Trends in Pancreatic Cancer Incidence and Mortality in Lithuania, 1998–2015

Background: Pancreatic cancer is one of the deadliest cancers worldwide, and its incidence is increasing. The aim of this study was to examine the time trends in the incidence and mortality rates of pancreatic cancer for the period of 1998–2015 for the first time in Lithuania by sex, age, subsite, and stage. Methods: This study was based on all cases (deaths) of pancreatic cancer diagnosed between 1998 and 2015. Age-standardized incidence (mortality) rates and group-specific rates were calculated for each sex using the direct method (European Standard). TNM classification-based information reported to the cancer registry was grouped into three categories: (1) localized cancer: T1-3/N0/M0; (2) cancer with regional metastasis: any 1-3/N+/M0; (3) advanced cancer: any T/any N/M+. Joinpoint regression was used to provide annual percentage changes (APCs) and to detect points in time where statistically significant changes in the trends occurred. Results: Overall, 8514 pancreatic cancer cases (4364 in men and 3150 in women) were diagnosed and 7684 persons died from cancer of the pancreas. Pancreatic cancer incidence rates were considerably lower for women than for men, with a female:male ratio of 1:2. Incidence rates changed during the study period from 14.2 in 1998 to 15.0/100,000 in the year 2015 in men, and from 6.7 to 9.8/100,000 in women. Incidence rates over the study period were stable for men (APC = 0.1%) and increasing for women by 1.1% per year. Similarly, mortality rates increased in women by 0.9% per year, and were stable in men. During the study period, incidence and mortality rates of pancreatic cancer were close. For the entire study period, rates increased significantly in the 50–74 years age group; only cancer of the head of pancreas showed a decline by 0.9%, while tail and not-specified pancreatic cancer incidence increased by 11.4% and 4.51%, respectively. Conclusions: The increasing pancreatic cancer incidence trend in the Lithuanian population may be related to the prevalence of its main risk factors (smoking, obesity, physical inactivity, diet, and diabetes).

Matrix stiffness drives stromal autophagy and promotes formation of a protumorigenic niche

Increased stiffness of solid tissues has long been recognized as a diagnostic feature of several pathologies, most notably malignant diseases. In fact, it is now well established that elevated tissue rigidity enhances disease progression and aggressiveness and is associated with a poor prognosis in patients as documented, for instance, for lung fibrosis or the highly desmoplastic cancer of the pancreas. The underlying mechanisms of the interplay between physical properties and cellular behavior are, however, not very well understood. Here, we have found that switching culture conditions from soft to stiff substrates is sufficient to evoke (macro) autophagy in various fibroblast types. Mechanistically, this is brought about by stiffness-sensing through an Integrin αV–focal adhesion kinase module resulting in sequestration and posttranslational stabilization of the metabolic master regulator AMPKα at focal adhesions, leading to the subsequent induction of autophagy. Importantly, stiffness-induced autophagy in stromal cells such as fibroblasts and stellate cells critically supports growth of adjacent cancer cells in vitro and in vivo. This process is Integrin αV dependent, opening possibilities for targeting tumor-stroma crosstalk. Our data thus reveal that the mere change in mechanical tissue properties is sufficient to metabolically reprogram stromal cell populations, generating a tumor-supportive metabolic niche.

Outcomes of neoadjuvant chemotherapy in resectable, borderline resectable and locally advanced pancreatic cancer

Background. The problem of neoadjuvant treatment of locally advanced (LA), borderline resectable (BR) and resectable pancreatic cancer (RPC) is being actively discussed at the present time, although the indications for its use have not been fully determined. In our work, we want to discuss the outcomes of using neoadjuvant chemotherapy (NACT) in these patients. Materials and methods. From 2016 to 2020, 85 patients with pancreatic cancer were observed in the clinic (37 patients with LA cancer of the pancreas; 15 with BR cancer of the pancreas and 33 with RPC). Of these, men 33 (38.8%), women 52 (61.2%). The average age was 64 (3183) years. All groups had GEMOX (41.2%) and FOLFIRINOX (58.8%) regimens. Increased CA 19-9 above normal had, in the LA group 21 (56.6%); in the BR group 9 (60%); and in the resectable group 26 (78.8%). From 3 to 6 courses of NACT were carried out, followed by computer tomography control and decision-making on treatment tactics. Results. In the LA group, the GEMOX (n=15) and FOLFIRINOX (n=22) modes were used. When evaluating the results after 1 follow-up examination after 2.5 months. found: 2 patients died; progression 14 patients (37.8%); remained inoperable 16 patients (43.2%), of whom 9 received radiation therapy. Removal of the primary tumor was performed in 5 patients (13.9%). The average OS in this group was 15 months. Fifteen patients with BR pancreatic tumors were observed. NACT was carried out with the same regimens GEMOX (n=7) and FOLFIRINOX (n=8) for 2.5 months. When evaluating the results after 1 follow-up examination after 2.5 months was found: 1 (7.7%) patient died; progression was noted in 6 (40%) patients; in 1 (7.7%) patient, surgical treatment was not performed due to pronounced concomitant diseases. Surgical treatment was performed in 7 (46.7%) patients. 33 patients were prescribed NACT for RPC. The main criteria for prescribing NACT for formally resectable pancreatic cancer were a high CA 19-9 level (100 IU/ml) [n=26 (75%)] and a large primary tumor [n=7 (25%)]. All patients received the same regimens for 3.3 months. up to 1 control. When evaluating the results, the following results were obtained: 1 (3%) patient died; 3 (9.3%) patients were not operated on due to refusal from surgical treatment; 7 patients (21.9%) were not operated on due to progression. Surgical treatment was performed in 22 (66.7%) patients; Whipple procedure in 17 patients, distal resection in 3 patients, total pancreatoduodenectomy in 2 patients. At the same time, complete morphological responce was noted in 2 (9%) patients, R0 resection in 19 (86%) patients, R1 in 1 patient (4.5%). The median survival rate of the operated patients was 20.2 months (CI 13.227.2 months). Most patients (65.9%) had a high level of CA 19-9, which was studied in dynamics and used as a marker of the biological activity of the tumor. Conclusion. Thus, we can claim that NACT is absolutely indicated for all patients with LA and BR pancreatic cancer, and its role in the selection of the most favorable in relation to the prognosis of patients is indisputable. Perioperative chemotherapy in patients with RPC is still controversial; however, having in mind the results in groups with LA and BR pancreatic cancer and the literature data, we dare to assume that for this issue it is a matter of time and future randomized trials. And here an important role can be played by the CA 19-9 level, which characterizes a biologically aggressive tumor, but again, prospective randomized studies are required to study this issue in more detail.

Modern approaches to the treatment of mechanical jaundice on the background of malignant damage of the pancreatobiliary zone

Aim. To study the role of tumors of the pancreatobiliary zone in the development of obstructive jaundice. To evaluate the effectiveness of endoscopic methods of diagnosis and treatment of this pathology. Materials and methods. The study is based on the results of the activities of JSC “MSU Neftyanik” in Tyumen for 2011-2020. During this period, 1284 patients with obstructive jaundice were admitted for emergency indications. Of this number, 181 patients had signs of cancerous lesions of the organs of the pancreatobiliary zone. The results obtained were used to evaluate effective endoscopic methods of diagnosis and treatment of patients in this group. Results. Malignant lesion of the pancreatobiliary zone is 14.3% of all cases of emergency treatment of patients with obstructive jaundice. The main cause is cancer of the pancreas, cancer of the bile ducts, as well as cancer of the large duodenal papilla and compression of the bile ducts “from the outside”. Performing emergency duodenoscopy on the first day after admission of patients made it possible to accurately verify the cancerous nature of the disease in the vast majority of patients. The most effective method for the relief of biliary hypertension syndrome in this group is bile duct stenting. Despite the varied nature of the cancer lesion, effective stenting was achieved in 71.3% of patients. If it is technically impossible to carry out stenting, minimally invasive puncture catheterization of the intrahepatic bile ducts is performed. Conclusion. Currently, cancer of the pancreatobiliary zone was established in every 5-7 patients with obstructive jaundice. Emergency duodenoscopy and ERCH is an effective diagnostic method that allows you to verify the “cancerous” nature of jaundice with a probability close to 100%. The most effective method of bile duct decompression in this group of patients is endoscopic transpapillary stenting.

The role of the muscular system in the pathogenesis of thrombotic complications of the lower extremities in cancer patients

Introduction. Thrombosis occurs in 15 % of cancer patients, most of these thrombosis is localized in the venous system of the lower extremities. In addition to biological and chemical factors that increase thrombosis, changes in the muscles of the lower extremities play an important role. Disorders of hemodynamic and metabolic processes in the muscles of the lower extremities lead to morphological changes and increase the risk of thrombosis in cancer patients. The aim of the study. Investigate morphological changes in the muscles of the lower extremities and evaluate their role in the formation of thrombosis in cancer patients. Materials and methods. Histological examination of 90 patients, which were divided into four groups depending on the location of the cancer process and the cause of death. The first group A – 34 patients with colon cancer, the second group B – 20 patients with pancreatic cancer, patients from these groups died as a result of thromboembolism. Group B – 19 patients, and group G – 17 patients - people whose cause of death was not thromboembolism. The analysis of biomaterial by means of histological and polarization methods of research is carried out. Additionally, electron microscopy of the obtained biopsy materials was performed. The number of citrate blood endothelial cells was determined in all subjects according to the method of J. Hladovez. Research results and their discussion. The study revealed a large number of morphological changes in blood vessels and muscle fibers. The data obtained indicate that patients with cancer of the pancreas and colon have significant changes in the endothelial lining of the venules and areterioles. All cells have signs of interstitial edema, changes in organelles and signs of hemodynamic disturbances. In some areas, there were complete atrophy of some muscle fibers and compensatory hypertrophy of others. Studies have shown areas of sarcoplasmic homogenization and myocytolysis. Conclusions. In the case of cancer of the pancreas or/and colon, there is significant damage to the endothelium of the vessels of the lower extremities, there are dystrophic-atrophic changes in the muscles with impaired function. Cells suffer from interstitial and perivascular edema, there are contractures of change, myocytolysis. Morphological changes lead to disruption of their function of damage, myocytolysis and remodeling of muscle fibers. The result is an increased risk of thrombosis with subsequent thrombus consideration and a possible risk of pulmonary embolism.

Poly (ADP-Ribose) Polymerase 1 Protein Expression in Normal Pancreas and Pancreatic Adenocarcinoma

Pancreatic cancer is a most frequent cancer in Europe, and the majority of cases of cancer of the pancreas are diagnosed above the age of 65. Radical surgery is the first curative treatment of pancreatic cancer, and alternative or combined therapeutic options, in particular, consist of adjuvant or neoadjuvant chemotherapy, with or without radiotherapy. Many factors, including diet and genetics, have been implicated in the development of cancer of the pancreas. Poly (ADP-ribose) polymerase 1 (PARP-1) protein is required for translocation of the apoptosis-inducing factor (AIF) from the mitochondria to the nucleus. It is involved in programmed cell death processes. Different PARP-1 gene expression proteins have been observed in various tumors such as lung, ovarian, endometrial, skin, and glioblastoma. We evaluated the expression of PARP-1 protein in pancreatic adenocarcinoma and normal pancreas tissues by immunohistochemistry. Protein PARP-1 in the nucleus was found in all samples (normal pancreas and pancreatic adenocarcinoma tissues). No cytoplasmic staining was observed in any sample. PARP-1-positive cells resulted higher in the normal pancreas compared with the pancreas with adenocarcinoma. PARP-1 overexpression in prostate cancer tissue compared with normal prostate suggests a greater activity of PARP-1 in these tumors. These findings suggest that PARP-1 expression in prostate cancer is an attempt to trigger apoptosis in this type of tumor, similarl to that reported in other cancers. This finding suggests that PARP-1-mediated cell death pathways are inhibited in this cancer.