Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine ...therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer.
We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin 85 mg per square meter of body-surface area, irinotecan 180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis, leucovorin 400 mg per square meter, and fluorouracil 2400 mg per square meter every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety.
At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval CI, 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis).
Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .).
The CpG island methylator phenotype (CIMP) is a distinct phenotype in colorectal cancer, associated with specific clinical, pathologic, and molecular features. However, most of the studies stratified ...methylation according to two subgroups (CIMP-High versus No-CIMP/CIMP-Low). In our study, we defined three different subgroups of methylation (No-CIMP, CIMP-Low, and CIMP-High) and evaluated the prognostic significance of methylation status on a population-based series of sporadic colon cancers. A total of 582 colon adenocarcinomas were evaluated using methylation-specific PCR for 5 markers (hMLH1, P16, MINT1, MINT2, and MINT31). No-CIMP status was defined as no methylated locus, CIMP-Low status as one to three methylated loci, and CIMP-High status as four or five methylated loci. Clinicopathologic and molecular characteristics were correlated to the methylation status. Crude and relative survival was compared according to methylation status. In the microsatellite-stable (MSS) group, CIMP-High was significantly associated with proximal location (P = 0.011) and BRAF mutation (P < 0.001). KRAS mutations were more associated with CIMP-High and CIMP-Low status (P = 0.008). A shorter 5-year survival was observed in MSS cancer patients with CIMP-Low or CIMP-High status. These results remained significant in multivariate analysis adjusted for age, stage, and BRAF and KRAS mutational status CIMP-Low: hazard ratio (HR), 1.85; 95% confidence interval (95% CI), 1.37-2.51; CIMP-High, HR, 2.90; 95% CI, 1.53-5.49 compared with No-CIMP. Within the high-level microsatellite instability group, no difference in survival was observed between the different CIMP groups. Our results show the interest of defining three subgroups of patients according to their methylation status (No-CIMP/CIMP-Low/CIMP-High). Methylation is an independent prognostic factor in MSS colon cancer.
Background
Septic complications after colorectal surgery are frequent and sometimes life threatening. It is well known that inflammation impairs the healing process. It has been suggested that ...preoperative ongoing inflammation could increase the risk of postoperative infections. This study aimed to elucidate the role of preoperative inflammation on postoperative infectious complications and to understand if, through biological markers, it is possible to identify preoperatively patients at higher risk of infection.
Methods
A prospective, observational study was conducted in three centers from November 2011 to April 2014. Consecutive patients undergoing elective colorectal surgery with anastomosis were included. Any ongoing infection was an exclusion criterion. C-reactive protein, albumin, prealbumin, and procalcitonin plasma levels were measured preoperatively. Postoperative infections were recorded according to the definitions of the Centers for Diseases Control. The areas under the receiver operating characteristic curve were analyzed and compared to assess the accuracy of each preoperative marker.
Results
Four-hundred and seventy two patients were analyzed. Infectious complications occurred in 118 patients (25 %) and mortality in 6 patients (1.3 %). In the univariate analysis, preoperative C-reactive protein and albuminemia were found significantly associated with postoperative infectious complications (
P
= 0.008 and
P
= 0.0002, respectively). Areas under the ROC curve for preoperative C-reactive protein and albuminemia were 0.57and 0.62, respectively.
Conclusions
This study confirms the association between preoperative inflammatory activity, hypoalbuminemia, and the onset of infections after surgery. Trials aiming to decrease the inflammatory activity before surgery in order to prevent postoperative complications are warranted.
CA 19–9 predicts resectability of pancreatic cancer even in jaundiced patients Santucci, Nicolas; Facy, Olivier; Ortega-Deballon, Pablo ...
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... et al.,
September 2018, 2018-Sep, 2018-09-00, 20180901, 2018-09, Volume:
18, Issue:
6
Journal Article
Peer reviewed
Surgical resection remains the only curative option for pancreatic adenocarcinoma. Despite recent improvements in medical imaging, unresectability is still often discovered at the time of surgery. It ...is essential to identify unresectable patients preoperatively to avoid unnecessary surgery. High serum CA 19-9 levels have been suggested as a marker of unresectability but considered inaccurate in patients with hyperbilirubinemia.
To evaluate CA 19-9 serum levels as a predictor of unresectability of pancreatic adenocarcinomas with a special focus on jaundiced patients.
All patients presenting with histologically-confirmed pancreatic adenocarcinoma and having serum CA 19-9 levels available prior to any treatment were included in this retrospective study. The relationship between serum concentrations of CA 19–9 and resectability was studied by regression analysis and theROC curves obtained. A cut-off value of CA 19–9 was calculated. In jaundiced patients, a CA 19–9 adjusted for bilirubinemia was also evaluated.
Of the 171 patients included, 49 (29%) were deemed resectable and 122 (71%) unresectable. Altogether, 93 patients (54%) had jaundice. The area under the ROC curve for CA 19–9 as a predictor of resectability was 0.886 (95%CI:0.832–0.932); in jaundiced patients it was 0.880 (95% CI 0.798–0.934. A cut-off in CA 19–9 at 178 UI/mlyielded 85% sensitivity, 81% specificity and 91% positive predictive value for resectability. There was no correlation between the levels of bilirubin and CA 19–9 (r = 0.149).
Serum CA 19–9 is a good predictive marker of unresectability of pancreatic adenocarcinoma, even in jaundiced patients. CA 19-9 levels over 178 UI/ml strongly suggest unresectable disease.
To report a large number of patients with peritoneal carcinomatosis (PC) treated with complete cytoreductive (CCR-0) plus intraperitoneal chemotherapy, and to compare the results according to the ...origin of the primary: colon, rectum, small bowel, and appendix (excluding peritoneal pseudomyxoma).
Among 615 patients treated for PC originating from these 4 types of primaries in 23 French centers, 440 were retrospectively selected as having undergone complete cytoreductive surgery and with complete data retrieval. Primary sites were: colon (n=341), rectum (n=27), appendix (n=41), and small bowel (n=31).
Postoperative mortality and morbidity (3.9% and 31%, respectively) did not differ according to the origin of the primary tumor. The mean follow-up was 60 months. The 5-year overall survival rates were not statistically different for the colon (29.7%), rectum (37.9%), nor the small bowel (33.8%), but was higher (P=0.01) for appendix adenocarcinoma (63.2%). The multivariate analysis of prognostic factors singled out the extent of peritoneal seeding (P<0.0001), positive lymph nodes (P=0.001), and adjuvant systemic chemotherapy (P=0.002), whereas the origin of the tumor was borderline (P=0.06) in favor of appendix tumors.
Cytoreductive surgery plus intraperitoneal chemotherapy yields satisfying and similar survival results in the treatment of PC from colon, rectum, and small bowel adenocarcinomas. Results were better for appendix adenocarcinoma. When feasible, this combined approach should become the gold standard treatment of PC.
Purpose
C-reactive protein and procalcitonin are reliable early predictors of infection after colorectal surgery. However, the inflammatory response is lower after laparoscopy as compared to open ...surgery. This study analyzed whether a different cutoff value of inflammatory markers should be chosen according to the surgical approach.
Methods
A prospective, observational study included consecutive patients undergoing elective colorectal surgery in three academic centers. All infections until postoperative day (POD) 30 were recorded. The inflammatory markers were analyzed daily until POD 4. Areas under the ROC curve and diagnostic values were calculated in order to assess their accuracy as a predictor of intra-abdominal infection.
Results
Five-hundred-one patients were included. The incidence of intra-abdominal infection was 11.8%. The median levels of C-reactive protein (CRP) and procalcitonin (PCT) were lower in the laparoscopy group at each postoperative day (
p
< 0.0001). In patients without intra-abdominal infection, they were also lower in the laparoscopy group (
p
= 0.0036) but were not different in patients presenting with intra-abdominal infections (
p
= 0.3243). In the laparoscopy group, CRP at POD 4 was the most accurate predictor of overall and intra-abdominal infection (AUC = 0.775). With a cutoff of 100 mg/L, it yielded 95.7% negative predictive value, 75% sensitivity, and 70.3% specificity for the detection of intra-abdominal infection.
Conclusion
The impact of infection on inflammatory markers is more important than that of the surgical approach. Defining a specific cutoff value for early discharge according to the surgical approach is not justified. A patient with CRP values lower than 100 mg/L on POD 4 can be safely discharged.
Background
Nowadays, most patients who undergo colorectal surgery are discharged early. An early predictor of septic complications could avoid readmissions and decrease morbidity. CRP could be a good ...predictor allowing a safe discharge.
Methods
A prospective, observational study was conducted from November 2007 to October 2008. All patients who underwent elective colorectal surgery were included. Clinical (temperature, pulse, abdominal tenderness, bowel movements) and laboratory data (C-reactive protein, leukocyte count) were recorded and evaluated as early predictors of septic complications (namely, anastomotic leaks). All detected leaks were considered fistulas, independently of their clinical significance. Clinical and inflammatory parameters were analyzed with univariate and multivariate techniques; logistic regression was performed and areas under the receiver operating characteristic curve were compared.
Results
A total of 133 patients were included. The overall incidence of anastomotic leaks was 15.5% and mortality was 4.5%. C-reactive protein at postoperative days 2 and 4 was a good predictor of anastomotic leak (areas under the curve were 0.715 and 0.845, respectively) and other postoperative septic complications (areas under the curve were 0.804 and 0.787), showing the highest accuracy among clinical and laboratory data. A cutoff of 125 mg/l in the level of C-reactive protein at postoperative day 4 yielded a sensitivity of 81.8% and a negative predictive value of 95.8% for the detection of anastomotic leakage.
Conclusions
C-reactive protein is a simple way to ensure a safe discharge from hospital after elective colorectal surgery. Patients with CRP values >125 mg/l on the fourth postoperative day should not be discharged.
Immune thrombocytopenia (ITP) is an autoimmune disease with a complex pathogenesis. As in many B cell–related autoimmune diseases, rituximab (RTX) has been shown to increase platelet counts in some ...ITP patients. From an immunologic standpoint, the mode of action of RTX and the reasons underlying its limited efficacy have yet to be elucidated. Because splenectomy is a cornerstone treatment of ITP, the immune effect of RTX on this major secondary lymphoid organ was investigated in 18 spleens removed from ITP patients who were treated or not with RTX. Spleens from ITP individuals had follicular hyperplasia consistent with secondary follicles. RTX therapy resulted in complete B-cell depletion in the blood and a significant reduction in splenic B cells, but these patients did not achieve remission. Moreover, whereas the percentage of circulating regulatory T cells (Tregs) was similar to that in controls, splenic Tregs were reduced in ITP patients. Interestingly, the ratio of proinflammatory Th1 cells to suppressive Tregs was increased in the spleens of patients who failed RTX therapy. These results indicate that although B cells are involved in ITP pathogenesis, RTX-induced total B-cell depletion is not correlated with its therapeutic effects, which suggests additional immune-mediated mechanisms of action of this drug.
Insulinomas, with an incidence of 4 cases per million individuals per year, remain amongst the most frequent functional neuroendocrine tumors. The usual diameter of insulinomas usually remains under ...3 cm of major axis. However, 44 exceptional cases of "giant insulinomas", have been reported worldwide, generally exceeding 9 cm in major axis. In this article, we report the case of a 38-year-old woman whom suffered from chronic hypoglycemia despite treatment with diazoxide. Abdominal CT-scan revealed a 88 x 73 mm mass located at the tail of the pancreas. Following surgical excision, histopathological analysis confirmed G1 neuroendocrine tumor, with focal cytoplasmic expression of insulin in tumor cells. After a 16-month follow-up period, the patient didn't address any specific complaint, and no disease recurrence and/or metastasis were observed. A
Ga-DOTATATE-PET scan was performed 6 months after surgery, which came back normal. Genetic evaluation has not been performed in our patient. The physiopathology of giant insulinomas remain unexplained, however with possible relationship with type 1 multiple endocrine neoplasia, sporadic somatic
mutations and possible transformation of bulky non-functional pancreatic neuroendocrine tumors to a functional phenotype, with slow insulin secretion. While giant insulinomas remain rare in the literature, multicentric genetic analysis of tumor samples might reveal unique features of this rare subtype of neuroendocrine pancreatic tumors. Insulinomas of large size tend to have greater malignancy and higher rates of invasiveness. Careful follow-up, especially for liver and lymph node metastases, must be performed using functional imaging techniques to avoid disease relapse.
Background Heated intraperitoneal chemotherapy (HIPEC) treats residual microscopic disease after cytoreductive surgery. In experimental models, the open HIPEC technique has shown a higher and more ...homogenous concentration of platinum in the peritoneum than achieved using the closed technique. A 25-cm H2 O pressure enhances the penetration of oxaliplatin. Because pressure is easier to set up with the closed technique, high pressure may counterbalance the drawbacks of this technique versus open HIPEC, and a higher pressure may induce a higher penetration. Because higher concentration does not mean deeper penetration, a study of tissues beneath the peritoneum is required. Finally, achieving a deeper penetration (and a higher concentration) raises the question of the passage of drugs through the surgical glove and the surgeon's safety. Methods Four groups of pigs underwent HIPEC with oxaliplatin (150 mg/L) for 30 minutes in open isobaric pressure and pressure at 25 cm H2 O, and closed pressure at 25 and 40 cm H2 O. Systemic absorption and peritoneal mapping of the concentration of platinum were analyzed, as well as in the retroperitoneal tissue and the surgical gloves. Results Blood concentrations were higher in open groups. In the parietal surfaces, the concentrations were not different between the isobaric and the closed groups (47.08, 56.39, and 48.57 mg/kg, respectively), but were higher in the open high-pressure group (85.93 mg/kg). In the visceral surfaces, they were lower in the closed groups (3.2 and 3.05 mg/kg) than in the open groups (7.03 and 9.56 mg/kg). Platinum concentrations were similar in the deep retroperitoneal tissue when compared between isobaric and high-pressure procedures. No platin was detected in the internal aspect of the gloves. Conclusion The use of high pressure during HIPEC does not counterbalance the drawbacks of closed techniques. The tissue concentration of oxaliplatin achieved with the open techniques is higher, even if high pressure is applied during a closed technique. Open 25 cm H2 O HIPEC achieved the highest tissue penetration of oxaliplatin, but did not enhance the depth of oxaliplatin penetration. High pressure did not enhance the risk of HIPEC.
PDF
