Survival rates for pancreatic cancer remain dismal. Current standard of care treatment regimens provide transient clinical benefit but eventually chemoresistance develops. Tumors deficient in deoxyribonucleic acid (DNA) damage repair mechanisms such as BRCA mutants show better responses to platinum based agents, however, such tumors can utilize the poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) pathway as a salvage mechanism. Therefore, inhibition of PARP pathway could lead to tumor destruction and synthetic lethality in presence of BRCA mutation. Various PARP inhibitors have been approved for treatment of patients with germline or somatic BRCA mutant breast and ovarian cancer. This provides basis of using PARP inhibitors in patients with pancreatic cancer that harbor BRCA mutation. A recent phase III Pancreas Cancer Olaparib Ongoing (POLO) study showed impressive results with near doubling of progression free survival compared to placebo (7.4 vs 3.8 months). These results highlight the importance of germline testing for all patients with pancreatic cancer and inclusion of additional deficiencies in homologous recombination repair (ATM and PALB2) including BRCA variants of uncertain significance should be further explored.

Keywords

Pancreatic cancer; Chemoresistance; DNA damage repair; Synthetic lethality; BRCA1/2; Germline mutations; Genomics.

Survival rates for pancreatic cancer (PC) remain dismal. Current standard of care treatment regimens provide transient clinical benefit but eventually chemoresistance develops leading to poor outcomes. PC is a relatively chemoresistant tumor and one of the explanations for this is attributed to desmoplasia that impedes drug delivery. Based on this, stromal modifying agent such as Pegvorhyaluronidase alfa (PEGPH20) was developed and investigated in phase I-III studies. Although phase I-II studies showed promising results in patients with high hyaluronic acid (HA) expressing tumors, the phase III HALO 301 study failed to miss it’s primary endpoint and further development of PEHPH20 is halted. This failure implies that targeting desmoplasia alone is not sufficient and other intrinsic factors such as lack of significant neoantigens, low tumor mutational burden, and epithelial to mesenchymal transition may be at play. It is also important to consider that although the tumor stroma may be a physical barrier hampering drug delivery, it may also have protective effects in restraining tumor growth and progression. Further studies in molecular biology to better characterize the complex interaction between the microenvironment and cancer cells are warranted.

Keywords

Pegvorhyaluronidase alfa (PEGPH20); Desmoplasia; Pancreatic cancer; Chemoresistance; HALO.

Pancreatic cancer remains a devastating disease with dismal outcomes despite the development of novel chemotherapeutic regimens and radiation techniques. Stereotactic body radiation therapy (SBRT) offers an advantage both in image guidance and radiation dose delivery to direct ablative doses to tumors with acceptable toxicity compared to conventional techniques. Recent literature is clustered with data pertaining to SBRT in patients with resectable, borderline resectable and locally advanced pancreatic tumors. We here present a summary of the current data and highlight the limitations and potential for future growth. Further clinical study in the form of multi-institutional trials is warranted to establish the role of SBRT in combination with new chemotherapeutic agents as well as a non-invasive alternative to surgery.

Keywords

Pancreatic neoplasms; Pancreas cancer; Radiosurgery; Stereotactic; Stereotactic body radiation therapy (SBRT); Radiation; Radiotherapy.

Introduction: Overt type 2 diabetes mellitus (T2DM) is a chronic progressive disease which is produced by the collusion of three metabolic defects-increased hepatic glucose production, impaired pancreatic β-cell insulin secretion and decreased insulin action. The measurement of plasma glucose 2 hours post-ingestion of 75 g of glucose during the oral glucose tolerance test (OGTT) may be used to classify individuals as normal glucose tolerant (NGT), impaired glucose tolerant, T2DM and T2DM with pancreatic β-cell failure.
Objectives: This study was undertaken primarily to show the importance of assessing the pancreatic β-cell function especially during the care of the diabetic patient.
Methods: A standard 75 g glucose tolerance test (OGTT) was administered to four groups of 8 subjects (4 male, 4 female). Blood was drawn every 15 minutes for 2 hours for the measurement of glucose, insulin and C-peptide and the measurement of the area under the curve (AUC(0→2)) over the 2-hour period.
Results: American Diabetes Association (ADA) criteria were used to classify the subjects. The normal glucose tolerant (NGT), had 2 h glucose 111±11 mg/dL, those with impaired glucose tolerance (IGT) had 2 h glucose 160±13 mg/dL. The 2 h glucose for the T2DM group was 258±27 mg/dL and those for the T2DM-PE group was 260±42 mg/dL. The AUC(0→2) for NGT group were 254±40 mg/dL/h, 112±61 μU/mL/h and 10.2±4.6 ng/ml/h for glucose, insulin and C-peptide, respectively. The AUC(0→2) for the IGT group were 394±32 mg/dL/h, 160±48 μU/mL/h and 19.8±7.7 ng/ml/h for glucose, insulin and C-peptide, respectively. The AUC(0→2) for the T2DM group were 474±62 mg/dL/h, 194±40 μU/mL/h and 13.4±4.7 ng/mL/h for glucose and insulin, and C-peptide, respectively. The AUC(0→2) for the T2DM-PE group were 481±80 mg/dL/h, 51±29 μU/mL/h and 7.2±2.8 ng/mL/h for glucose, insulin and C-peptide, respectively. There was no significant difference between the diabetic groups with respect to the glucose AUC(0→2) but a significant difference existed in the insulin AUC(0→2), (p<0.0001) mirrored by the fasting plasma insulin levels (30±8 μU/mL vs 14+8 μU/mL, for T2DM and T2DM-PE, respectively, p<0.0005). Although there was about a 300% increase in fasting insulin between the IGT and T2DM groups, the corresponding fasting C-peptide levels were only about 15%. This is probably due to differences in hepatic and renal functions in those two groups, the processes that control insulin and C-peptide levels in the body.
Conclusion: Although measurement of blood glucose appears adequate in the diagnosis of the diabetes, it seems that plasma insulin/C-peptide measurements could guide physicians in their choice of medications for the treatment of diabetic patients, especially when the pancreas begins to fail. To that end, larger studies are warranted to study the effects of hypoglycemic agents on hepatic insulin extraction and renal C-peptide excretion to ascertain the reliability of the plasma insulin and C-peptide levels.
Keywords
Type 2 diabetes mellitus; Pancreatic β-cells; Oral glucose tolerance test; Pancreatic exhaustion.