Recurrent pancreatitis in Gardner variant familial polyposis: etiology, diagnostic approach, and interventional results

HYPOTHESIS: Pancreatitis arising from an obstructing ampullary neoplasm in patients with Gardner variant familial polyposis is an infrequently described clinical entity. We reviewed all patients with Gardner variant polyposis presenting with pancreatitis during a 12-year period in our institution, hoping to better define etiology and the appropriate diagnostic and interventional approach. METHODS: A retrospective record review (1986-1998) defined patient demographics, presenting features, initial and subsequent endoscopic retrograde cholangiopancreatography (ERCP) findings, subsequent treatments, and both immediate and long-term outcomes. Particular consideration was given to initial post-ERCP diagnosis and to endoscopic interventions undertaken at that time. We also looked at those patients who eventually required surgical intervention after long-term failure of medical and endoscopic therapy, the indications for surgery, final pathological characteristics, and follow-up results. RESULTS: Eight patients (6 women and 2 men), with a mean age of 42 years at initial presentation, were found. Each patient was known to have Gardner variant familial polyposis at the time of the initial bout of pancreatitis. All had undergone prior colectomy and 4 of 8 had undergone prior cholecystectomy. None were known to be taking medications or ingesting pancreatoxic substances. Five of 8 patients had obstructing focal or diffuse adenomatous disease involving the ampulla. Two of 8 patients had pancreatitis attributed to other causes (divisum, stones) and a single patient had no clear etiology. Three of 5 patients with ampullary adenomatous disease underwent pancreaticoduodenectomy for recurrent adenomatous encroachment and ampullary stenosis, despite repetitive snare resection and papillotomy. All of these patients had ampullary and other duodenal adenomas, and none had malignant disease. CONCLUSIONS: Patients presenting with pancreatitis in the setting of Gardner variant familial polyposis will frequently have an obstructing ampullary neoplasm, although additional etiologies should be sought. Initial endoscopic therapy affords transient relief but may not be definitive. The abnormal scarring and fibrosis (keloid formation, desmoid reaction) that characterize this disease likely play a large role in endoscopic or subsequent surgical failure. A significant number of these patients will go on to require surgical referral and intervention.     

Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice

PEG-rHuMGDF injected daily in normal mice causes a rapid dose-dependent increase in megakaryocytes and platelets. At the same time that platelet numbers are increased, the mean platelet volume (MPV) and platelet distribution width (PDW) can be either decreased, normal, or increased depending on the dose and time after administration. Thus, PEG-rHuMGDF at a low dose causes decreases in MPV and PDW, MGDF at an intermediate dose causes an initial increase followed by a decrease in MPV and PDW, and PEG-rHuMGDF at higher doses causes an increase in MPV and PDW followed by a gradual normalization of these platelet indices. In addition to the expected thrombocytosis after 7 to 10 days of daily injection of high doses of PEG-rHuMGDF, a transient decrease in peripheral red blood cell numbers and hemoglobin is noted accompanied in the bone marrow by megakaryocytic hyperplasia, myeloid hyperplasia, erythroid and lymphoid hypoplasia, and deposition of a fine network of reticulin fibers. Splenomegaly, an increase in splenic megakaryocytes, and extramedullary hematopoiesis accompany the hematologic changes in the peripheral blood and marrow to complete a spectrum of pathologic features similar to those reported in patients with myelofibrosis and megakaryocyte hyperplasia. However, all the PEG-rHuMGDF-initiated hematopathology including the increase in marrow reticulin is completely and rapidly reversible upon the cessation of administration of PEG-rHuMGDF. Thus, transient hyperplastic proliferation of megakaryocytes does not cause irreversible tissue injury. Furthermore, PEG-rHuMGDF completely ameliorates carboplatin-induced thrombocytopenia at a low-dose that does not cause the hematopathology associated with myelofibrosis.     

Colorectal cancer extracellular acidosis decreases immune cell killing and is partially ameliorated by pH-modulating agents that modify tumor cell cytokine profiles

Tumor cells upregulate myriad proteins that are important for pH regulation, resulting in the acidification of the extracellular tumor microenvironment (TME). Abnormal pH is known to dampen immune function, resulting in a worsened anti-tumor immune response. Understanding how extrinsic alterations in pH modulate the interactions between immune cells and tumors cells will help elucidate opportunities for new therapeutic approaches. We observed that pH impacts the function of immune cells, both natural killer (NK) and T cells, which is relevant in the context of a highly acidic TME. Decreased NK and T cell activity was correlated with decreasing pH in a co-culture immune cell-mediated tumor cell-killing assay. The addition of pH-modulating drugs cariporide, lansoprazole, and acetazolamide to the co-culture assay was able to partially mitigate this dampened immune cell function. Treatment of colorectal cancer (CRC) cells with NHE1 inhibitor cariporide increased CRC cell-secreted cytokines involved in immune cell recruitment and activation and decreased cytokines involved in epithelial-mesenchymal transition (EMT). Cariporide treatment also decreased CRC cell shed TRAIL-R2, TRAIL-R3, and PD-L1 which is relevant in the context of immunotherapy. These experiments can help inform future investigations into how the pH of the tumor microenvironment may be extrinsically modulated to improve anti-tumor immune response in solid tumors such as colorectal cancer.     

Prevention of neonatal macrosomia in gestational diabetes by the use of intensive dietary therapy and home glucose monitoring

This study was undertaken to determine if intensive dietary therapy, home blood glucose monitoring, and the selective use of insulin can be effective in preventing fetal macrosomia. All patients were screened at 24 to 28 weeks' gestation using a modification of O'Sullivan's criteria. The 153 patients diagnosed as gestational diabetics by the study protocol were placed on a 1800 to 2000 Kcal American Diabetes Association diet and taught home glucose monitoring. Insulin therapy was initiated only if blood glucose control was inadequate. There were no significant differences (p greater than 0.05) between the study and reference populations in regard to mean birthweight or the incidence of macrosomia. Since our study criteria for diagnosing gestational diabetes were slightly different from those of the National Diabetes Data Group (NDDG), data from 99 patients meeting the NDDG criteria were analyzed in a similar manner. No significant differences were found between this subgroup and the reference population. Since only 7.2% of our study patients required insulin, we conclude that the incidence of fetal macrosomia in gestational diabetes can be kept equal to that of the general population by a program of intensive dietary therapy and home glucose monitoring, with insulin being used only therapeutically, not prophylactically.     

A comparison of rates of lymph node metastases between patients undergoing sentinel and axillary lymphadenectomy

BACKGROUND: Recommendations regarding credentialing for sentinel lymphadenectomy in the staging of breast cancer emphasize the need for a trial period during which novice surgeons remove both the sentinel lymph node and the axillary packet, to demonstrate acceptably low rates of both operative failure and inaccuracy. METHODS: We initiated sentinel lymph node mapping in our institution without planned axillary dissection. To establish our ability to accurately stage patients using sentinel lymphadenectomy, we compared 225 patients who underwent that procedure and 343 patients previously staged with axillary lymph node dissection. RESULTS: No differences in node positivity were found between the two groups. Among sentinel lymphadenectomy patients, no differences were found between patients in the first and second half of the institutional experience. CONCLUSIONS: We question the need for a trial period of planned axillary node dissection with sentinel lymph node mapping, and review the evidence from other investigators regarding its necessity.     

Simultaneous measurement of gallbladder emptying with cholescintigraphy and US during infusion of physiologic doses of cholecystokinin: a comparison

Both ultrasonography (US) and cholescintigraphy are used to study gallbladder dynamics. The present study was undertaken to determine whether the two methods provide the same or different information relating to gallbladder emptying. Emptying was simultaneously studied with both methods during infusion of graded physiologic doses of cholecystokinin (CCK) in six healthy subjects. Infusion of stepwise increasing doses of CCK, ranging from 0.03 to 0.5 Ivy dog units per kilogram of body weight per hour (IDU/kg.h), induced significant dose-related increases in plasma CCK, decreases in gallbladder volume assessed with US, and gallbladder emptying assessed with cholescintigraphy. The threshold dose for inducing significant gallbladder emptying was 0.13 IDU/kg.h, as determined with both techniques, indicating similar detection limits. There was a highly significant correlation between decreases in gallbladder volume and decreases in radioactive counts over the gallbladder region, with a tendency toward greater gallbladder responses at sonography during the early phase of gallbladder contraction and toward greater responses at cholescintigraphy during the later phase of gallbladder contraction. It is concluded that these methods can be used interchangeably for the quantitation of gallbladder emptying.