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Biomedical subjects

Mark P Callery

Publications and source records attributed to Mark P Callery.

At least 19 recordsLinked to original sources
PubMed2007

Impact of regional lymph node evaluation in staging patients with periampullary tumors.

BACKGROUND: Two distinct lymph nodes reproducibly assessed by computed tomography for the evaluation of periampullary tumors are the common bile duct (CBD) node and the gastroduodenal artery (GDA) node. We examined whether radiographical enlargement of either lymph node predicts tumor resectability, nodal metastasis, or patient survival. METHODS: Ninety-four consecutive patients underwent attempted curative resection of periampullary tumors between September 2001 and June 2003. A single radiologist recorded in a retrospective, blinded fashion the short- and long-axis measurements of the CBD and GDA nodes. RESULTS: Sixty-one percent (n = 57) of tumors were resectable by pancreaticoduodenectomy. Overall, actual 6-, 12-, and 18-month survival was 87%, 68%, and 63%, respectively. Enlarged radiographical nodal size by either axis was not associated with the presence of metastasis to these lymph nodes or with reduced overall patient survival. Only a CBD node short-axis size >10 mm predicted unresectability (odds ratio, 3.2; P = .036). Liver metastasis and/or carcinomatosis were present in 43% of unresectable patients, and this was associated with decreased survival at both 1 year (25% vs. 77%; P < .001) and 18 months (19% vs. 72%; P <.001). A pathologic diagnosis of metastasis to the GDA node, but not the CBD node, was associated with a similarly decreased survival (1 year: 33% vs. 78%, P = .028; 18 months: 22% vs. 70%, P = .023). CONCLUSIONS: For presumed periampullary malignancy, a CBD node short-axis size >10 mm predicts tumor unresectability. Metastatic disease to the GDA node, particularly for pancreatic adenocarcinoma, portends a poor prognosis equivalent to that of hepatic or peritoneal spread. Given these findings, radiographical CBD lymph node measurements may guide selection for performing laparoscopic staging with or without ultrasonography in conjunction with GDA nodal biopsy in patients with periampullary malignancy.

Abdomen↗
PubMed2006

Histone deacetylase inhibitor trichostatin A and proteasome inhibitor PS-341 synergistically induce apoptosis in pancreatic cancer cells.

UNLABELLED: Pancreatic cancer is a common and lethal malignancy. Pancreatic cancer cells overexpress multiple anti-apoptotic factors and death receptor decoys, and are strongly resistant to radiation and to 5-fluorouracil (5-FU)- or gemcitabine (Gem)-based chemotherapy regimens. We have found that low-dose proteasome inhibitor PS-341 and histone deacetylase inhibitor trichostatin A (TSA) synergistically induce cytotoxicity in a panel of eight diverse pancreatic cancer cell lines. Combining TSA with PS-341 effectively inactivated NFkappaB signaling, downregulated the predominant endogenous anti-apoptotic factor Bcl-XL overexpression, and disrupted MAP kinase pathway. The combined drug regimen effectively inflicted an average of 71.5% apoptotic cell death (55.2-80%) in diverse pancreatic cancer cell lines by activating the intrinsic apoptotic pathway. CONCLUSION: The TSA/PS-341 regimen may represent a potential novel therapeutic strategy for pancreatic cancer.

Antineoplastic Agents↗
PubMed2006

Postoperative pancreatic fistulas are not equivalent after proximal, distal, and central pancreatectomy.

It is uncertain whether postoperative pancreatic fistulas after distal and central pancreatectomies behave similarly to those after pancreaticoduodenectomy. To date, this concept has not been validated either clinically or economically. Overall, 256 consecutive pancreatic resections from October 2001 to February 2006 (184 pancreaticoduodenectomies, 66 distal pancreatectomies, and 6 central pancreatectomies) were evaluated according to the International Study Group of Pancreatic Fistula classification scheme. Pancreatic fistula was defined as any measurable drainage on or after postoperative day 3, with amylase content greater than three times the normal serum value. Outcomes were divided into four grades: (1) no fistula, (2) grade A: biochemical fistula without clinical sequelae, (3) grade B: fistula requiring any therapeutic intervention, or (4) grade C: fistula with severe clinical sequelae. Grades B and C are considered clinically relevant fistulas based on worsening morbidity, increased length of stay, frequent hospital readmission, and increased costs/resource utilization. Clinical and economic outcomes were compared-grade for grade-across the three resection types. Fistulas of any extent (Grades A-C) occurred in one third of all patients; two thirds had no fistula. Overall, there were 16 readmissions (6%), six reoperations (2%), and no deaths attributable to pancreatic fistula. Outcomes between no fistula and grade A patients were identical across resection types, though grade A fistula was more common in distal pancreatectomy. For each resection type, length of stay and costs progressively increased with grades B and C. However, the negative impact of these clinically relevant fistulas varied between resection types. Rates for intensive care unit admission and rehabilitation placement were higher among pancreaticoduodenectomy patients. Total parenteral nutrition and antibiotic use were similar, but percutaneous drainage was used more often for distal pancreatectomy. Grade B fistula was more severe after distal pancreatectomy, as indicated by increased length of stay, readmissions, and total cost. Although reoperation rates for grade C fistulas were equivalent, intervals to reoperation were substantially longer after distal and central pancreatectomies. When classified according to International Study Group of Pancreatic Fistula criteria, clinically relevant pancreatic fistulas behaved differently depending on type of pancreatectomy. This translates into variable severity that guides management decisions, which ultimately dictate clinical outcomes and economic impact.

Aged↗
PubMed2005

Predominant Bcl-XL knockdown disables antiapoptotic mechanisms: tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreatic cancer cells in vitro.

Pancreatic cancer is lethal because of its invasiveness, rapid progression, and profound resistance to chemotherapy and radiation therapy. To identify the molecular mechanisms underlying this, we have examined the expression and potency of three major death receptors: tumor necrosis factor receptor (TNF-R), TNF-related apoptosis-inducing ligand receptor (TRAIL-R), and Fas in mediating cytotoxicity in four invasive pancreatic cancer cell lines. We have analyzed the expression of major antiapoptotic factors, cell cycle regulators and death receptor decoys (DcR) in comparison with normal pancreas tissues and five other human malignant tumor cell lines. We have found that different pancreatic cancer cell lines coexpress high-level TRAIL-R, Fas, and TNF-R1 but are strongly resistant to apoptosis triggered by the death receptors. DcR2 and DcR3 overexpression may partly contribute to the resistance of pancreatic cancer cells to TRAIL-R- and Fas-mediated cytotoxicity. Bcl-XL and Bcl-2 are predominantly overexpressed in pancreatic cancer cell lines, respectively. Bcl-XL is also predominantly overexpressed in prostate, colorectal, and intestinal cancer cells. The knockdown of the predominant Bcl-XL overexpression significantly reduces the viability of pancreatic cancer cells to TNFalpha- and TRAIL-mediated apoptosis by sublethal-dose single and combined antitumor drugs, including geldanamycin, PS-341, Trichostatin A, and doxorubicine. Geldanamyin and PS-341 synergistically block NFkappaB activation, suppress Akt/PKB pathway, and down-regulate Bcl-XL, Bcl-2, cIAP-1, and cyclin D1 expression. This combined regimen dramatically enhances TRAIL cytotoxic effects and breaks through chemoresistance. Bcl-XL plays a vital role in pancreatic cancer chemoresistance. Geldanamycin, PS-341, and TRAIL triple combination may be a novel therapeutic strategy for pancreatic cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Advantages of mini-laparoscopic vs conventional laparoscopic cholecystectomy: results of a prospective randomized trial.

HYPOTHESIS: The use of smaller instruments during laparoscopic cholecystectomy (LC) has been proposed to reduce postoperative pain and improve cosmesis. However, despite several recent trials, the effects of the use of miniaturized instruments for LC are not well established. We hypothesized that LC using miniports (M-LC) is safe and produces less incisional pain and better cosmetic results than LC performed conventionally (C-LC). DESIGN: A patient- and observer-blinded, randomized, prospective clinical trial. SETTING: A tertiary care, university-based hospital. PATIENTS: Seventy-nine patients scheduled for an elective LC who agreed to participate in this trial were randomized to undergo surgery using 1 of the 2 instrument sets. The criteria for exclusion were American Society of Anesthesiologists class III or IV, age older than 70 years, liver or coagulation disorders, previous major abdominal surgical procedures, and acute cholecystitis or acute choledocholithiasis. INTERVENTION: Laparoscopic cholecystectomy performed with either conventional or miniaturized instruments. MAIN OUTCOME MEASURES: Patients' age, sex, operative time, operative blood loss, intraoperative complications, early and late postoperative incisional pain, and cosmetic results. RESULTS: Thirty-three C-LCs and 34 M-LCs were performed and analyzed. There were 8 conversions (24%) to the standard technique in the M-LC group. No intraoperative or major postoperative complications occurred in either group. The average incisional pain score on the first postoperative day was significantly less in the M-LC group (3.9 vs 4.9; P = .04). No significant differences occurred in the mean scores for pain on postoperative days 3, 7, and 28. However, 90% of patients in the M-LC group and only 74% of patients in the C-LC group had no pain (visual analog scale score of 0) at 28 days postoperatively (P = .05). Cosmetic results were superior in the M-LC group according to both the study nurse's and the patients' assessments (38.9 vs 28.9; P<.001, and 38.8 vs 33.4; P = .001, respectively). CONCLUSIONS: Laparoscopic cholecystectomy can be safely performed using 10-mm umbilical, 5-mm epigastric, 2-mm subcostal, and 2-mm lateral ports. The use of mini-laparoscopic techniques resulted in decreased early postoperative incisional pain, avoided late incisional discomfort, and produced superior cosmetic results. Although improved instrument durability and better optics are needed for widespread use of miniport techniques, this approach can be routinely offered to many properly selected patients undergoing elective LC.

Analgesia↗
PubMed2004

Increased expression of NF-kappa B subunits in human pancreatic cancer cells.

BACKGROUND: Activation of NF-kappa B-dependent antiapoptotic genes may factor in the chemoresistance of pancreatic cancer. It is not known whether NF-kappa B subunit composition changes during oncogenesis and regulates overall NF-kappa B activation. We compared the relative expression of NF-kappa B subunits with nuclear activation of p65 between variably differentiated pancreatic cancer cells. MATERIALS AND METHODS: Proliferating human pancreatic cancer cells (PANC-1, BxPC-3) and nonmalignant intestinal cells (FHS 74 Int) were harvested. Baseline expression of NF-kappa B subunits (p65, p52, p50, c-Rel) and its inhibitor I kappa B-alpha were determined by Western blot. Nuclear NF-kappa B p65 activity was measured by ELISA. Results were analyzed by ANOVA (P < 0.05) and Tukey's HSD for pairwise comparisons when appropriate (P < 0.05). RESULTS: Constitutive expression of NF-kappa B subunits was detected in proliferating, intestinal cells (FHS 74 Int). Both cytoplasmic (I kappa B-alpha, p50, p52, p65) and nuclear (p50, p52, p65, c-Rel) NF-kappa B subunits were significantly increased in both PANC-1 and BxPC-3 cells compared to FHS 74 Int. While nuclear p65 subunit levels were similarly elevated, actual p65 activity was only significantly greater in PANC-1 cells compared to either BxPC-3 or FHS 74 Int (P < 0.05). CONCLUSIONS: Compared to nonmalignant proliferating intestinal cells, these pancreatic cancer cell lines have increased levels of NF-kappa B subunits. Actual nuclear NF-kappa B activity, however, appears to correlate more with degree of tumor differentiation than with NF-kappa B subunit expression.

Cell Line, Tumor↗
PubMed2004

Caspase-3 drives apoptosis in pancreatic cancer cells after treatment with gemcitabine.

Pancreatic cancer remains a highly chemoresistant malignancy. Gemcitabine, the most effective first-line agent available, acts by disrupting cellular replication. Caspases belong to a family of proteases that function as key components of the apoptotic death machinery. We investigated the mechanisms by which gemcitabine blocks proliferation and whether it can induce apoptosis in pancreatic cancer cells. Quiescent pancreatic cancer cells (BxPC-3) were stimulated to proliferate (10% fetal calf serum) with or without gemcitabine, PS-341 (26S proteasome inhibitor), or both. Proliferation was measured by MTT assay and apoptosis by propidium iodine staining. To determine activation of the apoptotic regulatory cell proteins, caspase-3 and cleavage of poly(ADP-ribose)polymerase (PARP) into its 85-kDa fragment were assessed by Western blotting. Gemcitabine at even low doses (10 micromol/L) significantly inhibited cellular proliferation, whereas PS-341 (10 nmol/L) had no effect. With combined treatment, PS-341 potentiated the antiproliferative effects of gemcitabine (P=0.001). At 48 hours, the apoptotic fraction was greatly enhanced by the presence of PS-341 compared with gemcitabine alone. Caspase-3 accumulated as early as 30 minutes and was associated with cleavage of PARP to its apoptotic fragment. Gemcitabine, a nucleoside analogue, may in part exert its antiproliferative effects by directing pancreatic cancer cells to a default pathway of apoptosis. 26S proteasome inhibition potentiates this effect, suggesting its potential clinical value against chemoresistance in pancreatic cancer.

Adenocarcinoma↗
PubMed2003

Preoperative chemoradiation in resectable pancreatic cancer.

Despite advancements in the field of surgical oncology, the diagnosis of pancreatic cancer still carries a grave and dismal prognosis. Surgery alone for adenocarcinoma of the pancreatic head or uncinate process has a median survival time of 12 months. These grim statistics have led many to study the effects of combined multimodality therapy in the fight against pancreatic cancer. The long recovery time associated with pancreaticoduodenectomy has resulted in as many as 25% of patients unable to proceed with planned adjuvant therapy. For these reasons preoperative or neoadjuvantc hemoradiation therapy (CRT) has been evaluated. Pre-operative CRT ensures that all eligible patients receive the benefits of multimodality therapy, and patients who manifest metastatic disease on restaging evaluations are spared the morbidity of an unnecessary laparotomy. Multimodality therapy appears to lengthen the survival duration in patients with pancreatic cancer. It also affords a selection advantage, in that patients with aggressive disease biology with advanced metastatic disease following CRT are spared the morbidity of surgery. Conversely, a limited subset of patients may even be downstaged, allowing for a potentially curative resection. In this article we review the current status of neoadjuvant chemoradiation in adenocarcinoma of the pancreas. We discuss its rationale in light of the reported strengths and weaknesses of postoperative adjuvant CRT.

Adenocarcinoma↗
PubMed2002

Is the use of a bougie necessary for laparoscopic Nissen fundoplication?

HYPOTHESIS: Esophageal intubation with a bougie during laparoscopic Nissen fundoplication (LNF) is commonly used to prevent an excessively tight wrap. However, a bougie may cause intraoperative gastric and esophageal perforations. We hypothesized that LNF is safe and effective when performed without a bougie. DESIGN: Retrospective review of 102 consecutive patients who underwent LNF without a bougie. SETTING: Tertiary care university hospital. PATIENTS: All patients presented with symptoms of reflux disease. Mean (+/- SD) percentage of time with pH of less than 4 was 12.6% +/- 9.4%. Mean DeMeester score was 47.8. Mean (+/- SD) resting lower esophageal sphincter pressure was 15.0 +/- 9.4 mm Hg. Mean (+/- SD) distal esophageal amplitude was 69.4 +/- 39.2 mm Hg. INTERVENTION: During LNF, we obtained 2 to 3 cm of intra-abdominal esophagus, divided all short gastric vessels, reapproximated the crura, and performed a loose 360 degrees fundoplication without a bougie. MAIN OUTCOME MEASURES: Postoperative rates of dysphagia, gas bloat, and recurrent reflux. RESULTS: In the early postoperative period, 50 patients (49.0%) complained of mild, 11 (10.8%) of moderate, and 7 (6.9%) of severe dysphagia. Average (+/- SD) duration of early dysphagia was 4.6 +/- 2.1 weeks. Dysphagia resolved in 61 (89.7%) of 68 patients within 6 weeks. Late resolution of dysphagia was noted in 4 (5.8%) patients. Three patients were successfully treated with esophageal dilatations. Persistent dysphagia was found in 1 patient. Thirty patients (29.4%) had transient gas bloat. Mild persistent reflux, requiring daily medication, was noted in 5 (4.9%) patients. CONCLUSIONS: Performance of LNF without a bougie offers a safe and effective therapy for gastroesophageal reflux disease. While avoiding the potential risks for gastric and esophageal injury, it may provide low rates of long-term postoperative dysphagia and reflux recurrence.

Deglutition Disorders↗