XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Standards of Medical Care in Diabetes

Cancer of the pancreas

Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal

Insulinomas,the most common cause of hypoglycemia related to endogenous hyperinsulinism,occur in 1-4 people per million of the general population.Common autonomic symptoms of insulinoma include diaphroresis,tremor,and palpitations,whereas neuroglycopenenic symptoms include confusion,behavioural changes,personality changes,visual disturbances,seizure,and coma.Diagnosis of suspected cases is based on standard endocrine tests,especially the prolonged fasting test.Non-invasive imaging procedures,such as computed tomography and magnetic resonance imaging,are used when a diagnosis of insulinoma has been made to localize the source of pathological insulin secretion.Invasive modalities,such as endoscopic ultrasonography and arterial stimulation venous sampling,are highly accurate in the preoperative localization of insulinomas and have frequently been shown to be superior to noninvasive localization techniques.The range of techniques available for the localization of insulinomas means thatblind resection can be avoided.Intraoperative manual palpation of the pancreas by an experienced surgeon and intraoperative ultrasonography are both sensitive methods with which to finalize the location of insulinomas.A high proportion of patients with insulinomas can be cured with surgery.In patients with malignant insulinomas,an aggressive medical approach,including extended pancreatic resection,liver resection,liver transplantation,chemoembolization,or radiofrequency ablation,is recommended to improve both survival and quality of life.In patients with unresectable or uncontrollable insulinomas,such as malignant insulinoma of the pancreas,several techniques should be considered,including administration of ocreotide and/or continuous glucose monitoring,to prevent hypoglycemic episodes and to improve quality of life.

Diagnosis and management of insulinoma

Growth/differentiation factor-15 (GDF-15), also named macrophage inhibitory cytokine-1, is a divergent member of the transforming growth factor β superfamily. While physiological expression is barely detectable in most somatic tissues in humans, GDF-15 is abundant in placenta. Elsewhere, GDF-15 is often induced under stress conditions, seemingly to maintain cell and tissue homeostasis; however, a moderate increase in GDF-15 blood levels is observed with age. Highly elevated GDF-15 levels are mostly linked to pathological conditions including inflammation, myocardial ischemia, and notably cancer. GDF-15 has thus been widely explored as a biomarker for disease prognosis. Mechanistically, induction of anorexia via the brainstem-restricted GDF-15 receptor GFRAL (glial cell-derived neurotrophic factor [GDNF] family receptor α-like) is well-documented. GDF-15 and GFRAL have thus become attractive targets for metabolic intervention. Still, several GDF-15 mediated effects (including its physiological role in pregnancy) are difficult to explain via the described pathway. Hence, there is a clear need to better understand non-metabolic effects of GDF-15. With particular emphasis on its immunomodulatory potential this review discusses the roles of GDF-15 in pregnancy and in pathological conditions including myocardial infarction, autoimmune disease, and specifically cancer. Importantly, the strong predictive value of GDF-15 as biomarker may plausibly be linked to its immune-regulatory function. The described associations and mechanistic data support the hypothesis that GDF-15 acts as immune checkpoint and is thus an emerging target for cancer immunotherapy.

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Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint.

MicroRNAs (miRNAs) are short, noncoding, single-stranded RNA molecules that regulate gene expression at the post-transcriptional level by binding to mRNAs. miRNAs affect the course of processes of fundamental importance for the proper functioning of the organism. These processes include cell division, proliferation, differentiation, cell apoptosis and the formation of blood vessels. Altered expression of individual miRNAs has been shown in numerous cancers, which may indicate the oncogenic or suppressor potential of the molecules in question. This paper discusses the current knowledge about the possibility of using miRNA as a diagnostic marker and a potential target in modern anticancer therapies.

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miRNAs in Cancer (Review of Literature)

According to estimates from 2015, approximately 48,960 new pancreatic cancer cases had occurred, and around 40,560 patients had died from pancreatic cancer in the United States of America. [1]It is...

Metastatic Pancreatic Cancer

AIM: To assess the value of D-dimer level in determining resectability of pancreatic cancer.

METHODS: Preoperative prediction of pancreatic head cancer resectability remains inaccurate. The use of hemostatic factors may be of potential help, since D-dimers correlate with tumor stage. Single center clinical trial study comprised patients with potentially resectable pancreatic head tumor and without detectable venous thrombosis (n = 64). Resectability was defined as no evidence of nodal involvement, distant spread and no invasion of mesenteric vessels. Final decision of resectability was confirmed intraoperatively. Experienced pancreatic surgeon performed all surgeries. Following the dissection of hepatoduodenal ligament, samples of portal blood and bile were taken. Peripheral blood via central line and urine via Foley catheter were sampled. D-dimer levels were further measured.

RESULTS: At laparotomy only 29 (45.3%) tumors were found to be resectable. Our analysis showed higher by 57.5% (P < 0.001) mean D-dimer values in peripheral and 43.7% (P = 0.035) in portal blood of patients with unresectable pancreatic cancer. Significant differences were not observed when analyzing D-dimer levels in bile and urine. Peripheral D-dimer level correlated with pancreatic cancer resectability. When cut-off D-dimer value of 570.6 μg/L was used, the sensitivity for assessment of tumor unresectability was 82.8%. Furthermore, D-dimer level in peripheral blood of metastatic disease (n = 15) was significantly higher when compared to locally advanced (n = 20) pancreatic cancer (2470 vs 1168, P = 0.029). The area under ROC curve for this subgroup of patients was 0.87; for determination of unresectable disease when threshold of 769.8 μg/L was used, sensitivity and specificity was 86.6% and 80%, respectively.

CONCLUSION: Patients with resectable pancreatic head cancer based on preoperative imaging studies and high D-dimer level may be considered unresectable due to occult hepatic metastases. These patients may benefit from diagnostic laparoscopy to avoid exploratory laparotomy.

Preoperative high level of D-dimers predicts unresectability of pancreatic head cancer.

Cancer stem cells (CSC) play an important role in pancreatic carcinogenesis and prognosis The study aimed at examining the expression of CD24, CD44, and CD133 in human PDAC and CP in order to evaluate its clinicopathological correlations and the clinical significance Surgical specimens from 23 patients with PDAC and 15 patients with chronic pancreatitis after pancreatic resection were stained with CD24, CD44, and CD133 antibodies The intensity of staining was scored from 0 (negative) to 3 (strongly positive) Results Mean CD24 staining score in PDAC was 138 ± 076 and was significantly higher than that in CP: 070 ± 053 ( ); CD44 score in PDAC was 223 ± 042 and was significantly higher than that in CP: 187 ± 055 ( ); CD133 score 093 ± 058 was not different from CP: 071 ± 043 ( ) CD44 immunoreactivity was significantly higher ( ) in pT1 and pT2 patients together as regards pT3: 245 ± 037 versus 206 ± 038 as well as in N0 patients compared to N1 patients: 25 ± 038 versus 204 ± 034 Conclusions CD24 and CD44 are upregulated in human pancreatic cancer compared to chronic pancreatitis CD44 immunoreactivity decreases with the tumor advancement and may represent the negative PDAC prognostic factor Each CSC marker was differently related to PDAC advancement CD133 may lack clinical significance in PDAC

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Corrigendum to "Expression and Clinical Significance of Cancer Stem Cell Markers CD24, CD44, and CD133 in Pancreatic Ductal Adenocarcinoma and Chronic Pancreatitis".

Background Pancreatic cancer (PDAC) will have been the second leading cancer-related death in the United States by 2020, according to current estimation. Its late manifestation and the lack of good early detection methods are the cause of extremely low survival rates. Therefore, there is an urgent need to develop highly sensitive and specific marker. GDF-15, a member of TGFbeta family, has recently emerged as a protein playing an important role in carcinogenesis of various neoplasms. Objective Our aim was to assess the potential of GDF-15, IL-17, IL-23 serum concentration, and the panel of PDAC markers in differentiating pancreatic adenocarcinoma from chronic pancreatitis. Methods Sixty-three consecutive patients operated on due to pancreatobiliary lesions were enrolled in this study. Levels of CEA, CA125 and Ca19-9 were assessed using standard laboratory protocols. A sample of serum was collected prior to the surgery via central line. Levels of GDF-15, Il-17, Il-23 were measured using a ELISA kit. After standard pathological examination of specimens obtained on surgery, patients were divided into 2 groups: 42 patients with pancreatic adenocarcinoma and 21 patients with focal chronic pancreatitis. Results Mean GDF-15 concentration in patients with CP vs PDAC was 2247.95 (± 179.27) vs 7694.58 (± 1878.94) [pg/mL] respectively (p= 0.011). Mean concentration of Il-17, Il-23, Ca19-9, Ca125, Ca15-3, CEA in patients with CP and PDAC was 862.36 (± 30.84) vs 841.83 (± 33.94) p= 0.833; 127.85 (± 5.87) vs 127.51 (± 9.74) p= 0.175; 34.95 (± 23.34) vs 266.62 (± 49.7) p= 0.001; 13.4 (± 1.6) vs 39.27 (± 6.85) p= 0.005; 18.4 (± 1.48) vs 20.2 (± 1.38) p= 0.416; 1.96 (± 0.38) vs 5.93 (± 1.74) p= 0.004 respectively. In order to compare these markers with the routinely used ones, ROC curve was built. CA19-9 with clinically used cut-off point of ⩾ 36 IU/mL has specificity of 90.5% and sensitivity of 57.14%. At the same time GDF-15 with the optimal cut-off point of 2.7 ng/mL has specificity of 76.19% and sensitivity of 73.8%. Although in our research group CA19-9 has an excellent specificity, its usefulness is hampered by its low sensitivity. On the other hand, GDF-15 parameters are well-balanced making it a more useful biomarker of PDAC. Conclusions In conclusion, GDF-15 is more accurate than Ca19-9 in differentiating pancreatic mass due to chronic pancreatitis from pancreatic adenocarcinoma. Interleukin 17 and 23 cannot be considered as PDAC biomarkers. GDF-15 concentration in serum should be further investigated in order to assess their usefulness in pancreatic adenocarcinoma diagnosis.

Growth differentiation factor (GDF-15) concentration combined with Ca125 levels in serum is superior to commonly used cancer biomarkers in differentiation of pancreatic mass.

Piotr Hogendorf

Papers

miRNAs in Cancer (Review of Literature)

Metastatic Pancreatic Cancer

Preoperative high level of D-dimers predicts unresectability of pancreatic head cancer.

Corrigendum to "Expression and Clinical Significance of Cancer Stem Cell Markers CD24, CD44, and CD133 in Pancreatic Ductal Adenocarcinoma and Chronic Pancreatitis".

Growth differentiation factor (GDF-15) concentration combined with Ca125 levels in serum is superior to commonly used cancer biomarkers in differentiation of pancreatic mass.