications in patients with infected necrotizing pancreatitis. Patients randomly assigned to the postponed-drainage strategy received fewer invasive interventions