Robotic gastrectomy and esophagogastrectomy: A single center experience of 105 cases.

BACKGROUND: A robotic approach to general surgery procedures may provide improved postoperative outcomes compared to either open or laparoscopic approaches. The role of robotics for gastroesophageal surgery, however, is still being evaluated. STUDY DESIGN: A review of the prospective database for robotic surgery at Valley Hospital between January 2002 and March 2014 identified 105 patients who underwent robotic gastric and esophageal resection. Patient demographics and perioperative factors were studied. RESULTS: Over a 12 years period, 105 patients underwent robotic gastroesophageal resection. The median operative time for distal gastrectomy (230 min [112-327]) was significantly less compared to either total gastrectomy (302 min [214-364]) or esophagogastrectomy (309 min [190-682]). The length of stay for patients undergoing distal gastrectomy (6 days [4-32]) was also significantly less than patients undergoing total gastrectomy (11 days [7-43]), as well as esophagogastrectomy (9 days [5-64]). In regard to the learning curve to perform robotic gastroesophageal surgery, there was a significant correlation between operative time and overall experience. CONCLUSIONS: This study demonstrated that robotic gastroesophageal surgery is feasible and can be safely performed. Assuming familiarity with the open procedures and acquisition of basic robotic skills, the learning curve for robotic gastroesophageal surgery requires approximately 20 cases.

A phase I trial of thermal sensitization using induced oxidative stress in the context of HIPEC.

BACKGROUND: Inducing oxidative stress under hyperthermic conditions significantly decreases tumor cell growth in a murine model of human colon cancer carcinomatosis. This phase I study examines the safety and pharmacokinetics of induced oxidative stress by the addition of hydrogen peroxide (H2O2) to the perfusate in patients undergoing cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced abdominal-only malignancies. METHODS: Patients with advanced colon or appendiceal malignancies underwent maximal cytoreduction followed by HIPEC with mitomycin C (MMC). In addition, H2O2 was added to the perfusate at three concentrations (n = 3/level, 0.05, 0.075, 0.1 %). A control group consisted of patients perfused with MMC alone (n = 3). Perfusate, serum MMC, and H2O2 levels were measured, as were tissue levels of MMC. RESULTS: Twelve patients were enrolled onto this trial. The median (range) peritoneal carcinomatosis index was 13 (3-20) requiring a median operative time of 6.3 (4-8.5) h. The median postoperative length of stay was 9 (5-34) days, with six patients requiring readmission within 30 days. Similar complications were observed at all three H2O2 levels, as well as in the control group. One patient required reexploration for a colon perforation (control group), and three patients developed enterocutaneous fistulas (0.075 % H2O2, 0.1 % H2O2 and control group). There were no operative mortalities. CONCLUSIONS: Hyperthermic intraperitoneal chemotherapy with induced oxidative stress after maximal cytoreduction is well tolerated. On the basis of the encouraging toxicity profile after cytoreduction and HIPEC with induced oxidative stress, a phase II trial to verify activity is indicated.

Periaortic pancreatic rests: a case report.

BACKGROUND: Ectopic pancreatic tissue is a rare congenital anomaly and usually presents along the gastrointestinal tract. If not recognized, it can be confused histologically with an adenocarcinoma. CASE: We report a case arising in periaortic adipose tissue, found incidentally in a woman undergoing periaortic lymphadenectomy for recurrent ovarian carcinoma. CONCLUSION: We found no other reports of this lesion in periaortic tissue. Clinicians and pathologists need to be aware of this entity, which may rarely be encountered.

Thermal sensitization using induced oxidative stress decreases tumor growth in an in vivo model of hyperthermic intraperitoneal perfusion.

BACKGROUND: The purpose of this study was to extend our in vitro observations that induced oxidative stress under hyperthermic conditions decreases tumor cell growth into a preclinical murine model of hyperthermic perfusion. METHODS: A nude mouse model of colon cancer carcinomatosis with HT-29-Luc-D6 colon cancer cells was established, and tumor growth was measured by serial bioluminescent imaging. RESULTS: By means of a survival model of hyperthermic perfusion, we demonstrated that perfusion with normothermic saline decreased tumor growth compared with no perfusion controls, and tumor growth was further decreased with hyperthermic perfusion alone. The induction of oxidative stress with hydrogen peroxide in the perfusate at concentrations as high as 600 microM was well tolerated in this model of hyperthermic perfusion. Importantly, induced oxidative stress using hydrogen peroxide under hyperthermic conditions significantly decreased in vivo tumor cell growth compared with all other controls. CONCLUSIONS: On the basis of our observations, thermal sensitization through modulation of cellular oxidative stress may represent a novel approach to increase the efficacy of hyperthermia as an anticancer modality.

Simultaneous bicavitary hyperthermic chemoperfusion in the management of pseudomyxoma peritonei with synchronous pleural extension.

Extra-abdominal spread of pseudomyxoma peritonei (PMP) is a rare event, but extension of the tumor beyond the abdomen into the pleural cavity has been reported. We report a case with synchronous pleural manifestation of PMP confirmed during abdominal cytoreductive surgery that was managed by simultaneous bicavitary hyperthermic chemoperfusion. To the best of our knowledge, this is the first report of bicavitary hyperthermic chemoperfusion for PMP. During the abdominal cytoreductive surgery in a patient with known history of PMP, extensive disease under the right hemidiaphragm was noted, requiring partial diaphragmatic resection. Once the pleural space was entered, separate mucinous deposits on the pleural surface of the diaphragm and lung surface were observed. The involved portion of the right hemidiaphragm and lung were resected. The diaphragmatic defect was left open during the hyperthermic chemoperfusion to treat both the pleural and peritoneal surfaces. The patient's postoperative course was uneventful. Simultaneous bicavitary hyperthermic chemoperfusion is a potential therapeutic option for patients with pleural extension identified during cytoreductive surgery.

Epigenetic alteration of p16INK4a gene in dedifferentiation of liposarcoma.

The atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDLPS) is a locally aggressive subtype of liposarcoma unless dedifferentiation occurs. The mechanism driving this progression is not clear. Loss of p16 is believed to be an early and critical event in tumor progression. Gene silencing by methylation of p16INK4a gene promoter has been reported in several soft tissue sarcomas. The aim of this study is to study the role of p16INK4a gene promoter methylation and p16 expression in tumor progression (dedifferentiation) and recurrence of ALT/WDLPS. Four cases of dedifferentiated liposarcomas (DDLPS) and three cases of recurrent well-differentiated liposarcomas (WDLPS) were collected, and methylation status of p16INK4a gene promoter was analyzed using methylation-specific PCR (MSP) on DNA extracted from paraffin blocks. p16 expression was examined by immunohistochemistry on the same blocks. Methylation of p16INK4a gene promoter was seen in the dedifferentiated (DD) components only, in two out of four (2/4, 50%) DDLPS. The other two DDLPS and three recurrent WDLPS were not methylated. Both WD and DD components in all four DDLPS cases showed strong nuclear p16 expression. All three recurrent WDLPS showed positive p16 expression with similar intensity between primary and recurrent tumors. Even though linear correlation between p16 promoter hypermethylation and p16 protein expression was not present, there appears to be a role for p16INK4a gene promoter hypermethylation in DDLPS and not in recurrent WDLPS.

Hyperthermia in combination with oxidative stress induces autophagic cell death in HT-29 colon cancer cells.

The purpose of this study was to evaluate the mechanism of ROS-induced hyperthermic cell death in a colon cancer cell line. HT-29 colon cancer cells were exposed to heat (43 degrees C) in the presence of tert-butyl hydroperoxide (t-BOOH). t-BOOH combined with hyperthermia significantly decreased cell viability as compared with t-BOOH or hyperthermia alone. This decrease in cell numbers was associated with retardation in the S phase transit and not through apoptosis. Cell death was noted to be accompanied by specific features characteristic of autophagy: the presence of cytoplasmic autophagic vacuoles; autophagosome membrane association of microtubule-associated protein light chain 3; accumulation of acidic vesicular organelles; and increased incorporation of MDC in the autophagosome. Thermal sensitization through modulation of cellular ROS may represent a novel approach to increase the efficacy of hyperthermia as an anticancer modality.

Phase I trial of pegylated liposomal doxorubicin with hyperthermic intraperitoneal chemotherapy in patients undergoing cytoreduction for advanced intra-abdominal malignancy.

BACKGROUND: Cytoreduction coupled with hyperthermic intraperitoneal chemotherapy (HIPEC) is an attractive treatment option for a select group of patients with abdominal-only malignancy. The present phase I study examined the safety and pharmacokinetics of intraperitoneal pegylated liposomal doxorubicin (PLD) used in the context of HIPEC in patients with advanced abdominal-only malignancies. METHODS: Patients with advanced abdominal malignancies underwent maximal cytoreduction and HIPEC with escalating doses of PLD (15-100 mg/m(2)). Perfusate, serum, and tissue doxorubicin levels were measured in five patients undergoing HIPEC at the maximum tolerated dose. RESULTS: Twenty-one patients were enrolled in this trial. The maximum dose evaluated in this trial was 100 mg/m(2) and was well tolerated. The most common grade 3/4 complications were superficial wound infection and prolonged ileus. One patient developed an anastomotic leak in the postoperative period, requiring re-exploration. The median postoperative length of stay was 7 days (range, 4-29 days), three patients required readmissions within 30 days, and there were no operative mortalities The median follow-up time for was 13.7 months (range, 3-38 months). The median overall survival was 30.6 months with a median disease-free survival of 25 months. CONCLUSIONS: We report that HIPEC with PLD following maximal cytoreduction in patients with advanced abdominal-only gastrointestinal or gynecologic malignancies is well tolerated. Encouraging survival after cytoreduction and HIPEC with PLD suggest that a phase II trial to verify activity is indicated.

Thermal sensitization through ROS modulation: a strategy to improve the efficacy of hyperthermic intraperitoneal chemotherapy.

BACKGROUND: The purpose of this study was to investigate whether modulation of cellular reactive oxygen species (ROS) provides a synergistic effect with hyperthermia to induce tumor cell death in a colon cancer cell line. MATERIALS AND METHODS: HT-29 colon cancer cells were exposed to heat (43 degrees C) in the presence of the ROS-generating drug, 2-2'-azobis-(2-amidinopropane) dihydrochloride (AAPH) for 1 h. Viable cell mass and apoptosis was measured by MTT and annexin V staining, respectively. Oxidative stress was evaluated by DCFH fluorescence. Protein levels were determined by Western blot analysis. RESULTS: A synergistic effect on cell viability with AAPH was noted under hyperthermic conditions as compared with hyperthermia alone (P < .05). The number of nonviable cells after hyperthermia and AAPH exposure was also significantly increased compared with AAPH at 37 degrees C (42% vs 20%, P < .05). ROS levels were increased modestly with AAPH at 37 degrees C, whereas they increased significantly in a dose-dependent manner with AAPH at 43 degrees C. Transient increases of phosphorylated-p38 and ERK and decreases in phosphorylated-AKT were observed in the cells exposed to AAPH at 43 degrees C. Pretreatment of inhibitors of p38 yielded additional decreases in cell mass when used in combination with AAPH and hyperthermia (P < .05). Increased expression of HSP 27 observed at 43 degrees C was abrogated with AAPH exposure. CONCLUSIONS: Oxidative stress increased the cytotoxic effects of hyperthermia in colon cancer cells. Thermal sensitization through modulation of cellular ROS may represent a novel approach to increase the efficacy of hyperthermia as an anticancer modality.

Proteasome inhibition potentiates the cytotoxic effects of hyperthermia in HT-29 colon cancer cells through inhibition of heat shock protein 27.

BACKGROUND: The purpose of this study was to investigate whether proteasome inhibition acts as a thermal sensitizing agent to induce tumor cell death in a colon cancer cell line. METHODS: HT-29 colon cancer cells were exposed to hyperthermia (43 degrees C) in the presence of proteasome inhibition for 1 h. Viable cell mass and apoptosis were measured by MTT and annexin V staining, respectively. Protein levels were determined by Western blot analysis. RESULTS: A significant synergistic effect on cell viability with proteasome inhibition was noted under hyperthermic conditions compared to hyperthermia alone (p < 0.05). Increases in phosphorylated ERK and decreases in HSP27 levels were observed in the cells exposed to proteasome inhibition at 43 degrees C. Pretreatment with an inhibitor of ERK yielded an additional increase in apoptosis when used in combination with proteasome inhibition and hyperthermia. Decreased expression of HSP27 by siRNA also resulted in increased thermally induced apoptotic cell death. CONCLUSIONS: Thermal sensitization through proteasome inhibition may represent a novel approach to increase the efficacy of hyperthermia as an anticancer modality.

CDK5 is a novel regulatory protein in PPARgamma ligand-induced antiproliferation.

Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclin-dependent kinase family and has been studied mainly in the differentiation of post-mitotic neurons. The purpose of this study was to determine the presence of cdk5 expression and activity in colon cancer cells and to investigate its role in the regulation of PPARgamma ligand-induced antiproliferation. We observed that cdk5 protein levels and kinase activity were elevated in both HT-29 cells and human tumor tissue in comparison to decreased levels in normal colonic mucosa. To elucidate cdk5's role in PPARgamma ligand-induced antiproliferation of colon cancer cells, HT-29 cells were treated with ciglitazone. A dose- and time-dependent decrease in cell proliferation were observed after ciglitazone exposure, which correlated with a decrease in cdk5 protein expression and kinase activity. Importantly, these ciglitazone-induced antiproliferative changes were reversed when cdk5 was overexpressed. Although present, p35, the regulatory protein of cdk5, showed no significant changes in protein expression with the introduction of ciglitazone. This is the first report of cdk5/p35 expression and kinase activity in colon cancer cells, which is associated with ciglitazone-induced antiproliferation in HT-29 cells.

Ciglitazone-induced p27 gene transcriptional activity is mediated through Sp1 and is negatively regulated by the MAPK signaling pathway.

We have previously demonstrated that the PPARgamma ligand, ciglitazone, increases p27kip1 protein levels in HT-29 colon cancer cells through both inhibition of proteasome associated degradation and activation of transcriptional activity. [F. Chen, L.E. Harrison, Cell Signal. 17 (2005) 809] The purpose of this investigation was to further elucidate the mechanism of ciglitazone-induced activation of p27 gene transcription. We observed that the region -774/-462 of the p27 promoter plays a key role in ciglitazone-induced gene transcriptional activity and this region contains two Sp1 binding sites. When the p27PF-luc reporter was co-transfected with Sp1 expression plasmids, ciglitazone-induced p27PF-luc activity significantly increased, while mithramycin A, a Sp1 inhibitor, was able to abrogate its effects. Ciglitazone exposure increased both Sp1 protein expression and Sp1-DNA binding, which was also associated with a decrease of Erk1/2 phosphorylation. A similar increase of Sp1-DNA binding was observed when phosphorylation of Erk1/2 was inhibited by pretreatment with the MAP kinase inhibitor, U0126. In addition, a significant increase of p27PF-luc reporter luciferase activity was noted after MAP kinase inhibition, which could be abolished with co-treatment with mithramycin A. Based on these data, we postulate that ciglitazone induces p27 gene transcription through increased Sp1 binding to its promoter region, which in turn is mediated through increased Sp1 protein levels and decreased inhibitory regulation by the MAP kinase pathway.

Hepatitis status, child-pugh classification, and serum AFP levels predict survival in patients treated with transarterial embolization for unresectable hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents one of the most prevalent cancers worldwide. Most patients are not surgical candidates, and transarterial embolization (TAE) has been used to treat patients with unresectable HCC. The purpose of this study was to identify factors that predict survival in patients treated with TAE at a Western medical center. Review of a prospective database identified 345 patients treated for HCC at University Hospital (Newark, NJ) between July 1998 and July 2004. Of these patients, 109 patients underwent TAE. Eleven of these patients were subsequently treated surgically and excluded from this study. Of the remaining 98 patients, demographic data and laboratory values were analyzed to predict survival by univariate and multivariate analysis. Several factors, including hepatitis status, Child-Pugh classification, serum alpha fetoprotein levels <500 ng/ml, bilirubin <2.0 mg/dl, prothrombin time <16 seconds, platelet count <200 x 10(9)/l, albumin >3.5 gm/dl, and multiple treatments, predicted survival by univariate analysis. Serum alpha fetoprotein levels, Child-Pugh classification, and hepatitis status were found by multivariate analysis to independently predict survival. These factors may help to select patients with unresectable HCC who might benefit from TAE.

Cytoreductive surgery and intraoperative hyperthermic chemoperfusion for advanced ovarian carcinoma.

BACKGROUND: Optimal cytoreductive surgery combined with intraoperative hyperthermic chemoperfusion (IHCP) is a therapy that potentially could improve survival in a select group of patients with advanced ovarian cancer. The purpose of this study was to review the results of cytoreductive surgery and IHCP for advanced ovarian cancer and to identify factors that may predict which patients maximally benefit from this aggressive treatment. METHODS: Patients treated with cytoreduction followed by IHCP for ovarian cancer were identified from an IHCP database from 1/2001 through 3/2004. Several factors including resection status, peritoneal cancer index (PCI), and prior surgery were evaluated for their ability to predict survival in our cohort of patients. RESULTS: Thirteen patients with ovarian cancer treated with cytoreductive surgery followed by IHCP were identified. The 3-year overall survival rate for all thirteen patients was 55%. The median disease-free survival was 15.4 months (3-year disease-free survival, 11%). Several factors including PCI score (<6), ability to resect all gross disease, and previous surgical exploration appeared to impart an overall survival advantage. CONCLUSIONS: The use of IHCP coupled with optimal cytoreduction is a safe and effective treatment for advanced ovarian carcinoma. However, the proper selection of patients who will benefit most from the therapy is essential for the success of the treatment.

Ciglitazone-induced cellular anti-proliferation increases p27kip1 protein levels through both increased transcriptional activity and inhibition of proteasome degradation.

While it is well established that PPARgamma ligands inhibit cell growth and induce apoptosis in colon cancer cells, the mechanism of these effects of PPARgamma ligands is unclear. In this report, we demonstrate that the PPARgamma ligand, ciglitazone, exhibits an anti-proliferative effect and blocks G1/S cell cycle progression through regulation of p27kip1 protein levels and inhibition of Cdk2 activity in HT-29 colon cancer cells. The ciglitazone-induced G1/S cell cycle arrest was noted only after 72 h of exposure, corresponding to elevated protein levels of p27kip1. However, an increase in p27kip1 protein synthesis as evidenced by increased p27kip1 gene promoter activity and mRNA abundance was observed as early as 24 h after exposure to ciglitazone. Proteasome activity, an additional mechanism of p27kip1 regulation, was dramatically inhibited after ciglitazone exposure, but only after 72 h of exposure. We also note that the effects of ciglitazone on p27kip1 gene regulation are PPRE independent. These data suggest that ciglitazone-induced G1/S arrest is through Cdk2 inhibition and an increase of p27kip1 protein levels which in turn is due a balance of ciglitazone's affect on new protein synthesis and degradation.

Partial hepatectomy for metastases from noncolorectal, nonneuroendocrine carcinoma.

OBJECTIVE: To define perioperative and long-term outcome and prognostic factors in patients undergoing hepatectomy for liver metastases arising from noncolorectal and nonneuroendocrine (NCNN) carcinoma. SUMMARY BACKGROUND DATA: Hepatic resection is a well-established therapy for patients with liver metastases from colorectal or neuroendocrine carcinoma. However, for patients with liver metastases from other carcinomas, the value of resection is incompletely defined and still debated. METHODS: Between April 1981 and April 2002, 141 patients underwent hepatic resection for liver metastases from NCNN carcinoma. Patient demographics, tumor characteristics, treatment, and postoperative outcome were analyzed. RESULTS: Thirty-day postoperative mortality was 0% and 46 of 141 (33%) patients developed postoperative complications. The median follow up was 26 months (interquartile range [IQR]) 10-49 months); the median follow up for survivors was 35 months (IQR 11-68 months). There have been 24 actual 5-year survivors so far. The actuarial 3-year relapse-free survival rate was 30% (95% confidence interval [CI], 21-39%) with a median of 17 months. The actuarial 3-year cancer-specific survival rate was 57% (95% CI, 48-67%) with a median of 42 months. Primary tumor type and length of disease-free interval from the primary tumor were significant independent prognostic factors for relapse-free and cancer-specific survival. Margin status was significant for cancer-specific survival and showed a strong trend for relapse-free survival. CONCLUSIONS: Hepatic resection for metastases from NCNN carcinoma is safe and can offer long-term survival in selected patients. Hepatic resection should be considered if all gross disease can be removed, especially in patients with metastases from reproductive tract tumors or a disease-free interval greater than 2 years.

Ciglitazone induces early cellular proliferation and NF-kappaB transcriptional activity in colon cancer cells through p65 phosphorylation.

While it is well established that peroxisome proliferator activated receptor gamma (PPARgamma) ligands inhibit cell growth and induce apoptosis of colon cancer cells with a prolonged treatment (3-5 days), the early effects of PPARgamma exposure are less clear. In this report, we demonstrate that the PPARgamma ligand, ciglitazone, induces proliferation of HT-29 and Caco-2 colon cancer cells transiently (<48 h) prior to a decrease in cell proliferation (>72 h). Associated with this cellular proliferation phase, we observed an increase in NF-kappaB transcriptional activity. Ciglitazone exposure did not affect NF-kappaB DNA binding but rather, increased phosphorylation of p65 as well as the recruitment of the co-activator CBP. Pre-treatment of HT-29 cells with wortmannin, a phosphatidylinositol 3-kinase (PI3K) kinase inhibitor, inhibited ciglitazone-induced p65 phosphorylation, NF-kappaB transcriptional activity and cell proliferation. Interestingly, ciglitazone inhibited PPAR transcriptional activity, suggesting this early proliferative effect is PPRE independent. These data suggest that the early proliferative phase of PPARgamma ligand exposure is associated with activation of NF-kappaB by p65 phosphorylation and cofactor recruitment and not through increased DNA binding.

Racial discrepancies in the outcome of patients with hepatocellular carcinoma.

HYPOTHESIS: There is a marked variation in the outcome of patients with hepatocellular carcinoma with respect to race and ethnicity. Rates among African American and Hispanic individuals are elevated as compared with those among white individuals. DESIGN: Retrospective review of a prospective database. Demographic information, clinical staging, and other defining factors, including the absence or presence of hepatitis, cirrhosis, and alcohol abuse, were analyzed by patient interviews and review of the medical record. SETTING: Urban tertiary referral teaching hospital. PATIENTS: Patients diagnosed as having hepatocellular carcinoma between July 1997 and June 2003 (N = 264). Main Outcome Measure Overall survival rates. RESULTS: Based on multivariate analysis, race was identified as an independent predictor of survival. While there was no difference in the distribution of patient or tumor characteristics between the 2 groups, African American/Hispanic patients had a 5-year survival rate of 12%, which was significantly lower than that of white patients (50%; P = .001). CONCLUSIONS: This study demonstrates a significant discrepancy in overall survival of African American/Hispanic patients as compared with that of white patients. The reason for this difference cannot be explained by patient or tumor characteristics or completely by treatment allocation. These data suggest that there may be socioeconomic, biological, and/or cultural determinants contributing to this observed difference in outcome.