Serum miR-215-5p, miR-192-5p and miR-378a-5p as novel diagnostic biomarkers for periampullary adenocarcinoma.

OBJECTIVE: MicroRNAs (miRNAs) are present in human serum in a stable form. Circulating miRNAs are increasingly recognized as promising biomarkers for early cancer detection. The aim of this study was to identify serum miRNAs as biomarkers for periampullary adenocarcinoma (PAC). PATIENTS AND METHODS: 68 patients with PAC and 50 healthy controls (HCs) subjects were recruited in this study. The expression levels of 11 selected miRNAs were determined in serum samples using the SYBR-green quantitative reverse transcription polymerase chain reaction (qRT-PCR) method. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic potential of serum miRNAs. RESULTS: The expression levels of three miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) were significantly upregulated in the serum samples derived from the PAC patients compared with those from the HC (p < 0.001). The ROC analysis showed that all three significantly altered miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) could potentially discriminate patients with PAC from HC with AUC value of 0.771 (95% CI: 0.684-0.843), 0.877 (95% CI: 0.799-0.927) and 0.768 (95% CI: 0.674-0.853) respectively. Further comparisons showed that these three serum miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) can strongly discriminate early-stage PAC patients from HC with an AUC value of 0.802 (95% CI: 0.719-0.886), 0.870 (95% CI: 0.793-0.974) and 0.793 (95% CI: 0.706-0.880) respectively, may aid in early detection of PAC. CONCLUSIONS: Taken together, our findings demonstrated that these three serum miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) may serve as noninvasive biomarkers for the early detection of PAC.

Machine learning for differentiating between pancreatobiliary-type and intestinal-type periampullary carcinomas based on CT imaging and clinical findings.

PURPOSE: To develop a diagnostic model for distinguishing pancreatobiliary-type and intestinal-type periampullary adenocarcinomas using preoperative contrast-enhanced computed tomography (CT) findings combined with clinical characteristics. METHODS: This retrospective study included 140 patients with periampullary adenocarcinoma who underwent preoperative enhanced CT, including pancreaticobiliary (N = 100) and intestinal (N = 40) types. They were randomly assigned to the training or internal validation set in an 8:2 ratio. Additionally, an independent external cohort of 28 patients was enrolled. Various CT features of the periampullary region were evaluated and data from clinical and laboratory tests were collected. Five machine learning classifiers were developed to identify the histologic type of periampullary adenocarcinoma, including logistic regression, random forest, multi-layer perceptron, light gradient boosting, and eXtreme gradient boosting (XGBoost). RESULTS: All machine learning classifiers except multi-layer perceptron used achieved good performance in distinguishing pancreatobiliary-type and intestinal-type adenocarcinomas, with the area under the curve (AUC) ranging from 0.75 to 0.98. The AUC values of the XGBoost classifier in the training set, internal validation set and external validation set are 0.98, 0.89 and 0.84 respectively. The enhancement degree of tumor, the growth pattern of tumor, and carbohydrate antigen 19-9 were the most important factors in the model. CONCLUSION: Machine learning models combining CT with clinical features can serve as a noninvasive tool to differentiate the histological subtypes of periampullary adenocarcinoma, in particular using the XGBoost classifier.

Elevated levels of peripheral Th17 cells and Th17-related cytokines in patients with periampullary adenocarcinoma.

AIM: Periampullary adenocarcinoma (PAC) is a malignant tumor originating at the ampulla of Vater, distal common bile duct, head of the pancreas, ampulla and duodenum. The levels of circulating Th17 cells and Th17-related cytokines in patients with PAC remain unreported. Therefore, the aim of this study was to determine the levels of circulating Th17 cells and Th17-related cytokines in patients with PAC. MATERIALS AND METHODS: Flow cytometry was used to measure Th17 cell proportions in PBMCs from 60 PAC patients and 30 healthy controls. Enzyme-linked immunosorbent assay (ELISA) was used to quantify IL-17A and IL-23 levels in serum samples, while quantitative reverse transcription polymerase chain reaction (qRT-PCR) assessed IL-17A mRNA expression and Th17-related transcription factors (RORγt and STAT3) in tissue samples. RESULTS: The findings showed a substantial increase in Th17 cell percentages, elevated concentrations of IL-17A and IL-23, and higher mRNA expression levels of IL-17A, RORγt, and STAT3 in patients with PAC when compared to healthy controls (HCs). CONCLUSION: Th17 cells play an important role in the pathogenesis of PAC and may represent potential therapeutic targets.

Analysis of Pancreatobiliary and Intestinal Type Periampullary Carcinomas Using Volumetric Apparent Diffusion Coefficient Histograms.

RATIONALE AND OBJECTIVES: Magnetic resonance imaging plays an important role in the evaluation of patients with known or suspected periampullary masses. The utilization of volumetric apparent diffusion coefficient (ADC) histogram evaluation for the entire lesion eradicates the potential for subjectivity in the region of interest placement, thus guaranteeing the accuracy of computation and repeatability. PURPOSE: To investigate the value of volumetric ADC histogram analysis in the differentiation of intestinal-type (IPAC) and pancreatobiliary-type periampullary adenocarcinomas (PPAC). MATERIALS AND METHODS: This retrospective study included 69 patients with histopathologically confirmed periampullary adenocarcinoma (54 PPAC and 15 IPAC). Diffusion-weighted imaging was obtained at b values of 1000 mm²/s. The histogram parameters of ADC values, comprising the mean, minimum, maximum, 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles, as well as skewness, kurtosis, and variance, were calculated independently by two radiologists. Using the interclass correlation coefficient, the interobserver agreement was evaluated. RESULTS: The ADC parameters for the PPAC group were all lower than those of the IPAC group. The PPAC group had higher variance, skewness, and kurtosis than the IPAC group. However, the difference between the kurtosis (P = .003), the 5th (P = .032), 10th (P = .043), and 25th (P = .037) percentiles of ADC values was statistically significant. The area under the curve (AUC) of the kurtosis was the highest (AUC=0.752; cut-off value=-0.235; sensitivity=61.1%; specificity=80.0%). CONCLUSION: Volumetric ADC histogram analysis with b values of 1000 mm²/s can discriminate subtypes noninvasively before surgery.

Pancreaticoduodenectomy as a feasible choice for periampullary malignancy in octogenarians.

The efficacy and safety of pancreaticoduodenectomy (PD) has not been yet studied in octogenarians in Greece. The present study reviewed records of all consecutive patients that underwent PD at the 4th Surgical Department of Attikon University Hospital (Athens, Greece) between January 1st, 2010 and December 31st, 2019. Differences between two age groups (group Y <80 years; group O >80 years) were analyzed. Study endpoints were length of stay, overall morbidity, 30-day mortality and overall survival (OS). There were 198 patients in Group Y (mean age, 65 years) and 20 patients in Group O (mean age, 82 years). Octogenarians had worse American Society of Anesthesiology score (>2; 31.3 vs. 65%; P=0.018). Median stay was not significantly different between the two groups (14 days vs. 16 days; P=0.307), neither was the 30-day mortality (6.1 vs. 5.0%; P>0.99). Median OS was similar between the two groups (35 months vs. 28 months; P=0.577). In a tertiary center in Greece, morbidity and mortality rates after PD were similar between the two groups. Patients should not be denied a PD, solely based on advanced age.

The aborted Whipple: Why, and what happens next?

BACKGROUND: For patients with periampullary adenocarcinoma (PAC), pancreatoduodenectomy (PD) provides the best survival. Surgery on a subset of patients is aborted during PD. We analyzed these patients. METHODS: Patients who underwent laparotomy for planned PD for PAC were identified (2006-2019). From operative notes, we identified the subset with intraoperative decision to abort. Patient, treatment, and outcome data were analyzed. The subset with pancreatic ductal adenocarcinoma (PDAC) was analyzed for survival. RESULTS: Only 6.7% (n = 55/819) of cases were aborted. Majority 78% (n = 43) had pathologically-confirmed diagnoses at time of surgery, and 18.2% (n = 10) received preoperative chemotherapy. Reasons for aborted PD included: distant metastases (65.5%, n = 36) and local invasion (34.5%, n = 19). Of patients with metastatic disease, 75% (n = 27) had liver metastases. Eighty-nine percent (n = 49) of patients underwent at least one palliative bypass procedure and 81.8% (n = 45) had both gastric and biliary bypass. Patients with computed tomography (CT) scans before surgery more commonly had missed metastatic disease (79.2% CT compared to 54.8% magnetic resonance imaging [MRI], χ2 = 3.54, p = 0.059). In PDAC, 61.4% (n = 27/44) were aborted for metastatic disease and 38.7% (n = 17/44) for local invasion. Median overall survival for all PDAC patients after aborted PD was 334 days. CONCLUSION: Majority of pancreatoduodenectomies for periampullary adenocarcinoma are done to completion. Liver metastases is the most common reason for aborting. Preoperative MRI may help identify hepatic metastases.

Comparison of laparoscopic and open pancreaticoduodenectomy for the treatment of nonpancreatic periampullary adenocarcinomas: a propensity score matching analysis.

BACKGROUND: Use of laparoscopic pancreaticoduodenectomy (LPD) in place of open pancreaticoduodenectomy (OPD) remains controversial. Our aim was to evaluate the results of LPD versus OPD in non-pancreatic periampullary adenocarcinoma (NPPC), a less aggressive tumor. METHODS: Here, 488 NPPC patients who underwent LPD or OPD were analyzed in this study. The propensity score matching was used to balance the patients in two groups. Statistical analysis was conducted to investigate the differences between LPD and OPD in patients with NPPC. RESULTS: The LPD group had shorter operative time, less intraoperative bleeding, and less postoperative hospital stay than OPD group. The 30- and 90-day mortality rates were significantly lower in LPD than in OPD group. There was no statistical difference in long-term survival between the two groups. CONCLUSIONS: For NPPC, LPD may be the preferred surgical treatment due to its advantages over OPD in terms of intraoperative blood loss and short-term mortality.

Liquid biopsy and multi-analyte testing guided treatment of HER2 positive periampullary adenocarcinoma with durable complete response after trastuzumab based therapy.

Periampullary adenocarcinomas are rare neoplasm that originates from the pancreatic head, the ampulla of vater, the distal bile duct or the duodenum. Surgical resection followed by adjuvant therapy is considered as the standard of care treatment for these carcinomas. Despite several advances in diagnostics and therapeutics, only 5% of these patients have an overall survival of five years or more. Currently, there is a dearth of viable therapeutic targets for this disease. The role of HER2 in cancer biology has been studied extensively in several tumour subtypes, and HER2 based targeted therapies have shown to have therapeutic benefits on different cancers. In this case report, we present a case of HER2 positive distal common bile duct carcinoma - a subtype of periampullary carcinoma with multiple relapses where multi-analyte testing with Encyclopedic Tumor Analysis (ETA) (Exacta®) identified amplification and over expression of HER2 gene which was used as a potential target to treat the patient with trastuzumab. Synchronous in vitro chemosensitivity profiling on Circulating Tumor Asscociated Cells (C-TACs) isolated from blood aided us to design the personalized chemotherapeutic regimen with cyclophosphamide and methotrexate. The combination of trastuzumab with cyclophosphamide and methotrexate yielded excellent treatment response with the patient remaining in complete response till the last follow-up. Our study suggests HER2 directed therapy as a potent pathway for treatment in the subset of HER-2 amplified distal common bile duct carcinomas.

Prognostic factors for long-term survival after pancreaticoduodenectomy for periampullary adenocarcinoma. A retrospective cohort study.

BACKGROUND: Periampullary adenocarcinoma (PAAC) had a poor prognosis, and pancreaticoduodenectomy (PD) remains the only potentially curative treatment. The study aimed to identify the impact of different clinicopathological factors on long-term survival following PD for PAAC. PATIENTS AND METHODS: This study is a retrospective cohort study for the patients who underwent PD for pathologically proven PAAC from January 2010 to January 2019. Statistical analysis was done using Cox regression multivariate analyses for independent risk factors for survival. RESULT: There were 137 patients with PAAC who underwent PD, 79 patients (57.7%) underwent pylorus-preserving PD. Pancreatico-jejunostomy was done in 108 patients (78.8%). The primary analysis showed that risk factors for poor long-term survival include patients with co-morbidities like hypertension or ischemic heart disease, Carbohydrate Antigen 19-9 > 400U/ml, tumor size > 3 cm, poor tumor differentiation, positive lymph nodes invasion, lymphovascular invasion, and Perineural invasion. Multivariate analysis demonstrated that large tumor size > 3 cm (HR: 0.177, 95%CI: 0.084-0.374, P = 0.002), poorly differentiated tumor (HR: 0.059, 95%CI: 0.020-0.0174, P = 0.016), and perineural invasion in the pathological study (HR: 0.101, 95%CI: 0.046-0.224, P = 0.006) were independent risk factors for poor 5-years survival. The prognosis was better in ampullary adenocarcinoma (5-year survival was 42.1%) than pancreatic adenocarcinoma (5-year survival was 24.3%). The 1, 3, 5 and 7-year overall survival rates were 84.5%, 57.4%, 35.9% and 20.1% respectively. CONCLUSION: It seems from the current study that Tumor size > 3 cm, poor tumor differentiation, and Perineural invasion were independent predictors of poor survival in patients with PAAC.

A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients.

BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) is a cancer of the exocrine pancreas and 5-year survival rates remain constant at 7%. Along with PDAC, Periampullary Adenocarcinoma (PAC) accounts for 0.5-2% of all gastrointestinal malignancies. Genomic observations were well concluded for PDAC and PACs in western countries but no reports are available from India till now. METHODS: Targeted Next Generation Sequencing were performed in 8 (5 PDAC and 3 PAC) tumour normal pairs, using a panel of 412 cancer related genes. Primary findings were replicated in 85 tumour samples (31 PDAC and 54 PAC) using the Sanger sequencing. Mutations were also validated by ASPCR, RFLP, and Ion Torrent sequencing. IHC along with molecular dynamics and docking studies were performed for the p.A138V mutant of TP53. Key polymorphisms at TP53 and its associated genes were genotyped by PCR-RFLP method and association with somatic mutations were evaluated. All survival analysis was done using the Kaplan-Meier survival method which revealed that the survival rates varied significantly depending on the somatic mutations the patients harboured. RESULTS: Among the total 114 detected somatic mutations, TP53 was the most frequently mutated (41%) gene, followed by KRAS, SMAD4, CTNNB1, and ERBB3. We identified a novel hotspot TP53 mutation (p.A138V, in 17% of all patients). Low frequency of KRAS mutation (33%) was detected in these samples compared to patients from Western counties. Molecular Dynamics (MD) simulation and DNA-protein docking analysis predicted p.A138V to have oncogenic characteristics. Patients with p.A138V mutation showed poorer overall survival (p = 0.01). So, our finding highlights elevated prevalence of the p53p.A138V somatic mutation in PDAC and pancreatobiliary PAC patients. CONCLUSION: Detection of p.A138V somatic variant in TP53 might serve as a prognostic marker to classify patients. It might also have a role in determining treatment regimes. In addition, low frequency of KRAS hotspot mutation mostly in Indian PDAC patient cohort indicates presence of other early drivers in malignant transformation.

Clinical significance of stromal ER and PR expression in periampullary adenocarcinoma.

BACKGROUND: Tamoxifen treatment has previously been reported to confer life-prolonging effects in patients with advanced pancreatic cancer, and most evidently so in women. None of these trials did however include biomarkers, and the relevance of female hormone signaling in pancreatic or other periampullary adenocarcinoma remains largely unexplored. The aim of this study was to examine the extent and potential clinical significance of estrogen receptor-α (ER) and progesterone receptor (PR) expression in pancreatic and other periampullary cancers. METHODS: ER and PR expression was examined using immunohistochemistry on tissue microarrays with primary tumors from a retrospective consecutive cohort of 175 patients with resected periampullary adenocarcinoma, with long-term clinical follow-up. Non-parametric and Chi square tests were applied to examine the associations of stromal ER and PR expression with patient and tumor characteristics. Kaplan-Meier analysis and log rank test were applied to illustrate survival differences in relation to ER and PR expression. Cox regression proportional hazards models were applied to examine the associations between investigative factors and risk of death and recurrence, and to test for interactions between KRAS mutation status and hormone receptor expression in relation to survival. RESULTS: Expression of both ER and PR was more frequent in the tumor-associated stroma than in the epithelium. A significant prognostic interaction, independent of tumor morphology, was found between stromal PR expression and KRAS mutation status in relation to both overall and recurrence-free survival (pinteraction = 0.026 and pinteraction = 0.005), in particular in women (pinteraction = 0.002 and pinteraction = 0.005). Specifically, stromal PR expression was associated with a prolonged survival in patients with KRAS-mutated tumors, whereas the opposite was seen for KRAS wild-type tumors. The prognostic value of ER positivity was limited to the subgroup of women with tumors of pancreatic origin. CONCLUSIONS: These results demonstrate that stromal PR rather than ER expression, together with KRAS mutation status, provides long-term prognostic information in patients with periampullary adenocarcinoma. Further study into the mechanistic basis for these observations may unveil important clues to the pathogenesis of these cancers and open up for the discovery of novel treatment options.

Apparent diffusion coefficient-based histogram analysis differentiates histological subtypes of periampullary adenocarcinoma.

BACKGROUND: For periampullary adenocarcinoma, the histological subtype is a better prognostic predictor than the site of tumor origin. Intestinal-type periampullary adenocarcinoma (IPAC) is reported to have a better prognosis than the pan-creatobiliary-type periampullary adenocarcinoma (PPAC). However, the classification of histological subtypes is difficult to determine before surgery. Apparent diffusion coefficient (ADC) histogram analysis is a noninvasive, non-enhanced method with high reproducibility that could help differentiate the two subtypes. AIM: To investigate whether volumetric ADC histogram analysis is helpful for distinguishing IPAC from PPAC. METHODS: Between January 2015 and October 2018, 476 consecutive patients who were suspected of having a periampullary tumor and underwent magnetic resonance imaging (MRI) were reviewed in this retrospective study. Only patients who underwent MRI at 3.0 T with different diffusion-weighted images (b-values = 800 and 1000 s/mm2) and who were confirmed with a periampullary adenocarcinoma were further analyzed. Then, the mean, 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles of ADC values and ADCmin, ADCmax, kurtosis, skewness, and entropy were obtained from the volumetric histogram analysis. Comparisons were made by an independent Student's t-test or Mann-Whitney U test. Multiple-class receiver operating characteristic curve analysis was performed to determine and compare the diagnostic value of each significant parameter. RESULTS: In total, 40 patients with histopathologically confirmed IPAC (n = 17) or PPAC (n = 23) were enrolled. The mean, 5th, 25th, 50th, 75th, 90th, and 95th percentiles and ADCmax derived from ADC1000 were significantly lower in the PPAC group than in the IPAC group (P < 0.05). However, values derived from ADC800 showed no significant difference between the two groups. The 75th percentile of ADC1000 values achieved the highest area under the curve (AUC) for differentiating IPAC from PPAC (AUC = 0.781; sensitivity, 91%; specificity, 59%; cut-off value, 1.50 × 10-3 mm2/s). CONCLUSION: Volumetric ADC histogram analysis at a b-value of 1000 s/mm2 might be helpful for differentiating the histological subtypes of periampullary adenocarcinoma before surgery.

Role of Immunohistochemistry in the Subtyping of Periampullary Adenocarcinoma.

Context. Subtyping of periampullary adenocarcinoma into intestinal and pancreatobiliary subtypes has emerged as an important prognostic factor with potential therapeutic implications. This distinction on morphology alone is often difficult with significant interobserver variability. Objective. To analyze the usefulness of a panel of immunohistochemistry (IHC) markers as an aid to morphologic subtyping of periampullary adenocarcinoma. Design. A total of 172 periampullary adenocarcinomas were classified morphologically by 3 study pathologists. Interobserver agreement was assessed in each case. Cases were then typed using a predetermined IHC panel (comprising CK7, CK20, MUC1, and CDX2). Results. Morphologically, 66 (38.4%) cases were intestinal, 56 (32.6%) pancreatobiliary, 25 (14.5%) mixed, 16 (9.3%) poorly differentiated, 6 (3.5%) mucinous, and 3 (1.7%) signet ring cell adenocarcinoma. Concordant diagnosis was reached in 138 cases (80.2%) with moderate overall interobserver agreement (κ = 0.47). Concordance was higher in morphologically distinct mucinous (100%; κ = 0.94) and signet ring cell subtypes (100%; κ = 1.0) than in intestinal (84.6%; κ = 0.47) and pancreatobiliary (82.1%; κ = 0.43) types. Concordance was poor for mixed (64%; κ = 0.27) and poorly differentiated (68.8%; κ = 0.76) tumors. IHC subtyped 79 cases (46%) as pancreatobiliary, 73 (42.4%) as intestinal, and was inconclusive in 20 cases (11.6%). IHC helped classify 21 out of 25 (84%) mixed and 10 out of 16 poorly differentiated (62.5%) adenocarcinomas. Combination of histology and IHC classified 161 of the total 172 cases (93.6%). Conclusion. Use of an IHC panel aids in subtyping of periampullary adenocarcinomas, especially in tumors with mixed morphology and poor differentiation.

Synchronous Duodenal Adenocarcinoma and Colon Adenoma Following with Lynch Syndrome Requiring Pancreaticoduodenectomy and Completion Total Colectomy with Ileorectal Anastomosis.

BACKGROUND: A 59-year-old woman with strong family history of early-age colorectal cancer was found to have synchronous tubular adenomas of the duodenum and transverse colon during surveillance endoscopy 12 years after undergoing right colectomy and adjuvant chemotherapy for stage II colon adenocarcinoma. The duodenal lesion was endoscopically unresectable due to central depression, and the transverse colon adenoma was unresectable because it was confluent with the previous ileocolic anastomosis. Given the synchronous unresectable lesions in the setting of an Amsterdam positive kindred, the patient underwent simultaneous pancreaticoduodenectomy and completion total abdominal colectomy with ileorectal anastomosis. Histopathologic analysis of the specimens revealed T4N0 poorly differentiated MLH1 deficient duodenal adenocarcinoma with pancreatic invasion and tubular adenoma of the colon with high grade dysplasia. Following adjuvant chemotherapy, there is no evidence of recurrent cancer after two years of surveillance. SUMMARY: While the crude overall risk for small bowel and periampullary tumors remains low, clinicians must maintain awareness of a relatively increased risk of extracolonic tumors in Lynch syndrome (LS) patients. CONCLUSION: LS patients have an increased risk for developing small bowel cancer (SBC) when compared to the general population. However, given the low incidence of these tumors and uncertain efficacy of contemporary screening modalities, surveillance of the small bowel has not been recommended. The current case report exemplifies the challenges associated with waiting for patients to develop symptoms to develop before investigating for SBC.

Genetic Alterations of Periampullary and Pancreatic Ductal Adenocarcinoma: An Overview.

Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the most lethal malignancies of all solid cancers. Precancerous lesions for PDAC include PanIN, IPMNs and MCNs. PDAC has a poor prognosis with a 5-year survival of approximately 6%. Whereas Periampulary AdenoCarcinoma (PAC) having four anatomic subtypes, pancreatic, Common Bile Duct (CBD), ampullary and duodenum shows relative better prognosis. The highest incidence of PDAC has been reported with black with respect to white population. Similarly, incidence rate of PAC also differs with different ethnic populations. Several lifestyle, environmental and occupational exposures including long-term diabetes, obesity, and smoking, have been linked to PDAC, however, for PAC the causal risk factors were poorly described. It is now clear that PDAC and PAC are a multi-stage process resulting from the accumulation of genomic alterations in the somatic DNA of normal cells as well as inherited mutations. Approximately 10% of PDAC have a familial inheritance. Germline mutations in CDKN2A, BRCA2, STK11, PALB2, PRSS1, etc., as well as certain syndromes have been well associated with predisposition to PDAC. KRAS, CDKN2A, TP53 and SMAD4 are the 4 "mountains" (high-frequency driver genes) which have been known to earliest somatic alterations for PDAC while relatively less frequent in PAC. Our understanding of the molecular carcinogenesis has improved in the last few years due to extensive research on PDAC which was not well explored in case of PAC. The genetic alterations that have been identified in PDAC and different subgroups of PAC are important implications for the development of genetic screening test, early diagnosis, and prognostic genetic markers. The present review will provide a brief overview of the incidence and prevalence of PDAC and PAC, mainly, increased risk in India, the several kinds of risk factors associated with the diseases as well as required genetic alterations for disease initiation and progression.

Surgical management of periampullary adenocarcinoma: defining an optimal prognostic lymph node stratification schema.

Background: Lymph node (LN) metastasis is a strong predictor of unfavorable prognosis for patients with periampullary adenocarcinoma after surgical resection. We sought to assess the prognostic performance of several LN staging systems, including American Joint Committee on Cancer (AJCC)/ International Union Against Cancer (7th edition) N stage, the total number of LN (TLN), the number of metastatic LN (MLN), the lymph node ratio (LNR) and the log odds of MLNs (LODDS), in patients with periampullary adenocarcinoma after surgical resection and identify the optional LN staging system to accurately stratify patients with different prognoses. Methods: We retrospectively analyzed 205 patients with periampullary adenocarcinoma after surgical resection. The predictive effects of several LN staging systems on overall survival (OS) and progression free survival (PFS) for all included patients and patients with more than 12 TLNs examined were evaluated and compared using the time-dependent receive operating characteristic (ROC) curve and decision curve analysis (DCA), respectively. Results: Eighty-nine patients (43.4%) had LN metastasis and their survival was not significantly decreased compared with patients without LN metastasis. LODDS and LNR were able to stratify patients into various subgroups with significant differences of both OS and PFS. When assessed using ROC curve and DCA, LODDS outperformed LNR and other LN staging systems in predicting OS and PFS. In addition, when analyzed in patients with more than 12 TLNs examined, LODDS had a higher value of area under ROC curve (AUC) and showed better performance of DCA. Conclusion: LODDS performs better than other LN staging systems in predicting OS and PFS for patients with periampullary adenocarcinoma after surgical resection. Adequate LN dissection is necessary for curative surgery, as well as to achieve a more accurate staging of the disease and a more precise prediction of survival for these patients.

Nomograms predict long-term survival for patients with periampullary adenocarcinoma after pancreatoduodenectomy.

BACKGROUND: The prognosis of patients with periampullary adenocarcinoma after pancreatoduodenectomy is diverse and not yet clearly illustrated. The aim of this study was to develop a nomogram to predict individual risk of overall survival (OS) and progression-free survival (PFS) in patients with periampullary adenocarcinoma after pancreatoduodenectomy. METHODS: A total of 205 patients with periampullary adenocarcinoma after pancreatoduodenectomy were retrospectively included. OS and PFS were evaluated by the Kaplan-Meier method. Two nomograms for predicting OS and PFS were established, and the predictive accuracy was measured by the concordance index (Cindex) and calibration plots. RESULTS: Lymph node ratio (LNR), carbohydrate antigen 19-9 (CA19-9) and anatomical location were incorporated into the nomogram for OS prediction and LNR, CA19-9; anatomical location and tumor differentiation were incorporated into the nomogram for PFS prediction. All calibration plots for the probability of OS and PFS fit well. The Cindexes of the nomograms for OS and PFS prediction were 0.678 and 0.68, respectively. The OS and PFS survival times were stratified significantly using the nomogram-predicted survival probabilities. CONCLUSIONS: The present nomograms for OS and PFS prediction can provide valuable information for tailored decision-making for patients with periampullary adenocarcinoma after pancreatoduodenectomy.

Relationship between mismatch repair immunophenotype and long-term survival in patients with resected periampullary adenocarcinoma.

BACKGROUND: Periampullary adenocarcinomas, including pancreatic cancer, are a heterogeneous group of tumors with poor prognosis, where classification into intestinal type (I-type) or pancreatobiliary type (PB-type) is a relevant prognostic factor. The clinical significance of deficient mismatch repair (dMMR) in periampullary adenocarcinoma is comparatively unexplored. Herein, we examined the associations of MMR immunophenotype with long-term survival in patients with resected periampullary adenocarcinoma, with particular reference to morphology and adjuvant treatment response. METHODS: MMR protein expression was assessed by immunohistochemistry on tissue microarrays with primary tumors from a retrospective cohort of 175 patients with periampullary adenocarcinoma treated with pancreaticoduodenectomy during 2001-2011 in Malmö and Lund University Hospitals, Sweden. Cox proportional hazards models were applied to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: After a mean follow-up of 46.5 (1.9-185.1) months, 35 patients (20.3%) were alive, 24 with I-type and 11 with PB-type tumors. MMR protein expression could be evaluated in 172 cases, in which dMMR was denoted in 20 (11.6%) cases, 13/63 (20.6%) in I-type and 7/109 (6.4%) in PB-type tumors. dMMR was associated with a significantly prolonged overall survival in the entire cohort (HR = 0.28, 95% CI 0.13-0.57), and in I-type tumors (HR = 0.20, 95% CI 0.06-0.68), however not independent of conventional prognostic factors. In PB-type tumors, dMMR was not prognostic, but there was a significant negative interaction between dMMR and adjuvant treatment (pinteraction = 0.015). CONCLUSIONS: dMMR is more frequent in I-type compared to PB-type periampullary adenocarcinoma, and is a prognostic factor for long-term survival only in the former. The finding of the small number of PB-type tumors with dMMR potentially lacking benefit from adjuvant chemotherapy is however noteworthy and merits further validation.

Correlation between the skeletal muscle index and surgical outcomes of pancreaticoduodenectomy.

PURPOSES: Sarcopenia is known to be associated with a worse prognosis following abdominal operations; however, the relationship between sarcopenia and the outcomes of pancreaticoduodenectomy remains unclear. MATERIALS: We measured body composition parameters, including total abdominal muscle area, using preoperative staging computed tomography (CT), in patients undergoing pancreaticoduodenectomy for periampullary cancer. The incidence of sarcopenia among these patients was evaluated and multivariable analysis was performed to identify independent predictors of postoperative pancreatic fistula. RESULTS: We identified 335 consecutive patients who were eligible for the study. Patients with sarcopenia had significantly poorer 5-year survival rates than those without sarcopenia (32.4 vs. 51.6%, respectively, P = 0.009). Interestingly, the incidence of Grade B/C pancreatic fistula was significantly lower in the sarcopenia group than in the non-sarcopenia group. Multivariate analysis identified high body mass index and soft pancreatic texture as independent predictors of postoperative pancreatic fistula. CONCLUSION: Sarcopenia may have an independent prognostic effect on the survival of patients with periampullary cancer. Preoperative nutritional intervention and rehabilitation may improve the postoperative outcomes of pancreaticoduodenectomy for periampullary cancer.

Distinguishing Benign from Malignant Pancreatic and Periampullary Lesions Using Combined Use of ¹H-NMR Spectroscopy and Gas Chromatography-Mass Spectrometry.

Previous work demonstrated that serum metabolomics can distinguish pancreatic cancer from benign disease. However, in the clinic, non-pancreatic periampullary cancers are difficult to distinguish from pancreatic cancer. Therefore, to test the clinical utility of this technology, we determined whether any pancreatic and periampullary adenocarcinoma could be distinguished from benign masses and biliary strictures. Sera from 157 patients with malignant and benign pancreatic and periampullary lesions were analyzed using proton nuclear magnetic resonance (¹H-NMR) spectroscopy and gas chromatography-mass spectrometry (GC-MS). Multivariate projection modeling using SIMCA-P+ software in training datasets (n = 80) was used to generate the best models to differentiate disease states. Models were validated in test datasets (n = 77). The final ¹H-NMR spectroscopy and GC-MS metabolomic profiles consisted of 14 and 18 compounds, with AUROC values of 0.74 (SE 0.06) and 0.62 (SE 0.08), respectively. The combination of ¹H-NMR spectroscopy and GC-MS metabolites did not substantially improve this performance (AUROC 0.66, SE 0.08). In patients with adenocarcinoma, glutamate levels were consistently higher, while glutamine and alanine levels were consistently lower. Pancreatic and periampullary adenocarcinomas can be distinguished from benign lesions. To further enhance the discriminatory power of metabolomics in this setting, it will be important to identify the metabolomic changes that characterize each of the subclasses of this heterogeneous group of cancers.