Prognostic and predictive value of tumoral DNA damage repair protein expression in patients with resected pancreatic cancer.

OBJECTIVE: DNA damage repair (DDR) gene mutations gained interest in the treatment of metastatic pancreatic cancer (PC) patients, but their relevance in adjuvant setting is not well characterized. We assessed the prognostic and predictive potential of tumoral expression of DDR proteins along with clinical and tumor characteristics in patients with resected PC. PATIENTS AND METHODS: Patients with PC who underwent pancreatic resection in our institution between 2005 and 2017 were retrospectively retrieved. Tumoral expression of a panel of DDR proteins including BRCA1, BRCA2, ATM, and p53 with immunohistochemistry was evaluated and association with patient and tumor features as well as prognosis was assessed. RESULTS: 130 patients were included in the study. The median age was 61 and 66% were males, 57% had lymph node involvement and 17% had a vascular invasion. 25 patients (19%) had thrombosis at the time of diagnosis. Median overall survival (OS) and disease-free survival (DFS) were 21.6 and 11.8 months, respectively. More advanced disease stage (HR: 3.67 95% CI 1.48-9.12, p = 0.005), presence of thrombosis (HR: 2.01 95% CI 1.04-3.89, p = 0.039), high BRCA1 expression (HR: 2.25, 95% CI 1.13-5.48, p = 0.023) and high post-operative CA 19-9 level (>100 IU/ml) (HR:2.61 95% CI 1.40-4.89, p = 0.003) were associated with shorter DFS. BRCA2, ATM, and p53 expression were not associated with DFS or OS. Adjuvant gemcitabine-cisplatin regimen was not associated with increased DFS or OS in the whole group, neither in low or high expressors of BRCA1, BRCA2, ATM or p53. CONCLUSION: Contrary to BRCA2, ATM, and P53, BRCA1 expression may be beneficial for prognosis in resected pancreatic cancer, while no predictive role was observed in terms of adjuvant platinum efficacy.

Effects of 5-fluorouracil released from different prosthetic meshes on post-operative adhesion formation in rats.

OBJECTIVE: Post-operative adhesion is a common problem in abdominal surgery. Especially, foreign materials are strong stimulus for the development of adhesions. The aim of this study was to investigate whether drug release material coated prosthetic mesh decreases intra-abdominal adhesion formation or not. METHODS: 5-Fluorouracil (5-FU) releasing "chitosan gels" were loaded to polypropylene and polyglactin-910 grafts. Polypropylene, polyglactin-910 grafts, chitosan gel, and 5-FU-loaded polyglactin 910, polypropylene grafts were used to cover abdominal defects of rats which were created under sterile conditions (n=84). Each group was divided into two subgroups (n=6). Subgroups were sacrificed on the 7th and 30th days. RESULTS: The 7th day macroscopic examinations were similar. Polypropylene group was most adhesive group on the 30th day. There were less adhesions in chitosan gel and 5-FU-loaded groups. Capsule and capsule margins showed no difference on both the 7th and 30th days. Polypropylene-5-FU group and polypropylene-chitosan gel group showed significantly less macroscopic adhesions than polypropylene control group. Furthermore, polyglactin-910-chitosan gel group was less adhesive than polypropylene control group. CONCLUSION: This study showed that 5-FU decreases the adhesions but the dosage and release kinetics need further investigations.

CD66b+ monocytes represent a proinflammatory myeloid subpopulation in cancer.

Myeloid-derived suppressor cells (MDSC) populate the peripheral blood and contribute to immune regulation in cancer. However, there is limited knowledge on the myeloid cell types with proinflammatory capacities that may serve as opponents of MDSC. In the circulation of cancer patients, a monocyte subpopulation was identified with a specific immunophenotype and transcriptomic signature. They were predominantly CD14+CD33hiCD16-/+HLA-DR+/hi cells that typically expressed CD66b. In accordance with the transcriptomics data, NALP3, LOX-1 and PAI-1 levels were also significantly upregulated. The CD66b+ monocytes displayed high phagocytic activity, matrix adhesion and migration, and provided costimulation for T cell proliferation and IFN-γ secretion; thus, they did not suppress T cell responses. Irrespective of clinical stage, they were identified in various cancers. In conclusion, the CD66b+ monocytes represent a novel myeloid subpopulation which is devoid of immune regulatory influences of cancer and displays enhanced proinflammatory capacities.

Human splenic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are strategically located immune regulatory cells in cancer.

In contrast to the mouse, functional assets of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in the human spleen remain to be better elucidated. Here, we report that the spleen in gastric and pancreatic cancer adopts an immune regulatory character, harbors excessive amount of PMN-MDSC, and anatomically enables their interaction with T cells. Compared to the peripheral blood, the spleen from cancer patients contained significantly higher levels of low-density PMN-MDSC, but not early-stage MDSC (e-MDSC) and monocytic-MDSC (M-MDSC). Low-density fraction of polymorphonuclear (PMN) cells was enriched in immature myeloid cells and displayed higher levels of CD10, CD16, and ROS than their blood-derived counterparts. They were also positive for PD-L1, LOX-1, and pSTAT3. The white pulp and periarteriolar lymphoid sheath (PALS) were strategically surrounded by PMN cells that were in contact with T cells. Unlike those from the blood, both low-density and normal-density PMN cells from the human spleen suppressed T cell proliferation and IFN-γ production. Independent of clinical grade, high PMN-MDSC percentages were associated with decreased survival in gastric cancer. In summary, our results outline the immune regulatory role of the spleen in cancer where neutrophils acquire MDSC functions and feasibly interact with T cells.

Analysis of Fusobacterium nucleatum and Streptococcus gallolyticus in saliva of colorectal cancer patients.

Aim: The aim of the study was to examine the prevalence and amount of Fusobacterium nucleatum (Fn), Porphyromonas gingivalis (Pg) and Streptococcus gallolyticus (Sg) in the saliva of colorectal cancer (CRC) patients and controls. Methods: PCR analyses performed in 71 CRC patients and 77 controls. Results: Saliva samples of patients had higher amounts of Fn (p = 0.001) and Sg (p < 0.001) compared with controls. Amount of Fn and Sg were lower in the microsatellite instability (+) group. Evaluation of salivary Sg amount by receiver operating characteristics analysis found to have diagnostic value for CRC (AUC: 0.84, 95% CI: 0.72-0.96). Conclusion: We found higher amounts of Fn and Sg in the saliva of CRC patients. Salivary Sg could helpful in distinction of CRC.

Urinary and Fecal Diversion Following Pelvic Exenteration: Comparison of Double-Barrelled and Plain Wet Colostomy.

PURPOSE: To assess early and late-term outcomes of patients who had undergone pelvic exenteration and simultaneous fecal and urinary diversion with plain wet colostomy (PWC) or double-barrelled wet colostomy (DBWC). MATERIALS AND METHODS: The medical records of all patients who had undergone pelvic exenteration and urinary diversion between 2006 and 2017 at our hospital were reviewed retrospectively. RESULTS: In total, 15 patients with a mean age of 56 ± 13 years were included in the study. Simultaneous urinary and fecal diversions were carried out as PWC (n = 8), or DBWC (n = 7). No significant differences were found between PWC and DBWC groups in terms of operation time (373.7 ± 66.5 versus 394.2 ± 133.2 min, P = .955), estimated blood loss (862.8 ± 462.4 versus 726.2 ± 489.4 mL, P = .613), length of hospital stay (13.2 ± 9.1 versus 14.1 ±6.9 days), early complications (25% versus 28.6%, P = 1.0) and late term complications (37.5% versus 42.9%, P = 1.0). The rate of recurrent pyelonephritis in PWC group was higher than DBWC group but not statistically significant (37.5% versus 14.3%, P = .569). Overall survival (OS) of the patients was 385 ± 91 days. There was no difference between OS of patients with PWC and DBWC (414 ± 165 versus 352 ± 70 days, P = .618). CONCLUSION: PWC and DBWC are valid options for creating simultaneous urinary and fecal diversion after extensive pelvic surgery in patients with short life expectancy. DBWC might be superior to PWC in terms of decreased risk of recurrent pyelonephritis.

Impact of repeated abdominal surgery on wound healing and myeloid cell dynamics.

BACKGROUND: Even though wound dehiscence is a surgical complication, under certain medical conditions, repetition of the laparotomy (LT) (relaparotomy) can become inevitable. In addition to the risks associated with this surgical operation, relaparotomy can interfere with the tissue healing and contribute to the development of chronic wounds. METHODS: In an experimental relaparotomy wounding model, this study investigated the impact of repeated surgery on wound healing and on the immune cells of myeloid origin. RESULTS: The first repeat of the LT triggered fibrosis and marginally interfered with the wound healing; however, the second operation completely abrogated the healing process. Splenomegaly was observed as an indicator of the chronic inflammation and the systemic effect of repeated laparotomies. In the blood stream, the spleen, and the liver, these repeated surgeries exhibited a major impact on the CD11b+Ly6C+Ly6G- monocytes. On the other hand, especially, whespecially the second relaparotomy resulted in a massive purging of neutrophil granulocytes into the circulation. These CD11b+Ly6C+Ly6G+ neutrophils that were disseminated on repeated abdominal laparotomies had a proinflammatory character that positively influenced T cell proliferation and displayed a high capacity for production of reactive oxygen species. CONCLUSIONS: The repetition of abdominal LT not only interferes with the wound healing but also contributes to the development of imperfectly healing wounds which have systemic impact on immune compartments.

Splenectomy-Induced Leukocytosis Promotes Intratumoral Accumulation of Myeloid-Derived Suppressor Cells, Angiogenesis and Metastasis.

BACKGROUND: Enlargement of the spleen is commonly observed in animal models of cancer. Here, in a breast cancer model, it was aimed to determine the effect of splenectomy on circulating and tumor-infiltrating myeloid-derived suppressor cells (MDSCs), tumor angiogenesis, and metastasis. METHODS: Mice were inoculated with 4T1 breast cancer cells and underwent splenectomy or sham laparotomy. Tumor growth and survival of animals were followed. Macroscopic and histopathological analyses were performed to determine splenomegaly and metastasis. Immunophenotyping of myeloid cells was performed with flow cytometric analysis of CD11b, Gr-1, F4/80, CD206, CD11c, and F4/80 markers. Suppressive function of MDSCs on T cell proliferation was studied in cocultures. Tumor angiogenesis and granulocytic myeloid cell infiltration in the metastatic foci were studied by CD31 and Ly6G immunohistochemistry, respectively. RESULTS: The mice bearing breast tumors underwent total splenectomy at an early time point of tumorigenesis when only low levels of MDSCs had accumulated in the spleen. Circulating and tumor-infiltrating MDSCs, and tumor-associated macrophages (TAMs) were increased following splenectomy. Nevertheless, splenectomy could only lead to a temporary deceleration in tumor growth but favored lung metastasis and angiogenesis in the long run. CONCLUSION: Our data demonstrated a link among splenectomy-induced leukocytosis, accumulation of circulating and tumor-infiltrating MDSC, and enhanced angiogenesis and metastasis. Therefore, as a part of oncological surgery, favorable and unfavorable facets of the splenectomy must be considered to improve therapeutic efficacy.

Dual-energy CT characteristics of colon and rectal cancer allows differentiation from stool by dual-source CT.

PURPOSE: We aimed to determine dual-energy computed tomography (DECT) characteristics of colorectal cancer and investigate effectiveness of DECT method in differentiating tumor from stool in patients with colorectal cancer. METHODS: Fifty consecutive patients with colorectal tumors were enrolled. Staging was performed by DECT (80-140 kV) using dual-source CT after rectal air insufflation and without bowel preparation. Both visual and quantitative analyses were performed at 80 kV and 140 kV, on iodine map and virtual noncontrast (VNC) images. RESULTS: All colorectal tumors had homogeneous pattern on iodine map. Stools demonstrated heterogeneous pattern in 86% (43/50) and homogeneous pattern in 14% (7/50) on iodine maps and were less visible on VNC images. Median density of tumors was 54 HU (18-100 HU) on iodine map and 28 HU (11-56 HU) on VNC images. Median density of stool was 36.5 HU (8-165 HU) on iodine map and -135.5 HU (-438 HU to -13 HU) on VNC images. The density of stools was significantly lower than tumors on both iodine map and VNC images (P < 0.001). The cutoff point of density measurement on VNC images was -1 HU with area under the curve of 1 and a sensitivity and specificity of 100%. CONCLUSION: Density or visual analysis of iodine map and VNC DECT images allow accurate differentiation of tumor from stool.

Prevention and acute management of biliary injuries during laparoscopic cholecystectomy: Expert consensus statement.

Gallstone disease is very common and laparoscopic cholecystectomy is one of the most common surgical procedures all over the world. Parallel to the increase in the number of laparoscopic cholecystectomies, bile duct injuries also increased. The reported incidence of bile duct injuries ranges from 0.3% to 1.4%. Many of the bile duct injuries during laparoscopic cholecystectomy are not due to inexperience, but are the result of basic technical failures and misinterpretations. A working group of expert hepatopancreatobiliary surgeons, an endoscopist, and a specialist of forensic medicine study searched and analyzed the publications on safe cholecystectomy and biliary injuries complicating laparoscopic cholecystectomy under the organization of Turkish Hepatopancreatobiliary Surgery Association. After a series of e-mail communications and two conferences, the expert panel developed consensus statements for safe cholecystectomy, management of biliary injuries and medicolegal issues. The panel concluded that iatrogenic biliary injury is an overwhelming complication of laparoscopic cholecystectomy and an important issue in malpractice claims. Misidentification of the biliary system is the major cause of biliary injuries. To avoid this, the "critical view of safety" technique should be employed in all the cases. If biliary injury is identified intraoperatively, reconstruction should only be performed by experienced hepatobiliary surgeons. In the postoperative period, any deviation from the expected clinical course of recovery should alert the surgeon about the possibility of biliary injury.

Portal vein embolization with different embolic agents for right hepatectomy.

BACKGROUND/AIMS: We aimed to retrospectively evaluate our experience in portal vein embolization that induces hypertrophy of the future liver remnant before right hepatectomy and to determine the differences in outcome with respect to the embolic agents used. METHODS: Twenty right portal vein embolization procedures performed in our institution between 2004 and 2009 were reviewed in this study. The average patient age was 59 years (range: 45-72 years). Embolization was performed through a right portal vein percutaneous access with use of the combination of several agents. Computed tomography volumetry was performed before and 4-6 weeks after the procedure to measure total liver volume and future liver remnant. RESULTS: There was no major complication related to the embolization procedures. After embolization, future liver remnant/total liver volume ratio increased to 12.7%, which was statistically significant. No significant difference was noted in hypertrophic outcomes between alcohol and the other embolic agents. Although five patients had sufficient future liver remnant, they did not undergo subsequent hepatectomy for a variety of reasons. CONCLUSIONS: According to our results, the mean increase in the size of the future liver remnant was greater than reported in previous studies of portal vein embolization. Despite the limited patient number of our study, we believe that portal vein embolization is helpful especially in gray-zone patients who may be a good candidate for surgical resection and thus possible cure. However, randomized, controlled studies with hypertrophy- inducing agents are needed.

Papillary carcinoma with diffuse papillomatosis of gallbladder and cystic duct.

Biliary papillomatosis and papillary carcinoma are rare tumors of biliary tract; and because of their morphologic similarities, papillomatosis-papillary carcinoma sequel has been proposed. We report an unusual case of polypoid minimally invasive papillary carcinoma located at the junction between cystic and common bile ducts, complicated with biliary papillomatosis of gallbladder and cystic duct, showing focal areas of malignant change. Intrahepatic ducts, hepatic ducts, and distal common bile duct were spared. Both papillomatosis and papillary carcinoma showed areas of high p53 and p21 expression with high proliferative index. Patient is still alive for 4 years without evidence of disease after modified Whipple operation. Possible pathogenetic mechanisms are further discussed.

The effect of hepatectomy on coagulation: an evaluation by thromboelastography.

OBJECTIVES: Liver has a major role in coagulation. The hemostatic derangements measured by the mostly used coagulation parameters as prothrombin time, activated partial thromboplastin time, and thrombocyte count do not always correlate with the bleeding associated with liver diseases and these factors do not measure the thrombotic risks. So, thromboelastography is used in new clinical and laboratory research. The aim of this study is to study the effect of different levels of hepatectomy on coagulation. METHODS: Laparatomy, 40% hepatectomy, and 70% hepatectomy was performed in three different groups of rats. Prothrombin time, international normalized ratio, activated partial thromboplastin time, thrombocyte count, fibrinogen levels, and thromboelastography parameters were obtained at the 0, 6, and 24th hour of the study. RESULTS: Fibrinogen level at the 24th hour was greater than the early hours in both of the hepatectomy groups. Prothrombin time and international normalized ratio values were significantly higher in hepatectomy groups than in the sham group. There were no statistically significant difference in the clotting time, clot formation time, alpha-angle, and maximum clot firmness values in any of the thromboelastography channels, in any of the study times, in between the sham, 40% hepatectomy, and 70% hepatectomy groups. CONCLUSION: There is no difference between 40 and 70% hepatectomy when the coagulopathy is evaluated. The coagulation derangements as reflected by the increase in fibrinogen and prolongation of prothrombin time and activated partial thromboplastin time after hepatectomy were not supported by thromboelastography parameters in this study.

A case of recurrent metastatic hepatocellular cancer controlled with immunotherapy and antiviral therapy following resection.

Hepatocellular carcinoma (HCC) is the most frequent malignant tumour of the liver. The risk of HCC in chronically hepatitis B virus (HBV) infected individuals is approximately 100-fold higher than in the uninfected population. Despite all therapeutic advances, the benefit of systemic chemotherapy in patients with HCC has limited. But, the phase III clinical trial conducted in patients with advanced HCC treated with sorafenib has showed significant improvements in both overall and progression-free survival Metastasis from liver to extrahepatic tissues is reported to be quite uncommon and has a poor prognosis. Here we present a case of HCC which metastasized to the vertebrae, lung and kidney in order of appearance and controlled with immunotherapy and antiviral therapy following resection.

Renal cell carcinoma metastasis to focal nodular hyperplasia focus on liver in a patient with Von Hippel-Lindau disease.

Von Hippel-Lindau disease is an autosomal dominant disorder occurring in 1 of 36,000 births and associated with various tumors and cysts in the central nervous system and other visceral organs. At present, metastasis from renal cell carcinoma (RCC) and neurologic complications are the most common causes of death from Von Hippel-Lindau disease. We report a case of Von Hippel-Lindau disease diagnosed during a screening and was found to have metastasis of RCC to a focal nodular hyperplasia lesion on the liver. In the literature, misdiagnosis of benign liver lesions as metastases of RCC has been reported, but there has not been a case reported to have a metastasis of RCC within a benign liver lesion. To our knowledge, this is the first case of RCC metastasis to a benign lesion of the liver.

Determinants of postoperative infection after laparoscopic cholecystectomy.

BACKGROUND/AIMS: The aim of this study was to evaluate the effect of antibiotic prophylaxis on the development of infectious complications in laparoscopic cholecystectomy. METHODOLOGY: A total of 208 patients undergoing elective laparoscopic cholecystectomy were randomized, double-blinded into one of two treatment arms: 1) cefazolin 1 g intravenously after induction of anesthesia and 2) no prophylactic antibiotics. The patients were followed-up for infectious complications for 30 days at the out-patient clinic. The data collected included age, sex, body mass index, ultrasonography findings, accompanying diseases, perforation during surgery, stone spillage, operation time, port of gallbladder delivery, suture material used for skin closure, preoperative and length of postoperative hospitalization, bile culture, pathology of the gallbladder, serum biochemical findings including alanine aminotransferase, aspartate aminotransferase, gammaglutamyl transpeptidase, bilirubin, alkaline phosphatase and glucose. RESULTS: Overall rate of infection was 3.36%. Four out of 105 patients who received antibiotics and 3 out of 103 patients who did not receive antibiotics developed infection. The difference was not statistically significant. Obesity and closing the skin with nylon sutures were found to be associated with increased rate of infectious complications. CONCLUSIONS: Cefazolin prophylaxis in low risk patients has no effect on postoperative infection rate in laparoscopic cholecystectomy.

Pancreaticojejunostomy after pancreaticoduodenectomy: results of a new technique.

BACKGROUND/AIMS: Pancreaticoduodenectomy is the standard treatment for periampullary tumors. One of the major causes of morbidity after pancreaticoduodenectomy is the failure of the healing at the pancreaticoenteric anastomosis. The aim of this study is to summarize the results of a new technique which is designed to decrease the panreticoje-junostomy anastomotic leakage. METHODOLOGY: The demographic characteristics, operation indications, types of the pancreaticoduodenectomy, duration of the postoperative hospitalization, morbidity and mortality of the consecutive patients whose pancreaticojejunostomy anastomosis after pancreaticoduodenectomy was performed by modified invagination method at Hacettepe University Medical School Department of General Surgery between February 2005 and December 2007 were evaluated prospectively. RESULTS: Thirtyone patients were included in the study. The operation indications were pancreas cancer for 17 patients, ampulla Vateri cancer for 8 patients, duodenum cancer for 3 patients, cancer of the distal choleduct for 2 patients and gall bladder cancer for 1 patient. Twenty complications had occurred in a total of 15 patients. There were no pancreaticojejunostomy anastomotic leakage and mortality in any of the patients. CONCLUSIONS: An ideal pancreaticojejunostomy anastomosis after pancreaticoduodenectomy should be safe, simple and secure. This modified invagination method seems to be promising when these parameters are taken in to account.

Controversies in periampullary tumors.

Periampullary tumors are one of the most common tumors of the gastrointestinal tract. Despite the increase of 1-5% in five year life expectancy in periampullary tumors prognosis is still poor. The controversies in diagnosis, surgical and adjuvant treatment will be discussed in this article.

Does granulocyte-macrophage colony-stimulating factor prevent bacterial translocation in rats with surgical trauma and obstructive jaundice?

BACKGROUND/AIMS: The incidence of sepsis can be decreased by preventing bacterial translocation, as the first step in enhanced host defense. The aim of this study was to prevent translocation and to increase Kupffer cell incidence by using granulocytemacrophage colony-stimulating factor in rats with surgical trauma and obstructive jaundice. METHODS: Seventy-five Sprague- Dawley rats were randomized into 8 groups. After calibration of laboratory conditions by Group 0, SHAM operations in Groups I, II, IIA and common bile duct ligations in Groups III, IV, IVA and V were performed. Granulocyte-macrophage colony- stimulating factor doses were 6 microg/kg/d in Groups II, IV; 1 microg/kg/d in IIA, IVA postoperatively; and 6 microg/kg/d in Group V preoperatively, for 7 days. After one week, all rats were reoperated for cecal lymph node, liver and spleen biopsies for culture and histopathology. All culture specimens were identified as positive/negative/contaminated. Survivals were recorded, and after the 21st day surviving rats were sacrificed by decapitation. RESULTS: There was no translocation in Group 0 in the three specimens of liver, cecal lymph node and spleen. Group V showed minimal (10%) positivity in only liver, and other groups ranged between 20-70% in cecal lymph node, liver and spleen tissues, respectively (p<0.05). Kupffer cell incidences were higher in the granulocyte-macrophage colony-stimulating factor given groups than in controls, and lower in common bile duct ligation groups than in SHAM groups (p<0.001). Groups 0 and V showed the best (median 20 days) and Group III the worst (median 11.7 days) survival (p<0.001). CONCLUSIONS: Not only surgical trauma but also obstructive jaundice caused high incidence of translocation, decreased number of Kupffer cells and shortened survival. Translocation ratios were decreased by granulocyte- macrophage colony-stimulating factor in the SHAM and common bile duct ligation groups. Granulocyte-macrophage colony- stimulating factor prevented the decrease in Kupffer cell incidence caused by jaundice and prolonged the survival by preventing translocation at the first step.