Timothy L. Fitzgerald

Changing Incidence of Pancreatic Neoplasms: A 16-year Review of Statewide Tumor Registry

Objectives: Although most pancreatic neoplasms are adenocarcinoma, there are many other histological types, some of which may be increasing in frequency. To better define these trends, we reviewed 16 years of data from a statewide tumor registry. Methods: Using the State of Michigan tumor registry, all patients with primary pancreatic cancers from 1986 to 2002 were identified, and patients were excluded if there were insufficient data or the histological subtype was not clearly defined in the literature. Results: There were 17,610 pancreatic neoplasms identified, and 2425 were excluded, leaving a final population of 15,185. Twenty-five types of primary pancreatic neoplasms were identified. The most common were adenocarcinoma, mucinous cystadenocarcinoma, nonfunctional neuroendocrine, adenosquamous, anaplastic, intraductal papillary mucinous, and acinar cell (8.37, 0.43, 0.18, 0.05, 0.04, 0.04, and 0.02 per 100,000 per year, respectively). The mean age at presentation was similar for tumor types, 69.2 years old, with the exception of endocrine neoplasms occurring at a younger age, 58.5 years old (P < 0.0005). There was a significant change in the incidence of nonfunctional neuroendocrine neoplasms, greater than 2-fold increase (P = 0.0003). Conclusions: The incidence of most pancreatic neoplasms has changed a little; however, nonfunctional neuroendocrine neoplasms increased greater than 2-fold. The etiology of this change is unclear.

Adjuvant Chemotherapy After Resection in Elderly Medicare and Medicaid Patients With Colon Cancer

BACKGROUND This study investigated the influence of Medicaid enrollment on the receipt and completion of adjuvant chemotherapy and the likelihood of evaluation by an oncologist for those patients who do not initiate chemotherapy. METHODS Medicaid and Medicare administrative data were merged with the Michigan Tumor Registry to extract a sample of patients who had resection for a first primary colon tumor diagnosed between January 1, 1997, and December 31, 2000 (n = 4765). We used unadjusted and adjusted logistic regression to assess the relationship between Medicaid enrollment and the outcomes of interest. RESULTS Relative to Medicare patients, Medicaid patients were less likely to initiate chemotherapy (odds ratio, 0.50; 95% confidence interval, 0.39-0.65) or complete chemotherapy (odds ratio, 0.52; 95% confidence interval, 0.31-0.85). When the sample was restricted to patients with TNM-staged disease, Medicaid patients were less likely to initiate chemotherapy. Older patients and patients with comorbidities were also less likely to initiate or, in some cases, to complete chemotherapy. CONCLUSION Medicaid enrollment is associated with disparate colon cancer treatment, which likely compromises the long-term survival of these patients.

Roles of signaling pathways in drug resistance, cancer initiating cells and cancer progression and metastasis

The EGFR/PI3K/PTEN/Akt/mTORC pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance, cancer initiating cells (CICs) and metastasis. The expression of this pathway is frequently altered in breast and other cancers due to mutations at or aberrant expression of: HER2, EGFR1, PIK3CA, and PTEN as well as other oncogenes and tumor suppressor genes. miRs and epigenetic mechanisms of gene regulation are also important events which regulate this pathway. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway has been associated with CICs and in some cases resistance to therapeutics. We will review the effects of activation of the EGFR/PI3K/PTEN/Akt/mTORC pathway primarily in breast cancer and development of drug resistance. The targeting of this pathway and other interacting pathways will be discussed as well as clinical trials with novel small molecule inhibitors as well as established drugs that are used to treat other diseases. In this manuscript, we will discuss an inducible EGFR model (v-ERB-B:ER) and its effects on cell growth, cell cycle progression, activation of signal transduction pathways, prevention of apoptosis in hematopoietic, breast and prostate cancer models.

Roles of EGFR and KRAS and their downstream signaling pathways in pancreatic cancer and pancreatic cancer stem cells.

Pancreatic cancer is currently the fourth most common cancer, is increasing in incidence and soon will be the second leading cause of cancer death in the USA. This is a deadly malignancy with an incidence that approximates the mortality with 44,000 new cases and 36,000 deaths each year. Surgery, although only modestly successful, is the only curative option. However, due the locally aggressive nature and early metastasis, surgery can be performed on less than 20% of patients. Cytotoxic chemotherapy is palliative, has significant toxicity and improves survival very little. Thus new treatment paradigms are needed desperately. Due to the extremely high frequency of KRAS gene mutations (>90%) detected in pancreatic cancer patients, the roles of the epidermal growth factor receptor (EGFR), Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTORC1/GSK-3 pathways have been investigated in pancreatic cancer for many years. Constitutively active Ras can activate both of these pathways and there is cross talk between Ras and EGFR which is believed to be important in driving metastasis. Mutant KRAS may also drive the expression of GSK-3 through Raf/MEK/ERK-mediated effects on GSK-3 transcription. GSK-3 can then regulate the expression of NF-kappaB which is important in modulating pancreatic cancer chemoresistance. While the receptors and many downstream signaling molecules have been identified and characterized, there is still much to learn about these pathways and how their deregulation can lead to cancer. Multiple inhibitors to EGFR, PI3K, mTOR, GSK-3, Raf, MEK and hedgehog (HH) have been developed and are being evaluated in various cancers. Current research often focuses on the role of these pathways in cancer stem cells (CSC), with the goal to identify sites where therapeutic resistance may develop. Relatively novel fields of investigation such as microRNAs and drugs used for other diseases e.g., diabetes, (metformin) and malaria (chloroquine) have provided new information about therapeutic resistance and CSCs. This review will focus on recent advances in the field and how they affect pancreatic cancer research and treatment.

Notch-1 Promotes Stemness and Epithelial to Mesenchymal Transition in Colorectal Cancer

Colorectal cancer (CRC) is the third leading cause of cancer death in the United States, resulting in an average of 50,000 deaths per year. Surgery and combination chemotherapy comprise current treatment strategies. However, curative options are limited if surgery and chemotherapy are unsuccessful. Several studies have indicated that CRC aggressiveness and potential for metastatic spread are associated with the acquisition of stem cell like properties. The Notch‐1 receptor and its cognate signaling pathway is well known for controlling cell fate decisions and stem‐cell phenotypes. Alterations in Notch receptors and Notch signaling has been reported for some colon cancers. Herein, we examine a potential role for Notch‐1 signaling in CRC. In CRC patient samples, Notch‐1 expression was increased in colon tumor tissue as compared with normal colon tissue. Retroviral transduction of constitutively active Notch‐1 (ICN1) into the colon tumor cell line HCT‐116 resulted in increased expression of the EMT/stemness associated proteins CD44, Slug, Smad‐3, and induction of Jagged‐1 expression. These changes in ICN1 expressing cells were accompanied by increased migration and increased anchorage independent growth by 2.5‐fold and 23%, respectively. Experiments with the pan‐Notch inhibitor DAPT, and soluble Jagged‐1‐Fc protein provided evidence that Notch‐1 signaling activates CD44, Slug, and Smad‐3 via a cascade of other Notch‐receptors through induction of Jagged‐1 expression. These data indicate a key role for Notch signaling in the phenotype of CRC and suggest that targeting of Notch signaling may be of therapeutic value in colon cancers. J. Cell. Biochem. 116: 2517–2527, 2015.

Pancreatic cancer stem cells: association with cell surface markers, prognosis, resistance, metastasis and treatment.

In this review, we will discuss the recent advances in understanding the pancreatic cancer stem cells. Identification and characterization of pancreatic cancer stem cells may aid our ability to improve diagnosis and treatment of pancreatic cancer. Novel approaches are necessary for the earlier diagnosis of pancreatic cancer as well as improved treatment to prevent distal metastasis. Key markers for the identification of pancreatic cancer stem cells include CD133, ALDH, side population cells and the triplet combination CD44+ CD24+ESA+. The roles of these proteins as markers for stemness in pancreatic cancer as well as recent studies with the c-Met proto-oncogene will be discussed. The ability of these markers to predict survival of pancreatic cancer patients is being examined clinically. Stemness and resistance to chemotherapy and radiotherapy may be linked. Expression of some of these markers may be associated with distant metastasis. Treatment of pancreatic cancer patients by targeting the pancreatic cancer stem cells holds promise.

Effects of mutations in Wnt/β-catenin, hedgehog, Notch and PI3K pathways on GSK-3 activity-Diverse effects on cell growth, metabolism and cancer.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that participates in an array of critical cellular processes. GSK-3 was first characterized as an enzyme that phosphorylated and inactivated glycogen synthase. However, subsequent studies have revealed that this moon-lighting protein is involved in numerous signaling pathways that regulate not only metabolism but also have roles in: apoptosis, cell cycle progression, cell renewal, differentiation, embryogenesis, migration, regulation of gene transcription, stem cell biology and survival. In this review, we will discuss the roles that GSK-3 plays in various diseases as well as how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK, Wnt/beta-catenin, hedgehog, Notch and TP53. Mutations that occur in these and other pathways can alter the effects that natural GSK-3 activity has on regulating these signaling circuits that can lead to cancer as well as other diseases. The novel roles that microRNAs play in regulation of the effects of GSK-3 will also be evaluated. Targeting GSK-3 and these other pathways may improve therapy and overcome therapeutic resistance.

Pushing the Envelope Beyond a Centimeter in Rectal Cancer: Oncologic Implications of Close, But Negative Margins

BACKGROUND The treatment of rectal cancer has improved significantly over the last century. Advances in surgical and adjuvant therapy coupled with a better understanding of the natural history have allowed for acceptance of progressively diminished margins for distal neoplasms. In order to better define oncologically safe distal margins, we performed a meta-analysis of the existing worlds literature. STUDY DESIGN Studies were identified on Medline and ISI Web of Science using key words rectal cancer and margin. Studies were excluded if specific margins and local recurrence rates could not be extracted. All analyses were performed using Comprehensive Meta-Analysis Software (Biostat). RESULTS Twenty-one studies reported outcomes in relationship to distal margins. Seventeen studies, 4,885 patients, reported outcomes with margins of less than 1 cm. Analysis of all studies indicated a nonsignificant trend favoring greater margins. However, in order to understand distal margins in the context of current care standards, additional analyses were performed. Thirteen studies reported application of total mesorectal excision and/or radiation. There was no significant difference in local recurrence rates for margins less than 1 cm. In the 4 studies that reported neither total mesorectal excision nor radiation, a margin greater than 1 cm was favored. Increased recurrence rates and decreased survival were associated with positive final margins. CONCLUSIONS When total mesorectal excision is combined with radiotherapy, excellent local control can be expected with sphincter preservation for distal rectal cancers when margins are less than 1 cm, as long as final pathologic margins are negative.

Amelioration of Insulin Requirement in Patients Undergoing Duodenal Bypass for Reasons Other than Obesity Implicates Foregut Factors in the Pathophysiology of Type II Diabetes

BACKGROUND Foregut diversion and weight loss have been proposed as potential mechanisms for resolution of type II diabetes mellitus (T2DM) observed in patients undergoing gastric bypass for obesity. To support or refute the role of the foregut, we analyzed glycemic control in T2DM patients before and after foregut bypass for reasons other than morbid obesity. STUDY DESIGN Using ICD9/CPT codes, we identified patients undergoing Roux-en-Y gastrojejunostomy (RY) or Billroth II (BII) reconstruction over 10 years. Fasting blood glucose, insulin or oral diabetic agent requirement, and body mass index (BMI) before and after surgery were tabulated and compared using the Students t-test. Linear regression was applied to determine specific factors predictive of resolution or improvement in glycemic control including age, duration of diabetes, antidiabetic regimen, type of operation, and surgical indication. RESULTS Between 1996 and 2006, we identified 24 patients with T2DM out of a cohort of 209 who underwent either RY (12 of 24) or BII reconstruction (12 of 24) for cancer or peptic ulcer disease and survived more than 30 days after operation. Of this group, 75% were overweight (18 of 24 with BMI < 30 kg/m(2)) and 25% were class I morbidly obese (6 of 24 with BMI 30 to 35 kg/m(2)). Seventeen patients (71%) had either complete resolution (7 of 24 or 29%) or significant reduction (10 of 24 or 42%) in medication requirements; 7 patients (29%) did not have any improvement. Logistic regression failed to identify specific factors predicting improved glycemic control. CONCLUSIONS Complete resolution of T2DM in patients undergoing duodenal diverting surgery occurs in about one-third of nonobese patients. Improved glycemic control occurs in more than two-thirds and cannot be explained by surgically related weight loss alone. Surgical cure of T2DM may be possible in carefully selected nonobese patients.

Cutaneous apocrine adenocarcinoma: defining epidemiology, outcomes, and optimal therapy for a rare neoplasm.

Apocrine adenocarcinoma is a rare neoplasm. There is a paucity of data on demographics and survival with no clear consensus on management of at risk lymph nodes, therefore, we analyzed a large cohort of patients identified via a national tumor registry.