Pancreatic cancer is a highly lethal malignancy. Lack of early diagnostic markers makes timely detection of pancreatic cancer a highly challenging endeavor. Exosomes have emerged as information-rich ...cancer specific biomarkers. However, characterization of tumor-specific exosomes has been challenging. This study investigated the proof of principle that exosomes could be used for the detection of pancreatic cancer. Label-free analysis of exosomes purified from normal and pancreatic cancer cell lines was performed using surface enhanced Raman Spectroscopy (SERS) and principal component differential function analysis (PC-DFA), to identify tumor-specific spectral signatures. This method differentiated exosomes originating from pancreatic cancer or normal pancreatic epithelial cell lines with 90% accuracy. The cell line trained PC-DFA algorithm was next applied to SERS spectra of serum-purified exosomes. This method exhibited up to 87% and 90% predictive accuracy for HC and EPC individual samples, respectively. Overall, our study identified utility of SERS spectral signature for deciphering exosomal surface signature.
The present study utilizes exosomes purified from pancreatic cancer and pancreatic epithelial cell lines and surface enhanced Raman spectroscopy (SERS) spectra to train an algorithm by Principle Component-Differential Functional Analysis (PC-DFA). This trained PC-DFA algorithm was subsequently applied to SERS spectra to characterize exosomes as originating from pancreatic patient or healthy patient serum with up to 90% accuracy. Display omitted
Pancreatic cancer (PC) is a lethal malignancy that lacks specific diagnostic markers. The present study explores the diagnostic potential of the most differentially overexpressed secretory mucin ...MUC5AC alone and in combination with CA19-9 using multi-center training and validation sets.
The expression of MUC5AC in benign pancreatic pathologies, PC precursor lesions, primary PC tissues and metastatic lesions was evaluated by immunohistochemistry. Circulating MUC5AC levels were measured using sandwich ELISA assay developed in-house, and CA19-9 was measured using radioimmunoassay. A combined training set (n=346) was used to evaluate the diagnostic (n=241) and predictive (n=105, total samples 201 from pre- and post-surgical and chemotherapy set) significance of MUC5AC. Results were further validated with a pre-defined cut-off value using independent sets from the Mayo Clinic (n=94) and the University of Pittsburgh Medical Center (n=321).
Tissue expression analyses indicated the de novo expression of MUC5AC in pancreatic intraepithelial precursor lesions 1A (PanIN1A); the expression was maintained through all stages of progression to invasive adenocarcinoma. The median circulating MUC5AC levels in patients with resectable early-stage PC (EPC) (stage 1/2; 67.2 ng/ml, IQR: 23.9-382.1) and unresectable late-stage PC (LPC) (stage 3/4; 389.7 ng/ml, IQR: 87.7-948.6) were significantly higher compared with (P-value ≤0.0001) benign controls (BC) (7.2 ng/ml, IQR: 0.4-26.5) and (P-value ≤0.0001) chronic pancreatitis (CP) controls (8.4 ng/ml, IQR: 1.5-19.2). In the diagnostic training set (n=241), MUC5AC efficiently differentiated EPC from healthy controls (HC) (83%/80% sensitive (SN)/specific (SP)), BC (67%/87% SN/SP), and CP (83%/77% SN/SP). Independent validation sets from the Mayo Clinic and UPMC confirmed the diagnostic potential of MUC5AC to differentiate EPC from BC (68%/73%; 65%/83%) and CP (68%/79%; 65%/72%). Furthermore, MUC5AC and CA19-9 combination significantly improved (p-value < 0.001) the diagnostic accuracy for differentiating resectable cases from controls.
MUC5AC is a valuable diagnostic biomarker, either alone or in combination with CA19-9, to differentiate PC from CP and benign controls.
Pancreatic ductal adenocarcinoma (PDAC) is an incredibly deadly disease with a 5-year survival rate of 9%. The presence of pancreatic cystic lesions (PCLs) confers an increased likelihood of future ...pancreatic cancer in patients placing them in a high-risk category. Discerning concurrent malignancy and risk of future PCL progression to cancer must be carefully and accurately determined to improve survival outcomes and avoid unnecessary morbidity of pancreatic resection. Unfortunately, current image-based guidelines are inadequate to distinguish benign from malignant lesions. There continues to be a need for accurate molecular and imaging biomarker(s) capable of identifying malignant PCLs and predicting the malignant potential of PCLs to enable risk stratification and effective intervention management. This review provides an update on the current status of biomarkers from pancreatic cystic fluid, pancreatic juice, and seromic molecular analyses and discusses the potential of radiomics for differentiating PCLs harboring cancer from those that do not.
Display omitted
Disseminated peritoneal adenomucinosis (DPAM) patients often have a history of appendectomy with identification of an incidental mucinous neoplasm (low-grade appendiceal mucinous neoplasm (LAMN)). ...The rate of developing DPAM is not well established.
Twenty-two patients with incidental LAMN were identified and monitored with cancer markers and CT every 4-6 months. Laparoscopy with peritoneal washing was performed in patients either in the event of radiographic disease or after 12 months in absence of radiographic disease. The rate of detecting peritoneal metastasis was determined for CT scan and laparoscopy.
Peritoneal metastasis was detected in 5 (23 %) patients. Occult disease was detected in four patients at laparoscopy without a detectable disease on CT scan. One patient developed radiographic progression at 6 months confirmed with laparoscopy. Four patients were treated with cytoreductive surgery (CRS)/HIPEC and one with CRS only. The 17 patients with negative laparoscopy remain disease free with a median follow-up of 50 months.
The rate of peritoneal metastasis in incidental LAMN patients was 23 %. Laparoscopy was the primary screening tool identifying occult metastasis. The median PCI of 7 was low, and all the patients underwent R0/R1 resections. This study revealed 1 in every 4.4 patients with LAMN may develop PMP. Longer follow-up and further patient surveillance is warranted.
Sessile serrated adenoma/polyps (SSA/P) are premalignant lesions of colorectal cancer that are difficult to distinguish histologically from hyperplastic polyps (HP) of minimal to no malignant ...potential. Specific markers for differentiating SSA/P from HP can aid clinicians for optimizing colon surveillance intervals. The present study investigates the potential of mucins and associated O-glycans to distinguish SSA/P from HP. Expression of colonic mucins (MUC1, MUC4, MUC17, MUC2, and MUC5AC) and O-glycans Sialyl LewisA (CA19-9) and Tn/Sialyl-Tn on MUC1 were analyzed in HP (n=33), SSA/P (n=39), and tubular adenoma (TA) (n=36) samples by immunohistochemistry. A significantly reduced expression of MUC4 (p=0.0066), elevated expression of MUC17 (p=0.0002), and MUC5AC (p<0.0001) was observed in SSA/P cases in comparison to HP cases. Interestingly, significantly higher number of SSA/P cases (p<0.0001) exhibited MUC5AC expression in the goblet cells as well as filled the crypt lumen compared to only goblet cells in majority of the HP cases. Improved diagnostic potential was revealed by multivariate logistic regression analysis where combinatorial panel of MUC5AC/MUC17 discriminated SSA/P from HP (SN/SP=85/82%). Finally, the decision tree model based marker panel (CA19-9/MUC17/MUC5AC) predicted HP, SSA/P and TA with SN/SP of 58%/95%, 79%/90% and 97%/83%, respectively. Overall, the mucin and associated O-glycan based panel defined in the present study could aid in discriminating SSA/P from HP to devise better colon surveillance strategies.
Currently, rates of referral of patients with peritoneal metastasis in the United States who qualify for cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) are ...low, in part because of the misperception of high morbidity and mortality rates. However, patients requiring major gastrointestinal surgical procedures with similar complication rates are routinely referred.
To evaluate the relative safety of CRS/HIPEC.
Retrospective cohort study of 34 114 patients who underwent CRS/HIPEC, right lobe hepatectomy, trisegmental hepatectomy, pancreaticoduodenectomy, and esophagectomy between January 1, 2005, and December 31, 2015, included in the American College of Surgeons National Surgical Quality Improvement Project (NSQIP) database. Data analysis was performed in 2018.
Data from the NSQIP database were used to compare perioperative and 30-day postoperative morbidity and mortality rates of CRS/HIPEC (1822 patients) with other, well-accepted, high-risk surgical oncology procedures: right lobe hepatectomy (5109 patients), trisegmental hepatectomy (2449 patients), pancreaticoduodenectomy (Whipple) (16 793 patients), and esophagectomy (7941 patients).
For 34 114 patients, median (interquartile range IQR) age was 63 (55-71) years and 42% were female. Patients undergoing CRS/HIPEC tended to be younger, with a median age of 57 years, and esophagectomy had the highest median (IQR) American Society of Anesthesiologists classification (3 3-3). When compared with CRS/HIPEC, higher complication rates were reported in the following categories: (1) superficial incisional infection in Whipple and esophagectomy (5.4% 95% CI, 4.4%-6.4% vs 9.7% 95% CI, 9.3%-10.1% and 7.2% 95% CI, 6.6%-7.8%, respectively; P < .001); (2) deep incisional infection in Whipple (1.7% 95% CI, 1.1%-2.3% vs 2.7% 95% CI, 2.5%-2.9%; P < .01); (3) organ space infection in right lobe hepatectomy (7.2% 95% CI, 6.0%-8.4% vs 9.0% 95% CI, 8.2%-9.8%; P = .02), trisegmental hepatectomy (12.4% 95% CI, 11.1%-13.7%; P < .001), and Whipple (12.9% 95% CI, 12.4%-13.4%; P < .001); and (4) return to the operating room for esophagectomy (6.8% 95% CI, 5.6%-8.0% vs 14.4% 95% CI, 13.6%-15.2%; P < .001). Median (IQR) length of hospital stay was lower in CRS/HIPEC (8 5-11 days) than Whipple (10 7-15 days) and esophagectomy (10 8-16 days) (P < .001). Overall 30-day mortality was lower in CRS/HIPEC (1.1%; 95% CI, 0.6%-1.6%) compared with Whipple (2.5%; 95% CI, 2.3%-2.7%), right lobe hepatectomy (2.9%; 95% CI, 2.4%-3.4%), esophagectomy (3.0%; 95% CI, 2.6%-3.4%), and trisegmental hepatectomy (3.9%; 95% CI, 3.1%-4.7%) (P < .001).
Comparative analysis revealed CRS/HIPEC to be safe, often safer across the spectrum of NSQIP safety metrics when compared with similar-risk oncologic procedures. Patient selection was important in achieving observed outcomes. High complication rates are a misperception from early CRS/HIPEC experience and should no longer deter referral of patients to experienced centers or impede clinical trial development in the United States.
Background
The global cancer burden (GCB) is expected to rise significantly during the next few decades with most of the new cancers and cancer-related deaths afflicting the low- to middle-income ...countries. The ability to tackle this rising GCB requires the presence of an adequately trained surgical oncology workforce, which is dependent on credible training pathways and sustainable certification pipelines. The purpose of this article is to review briefly the training patterns and certification requirements for surgical oncologists globally by sampling representative countries across all regions of the world.
Methods
A thorough literature search was conducted using multiple websites of credible national/global organizations as well as the websites of individual countries. Countries from select regions in the world were included (based on the World Health Organization regions and Human Development Index) in the analysis to determine the prevalent trends in the training of surgical oncologists globally.
Results
Several trends and significant differences were noted in the training patterns of surgical oncologists globally. The presence or absence of domestic surgical oncology fellowships had an inverse correlation to the income level of the country. Countries without domestic fellowships usually relied on high-income foreign destinations for their training.
Conclusions
The results of the analysis demonstrated significant variability in training of surgical oncologists globally. Despite the diversity, we noticed some general trends based on which some recommendations were put forth for increasing the global surgical oncology workforce.
Alternative gene splicing, occurring ubiquitously in multicellular organisms can produce several protein isoforms with putatively different functions. The enormously extended genomic structure of ...mucin genes characterized by the presence of multiple exons encoding various domains may result in functionally diverse repertoire of mucin proteins due to alternative splicing. Splice variants (Svs) and mutations in mucin genes have been observed in various cancers and shown to participate in cancer progression and metastasis. Although several mucin Svs have been identified, their potential functions remain largely unexplored with the exception of the Svs of MUC1 and MUC4. A few studies have examined the expression of MUC1 and MUC4 Svs in cancer and indicated their potential involvement in promoting cancer cell proliferation, invasion, migration, angiogenesis and inflammation. Herein we review the current understanding of mucin Svs in cancer and inflammation and discuss the potential impact of splicing in generating a functionally diverse repertoire of mucin gene products. We also performed mutational analysis of mucin genes across five major cancer types in International Cancer Genome Consortium database and found unequal mutational rates across the panel of cancer-associated mucins. Although the functional role of mucins in the pathobiology of various malignancies and their utility as diagnostic and therapeutic targets remain undisputed, these attributes need to be reevaluated in light of the potentially unique functions of disease-specific genetic variants of mucins. Thus, the expressional and functional characterization of the genetic variants of mucins may provide avenues to fully exploit their potential as novel biomarkers and therapeutic targets.
PDF
