Influence of Klebsiella pneumoniae and quinolone treatment on prognosis in patients with pancreatic cancer.

BACKGROUND: An increasing body of evidence suggests that microbiota may promote progression of pancreatic ductal adenocarcinoma (PDAC). It was hypothesized that gammaproteobacteria (such as Klebsiella pneumoniae) influence survival in PDAC, and that quinolone treatment may attenuate this effect. METHODS: This was a retrospective study of patients from the Massachusetts General Hospital (USA) and Ludwig-Maximilians-University (Germany) who underwent preoperative treatment and pancreatoduodenectomy for locally advanced or borderline resectable PDAC between January 2007 and December 2017, and for whom a bile culture was available. Associations between tumour characteristics, survival data, antibiotic use and results of intraoperative bile cultures were investigated. Survival was analysed using Kaplan-Meier curves and Cox regression analysis. RESULTS: Analysis of a total of 211 patients revealed that an increasing number of pathogen species found in intraoperative bile cultures was associated with a decrease in progression-free survival (PFS) (-1·9 (95 per cent c.i. -3·3 to -0·5) months per species; P = 0·009). Adjuvant treatment with gemcitabine improved PFS in patients who were negative for K. pneumoniae (26·2 versus 15·3 months; P = 0·039), but not in those who tested positive (19·5 versus 13·2 months; P = 0·137). Quinolone treatment was associated with improved median overall survival (OS) independent of K. pneumoniae status (48·8 versus 26·2 months; P = 0·006) and among those who tested positive for K. pneumoniae (median not reached versus 18·8 months; P = 0·028). Patients with quinolone-resistant K. pneumoniae had shorter PFS than those with quinolone-sensitive K. pneumoniae (9·1 versus 18·8 months; P = 0·001). CONCLUSION: K. pneumoniae may promote chemoresistance to adjuvant gemcitabine, and quinolone treatment is associated with improved survival.

Risk of malignancy in small pancreatic cysts decreases over time.

BACKGROUND: Pancreatic cysts <15 mm without worrisome features have practically no risk of malignancy at the time of diagnosis but this can change over time. Optimal duration of follow-up is a matter of debate. We evaluated predictors of malignancy and attempted to identify a time to safely discontinue surveillance. METHODS: Bi-centric study utilizing prospectively collected databases of patients with pancreatic cysts measuring <15 mm and without worrisome features who underwent surveillance at the Massachusetts General Hospital (1988-2017) and at the University of Verona Hospital Trust (2000-2016). The risk of malignant transformation was assessed using the Kaplan-Meier method and parametric survival models, and predictors of malignancy were evaluated using Cox regression. RESULTS: 806 patients were identified. Median follow-up was 58 months (6-347). Over time, 58 (7.2%) cysts were resected and of those, 11 had high grade dysplasia (HGD) or invasive cancer. Three additional patients had unresectable cancer for a total rate of malignancy of 1.7%. Predictors of development of malignancy included an increase in size ≥2.5 mm/year (HR = 29.54, 95% CI: 9.39-92.91, P < 0.001) and the development of worrisome features (HR = 9.17, 95% CI: 2.99-28.10, P = 0.001). Comparison of parametric survival models suggested that the risk of malignancy decreased after three years of surveillance and was lower than 0.2% after five years. CONCLUSIONS: Pancreatic cysts <15  mm at the time of diagnosis have a very low risk of malignant transformation. Our findings indicate the risk decreases over time. Size increase of ≥2.5 mm/year is the strongest predictor of malignancy.

An elevated CA 19-9 is associated with invasive cancer and worse survival in IPMN.

BACKGROUND: Current guidelines for IPMN include an elevated serum carbohydrate antigen (CA) 19-9 among the worrisome features. However, the correlation of CA 19-9 with histological malignant features and survival is unclear. Serum CEA is also currently used for preoperative management of IPMN, although its measurement is not evidence-based. Accordingly, we aimed to assess the role of these tumor markers as predictors of malignancy in IPMN. METHODS: IPMN resected between 1998 and 2018 at Massachusetts General Hospital were analyzed. Clinical, pathological and survival data were collected and compared to preoperative levels of CA 19-9 and CEA. Receiver operating characteristic (ROC) and Cox regression analyses were performed considering cut-offs of 37 U/ml (CA 19-9) and 5 µg/l (CEA). RESULTS: Analysis of 594 patients showed that preoperative CA 19-9 levels > 37 U/ml (n = 128) were associated with an increased likelihood of invasive carcinoma when compared to normal levels (45.3% vs. 18.0%, P < 0.001), while there was no difference with respect to high-grade dysplasia (32.9% vs 31.9%, P = 0.88). The proportion of concurrent pancreatic cancer was higher in patients with CA 19-9 > 37 U/ml (17.2% vs 4.9%, P < 0.001). An elevated CA 19-9 was also associated with worse overall and disease-free survival (HR = 1.943, P = 0.007 and HR = 2.484, P < 0.001 respectively). CEA levels did not correlate with malignancy. CONCLUSION: In patients with IPMN, serum CA19-9 > 37 U/ml is associated with invasive IPMN and concurrent pancreatic cancer as well as worse survival, but not with high-grade dysplasia. Serum CEA appears to have minimal utility in the management of these patients.

Major Complications Independently Increase Long-Term Mortality After Pancreatoduodenectomy for Cancer.

BACKGROUND: Postoperative major morbidity has been associated with worse survival gastrointestinal tumors. This association remains controversial in pancreatic cancer (PC). We analyzed whether major complications after surgical resection affect long-term survival. METHODS: Records of all PC patients resected from 2007 to 2015 were reviewed. Major morbidity was defined as any grade-3 or higher 30-day complications, per the Clavien-Dindo Classification. Patients who died within 90 days after surgery were excluded from survival analysis. RESULTS: Of 616 patients, 81.7% underwent pancreatoduodenectomy (PD) and 18.3% distal pancreatectomy (DP). Major complications occurred in 19.1% after PD and 15.9% after DP. In patients who survived > 90 days, the likelihood of receiving adjuvant treatment was 43.9% if major complications had occurred, vs. 68.5% if not (p < 0.001), and those who received it started the treatment median 10 days later compared with uncomplicated patients (median 60 days (50-72) vs. 50 days (41-61), p = 0.001). By univariate analysis, in addition to the conventional pathology-related prognostic determinants and the receipt of adjuvant treatment, major complications worsened long-term survival after PD (median OS 26 months vs. 15, p = 0.008). A difference was also seen after DP, but it did not reach statistical significance, likely related to the small sample size (median OS 33 months vs. 18, p = 0.189). At multivariate analysis for PD, major postoperative complications remained independently associated with worse survival [HR 1.37, 95%CI (1.01-1.86)]. CONCLUSIONS: Major surgical complications after pancreaticoduodenectomy are associated with worse long-term survival in pancreatic cancer. This effect is independent of the receipt of adjuvant treatment.

Intraoperative Fluid Administration and Surgical Outcomes Following Pancreaticoduodenectomy: External Validation at a Tertiary Referral Center.

BACKGROUND: While intraoperative fluid overload is associated with higher complication rates following surgery, data for pancreaticoduodenectomy are scarce and heterogeneous. We evaluated multiple prior definitions of restrictive and liberal fluid regimens and analyzed whether these affected surgical outcomes at our tertiary referral center. METHODS: Studies evaluating different intraoperative fluid regimens on outcomes after pancreatic resections were retrieved. After application of all prior definitions of restrictive and liberal fluid regimens to our patient cohort, relative risks of each outcome were calculated using all reported infusion regimens. RESULTS: Five hundred and seven pancreaticoduodenectomies were included. Nine different fluid regimens were evaluated. Two regimens utilized absolute volume cutoffs, and the remaining evaluated various infusion rates, ranging from 5 to 15 mL/kg/h. Total volume administration of >5000 mL and >6000 mL was associated with increased complications (RR 1.25 and RR 1.17, respectively) and >6000 mL with increased sepsis (RR 2.14). Conversely, a rate of <5 mL/kg/h was associated with increased risk of postoperative pancreatic fistula (POPF, RR 3.16) and sepsis (RR 3.20), <6.8 mL/kg/h with increased major morbidity (RR 1.64) and sepsis (RR 2.27), and <8.2 mL/kg/h with increased POPF (RR 2.16). No effects were observed on pulmonary complications, surgical site infections, length of stay, or mortality. CONCLUSIONS: In an uncontrolled setting with no standard intraoperative or postoperative care map, the volume of intraoperative fluid administration appears to have limited impact on early postoperative outcomes following pancreaticoduodenectomy, with adverse outcomes only seen at extreme values.

Pancreatic neuroendocrine tumors in patients with tuberous sclerosis complex.

We explored pancreatic neuroendocrine tumors (PanNETs) associated with tuberous sclerosis complex (TSC) to determine their incidence in the TSC population; define their clinical, radiological, and pathological characteristics; and investigate their association with underlying genotypes. Retrospectively reviewed abdominal imaging of 219 patients with TSC, evaluating the incidence, size, and architecture of pancreatic lesions. Pathology records at Massachusetts General Hospital (MGH) were reviewed for all PanNET diagnoses in patients with TSC. Literature was reviewed for TSC-related PanNET cases. Nine patients with TSC were found to have a pancreatic lesion(s) on abdominal imaging and six patients have been diagnosed with a PanNET by pathology at MGH. Twelve cases of TSC-associated PanNETs have been reported in the literature. Of these 18 PanNET cases, one third were cystic, and the average age at resection was 26 years. Germline TSC2 mutations were found in all patients for whom genetic data were available (n = 3). We did not identify pancreatic angiomyolipomas in this series. Our results suggest that PanNETs are the most common pancreatic lesion in patients with TSC. Focal pancreatic mass lesions, solid or cystic, in patients with TSC should be considered possible PanNETs, and resection of the lesion may be clinically indicated.

CSPG4 in cancer: multiple roles.

Chondroitin sulfate proteoglycan 4 (CSPG4), also known as High Molecular Weight-Melanoma Associated Antigen, is a cell surface proteoglycan which has been recently shown to be expressed not only by melanoma cells, but also by various types of human carcinoma and sarcoma. Furthermore, at least in squamous cell carcinoma of head and neck and in basal breast carcinoma, CSPG4 is expressed by cancer stem cells. CSPG4 plays an important role in tumor cell growth and survival. These CSPG4-associated functional properties of tumor cells are inhibited by CSPG4-specific monoclonal antibodies (mAb) in vitro. Moreover, CSPG4-specific mAb can also inhibit tumor growth and metastasis in vivo. The anti-tumor effects of CSPG4-specific mAb are likely to reflect the blocking of important migratory, mitogenic and survival signaling pathways in tumor cells. These results indicate that CSPG4 is a promising new target to implement mAb-based immunotherapy of various types of cancer.