Pictilisib-Induced Resistance Is Mediated through FOXO1-Dependent Activation of Receptor Tyrosine Kinases in Mucinous Colorectal Adenocarcinoma Cells.

The phosphatidylinositol (PI3K)/AKT/mTOR axis represents an important therapeutic target to treat human cancers. A well-described downstream target of the PI3K pathway is the forkhead box O (FOXO) transcription factor family. FOXOs have been implicated in many cellular responses, including drug-induced resistance in cancer cells. However, FOXO-dependent acute phase resistance mediated by pictilisib, a potent small molecule PI3K inhibitor (PI3Ki), has not been studied. Here, we report that pictilisib-induced adaptive resistance is regulated by the FOXO-dependent rebound activity of receptor tyrosine kinases (RTKs) in mucinous colorectal adenocarcinoma (MCA) cells. The resistance mediated by PI3K inhibition involves the nuclear localization of FOXO and the altered expression of RTKs, including ErbB2, ErbB3, EphA7, EphA10, IR, and IGF-R1 in MCA cells. Further, in the presence of FOXO siRNA, the pictilisib-induced feedback activation of RTK regulators (pERK and pAKT) was altered in MCA cells. Interestingly, the combinational treatment of pictilisib (Pi3Ki) and FOXO1i (AS1842856) synergistically reduced MCA cell viability and increased apoptosis. These results demonstrate that pictilisib used as a single agent induces acute resistance, partly through FOXO1 inhibition. Therefore, overcoming PI3Ki single-agent adaptive resistance by rational design of FOXO1 and PI3K inhibitor combinations could significantly enhance the therapeutic efficacy of PI3K-targeting drugs in MCA cells.

Gastrointestinal Cancers With Peritoneal Carcinomatosis: Surgery and Hyperthermic Intraperitoneal Chemotherapy.

This review focuses on the underlying rationale for the use of cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CS+HIPEC) in the treatment of patients with primary gastrointestinal tumors with metastatic peritoneal disease. It examines the advantages of CS+HIPEC in peritoneal cancers and explores the controversies surrounding this treatment. For low-grade cancers, such as pseudomyxoma peritonei, CS+HIPEC is standard of care. However, for more aggressive tumors, such as gastric cancers, the results with this approach are not as encouraging and patient selection is very important. Generally, the cost of HIPEC is not prohibitive and increases the cost of surgery by only a small percentage. Overall, the consensus is that HIPEC is probably beneficial for less aggressive cancers. We believe that CS+HIPEC should be standard of care for appendiceal and colorectal cancers with peritoneal disease. For other cancers, such as gastric, pancreatic, or small bowel cancers, further study is warranted.

Determinants of outcomes in pancreatic surgery and use of hospital resources.

BACKGROUND AND OBJECTIVES: Outcomes for patients undergoing major pancreatic surgery have improved, but a subset of patients that significantly utilize more resources exists. Variables that can lead to an increase in resource utilization in patients undergoing pancreatic surgery were identified. METHODS: Patients undergoing pancreatic surgery for neoplasms were identified from the NSQIP database (2006-2008). Indices associated with increased resource utilization that we included were operative time (OT), length of stay (LOS), intraoperative RBC transfusion, return to operating room, and occurrence of postoperative complications. Analysis of covariance and multivariable logistic regression were performed. RESULTS: The 4,306 included patients had a median age of 66 years and 50.3% were males. The 30-day morbidity and mortality were 29.3% and 3.2%, respectively. Median OT was 362 min and median LOS was 10 days. Malignancy, neoadjuvant radiation, and medical co-morbidities were associated with increased OT (P < 0.0001 for all). Declining preoperative functional status was the most important predictor of LOS (P < 0.0001). Age, male gender, hypertension, severe COPD, and higher BMI were significantly associated with postoperative complications (P < 0.050 for all). CONCLUSIONS: Morbidity after pancreatic surgery remains high. Age, obesity, performance status, medical co-morbidities, and neoadjuvant radiation affect outcomes and may lead to increased use of hospital resources.

Hyperthermic intraperitoneal chemotherapy in ovarian cancer: first report of the HYPER-O registry.

INTRODUCTION: An analysis of experience of surgical and gynecologic oncologists in the United States with the use of hyperthermic intraperitoneal chemotherapy for women with invasive epithelial ovarian cancer (EOC). METHODS: An Internet-based registry (HYPER-O) collected data from collaborating institutions. Eligibility included women with EOC treated with hyperthermic intraperitoneal chemotherapy. Borderline and nonepithelial cancers were excluded. RESULTS: As of July 1, 2008, 141 women were eligible for analysis treated at the following time points: frontline (n = 26), interval debulking (n = 19), consolidation (n = 12), and recurrence (n = 83). The mean perfusion temperatures were 38.5 to 43.6 degrees C (median, 41.9 degrees C) for inflow and 36.9 to 42.9 degrees C (median, 41 degrees C) for outflow for 30 to 120 minutes. Treatment was with a platinum agent (n = 72), mitomycin (n = 53), or a combination (n = 14). Median follow-up was 18 months (range, 0.3-140.5 months) and median overall survival 30.3 months (95% confidence interval, 23.0-37.6) with 2-, 5-, and 10-year overall survival probabilities of 49.1%, 25.4%, and 14.3%, respectively. Of the 141 patients, 110 (78%) experienced recurrence of ovarian cancer and 87 died, 3 (0.5%) dying within 30 days of surgery. In the multivariable analysis, the factors significant for increased survival were sensitivity to platinum response (P = 0.048), completeness of cytoreduction scores of 1 or 0 (P = 0.025), carboplatin alone or a combination of 2 or more chemotherapy agents used (P = 0.011), and duration of hospital stays of 10 days or less (P = 0.021). CONCLUSIONS: Hyperthermic intraperitoneal chemotherapy is a viable additional treatment option for patients with invasive EOC and may extend life in selected groups. It warrants further study in randomized controlled trials.

Clinical implications of novel activating EGFR mutations in malignant peritoneal mesothelioma.

BACKGROUND: There is a paucity of information about the molecular perturbations involved in MPM tumor formation. We previously reported that EGFR-TK mutations in MPM were predictive of achieving optimal surgical cytoreduction, but the status of EGFR pathway activation potential of these mutations was not known. Here we present the mutant EGFR activating potential and the matured survival data of the EGFR mutant(mut+) relative to wild type EGFR(mut-) mesothelioma. METHODS: Twenty-nine patients were evaluated and their tumors were probed for mutations in the catalytic TK-domain. Twenty-five patients were treated with cytoreductive surgery and complete clinical data was available for comparison of the mut+ and mut- groups. A COS-7 cell expression model was used to determine mutation activating profiles and response to erlotinib. RESULTS: Functional mutations were found in 31%(9/29) of patients; 7 of these mutations were novel and another was the L858R mutation. All missense mutations were found to be activating mutations and responsive to erlotinib. Of the 25 patients managed surgically, there were 7 mut+ and 18 mut-. Two of 7 (29%) mut+ developed progressive disease and died with a median follow-up time of 22 months; while 13/18 (72%) mut- developed progressive disease and 10/18 (56%) died with median TTP of 12 months and median survival of 14 months. CONCLUSIONS: The novel EGFR mutations identified are activating mutations responsive to erlotinib. The mut+ subset have a 'relative' improved outcome. Erlotinib may have a role in MPM and exploration for mutations in a larger patient cohort is warranted.

Cytoreduction with hyperthermic intra peritoneal and intra thoracic chemotherapy for metastatic Sertoli-Leydig cell tumor of the ovary.

Sertoli Leydig cell tumor (SLCT) is a rare sex-cord stromal tumor of the ovary that generally has a benign course. Here, we report an unusual case of recurrent, metastatic SLCT and its unique management with a combination of cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, hyperthermic intrathoracic chemotherapy, and systemic chemotherapy.

Novel and existing mutations in the tyrosine kinase domain of the epidermal growth factor receptor are predictors of optimal resectability in malignant peritoneal mesothelioma.

Malignant peritoneal mesotheliomas (MPM) are rare tumors representing 20% of all malignant mesothelioma cases. The median survival for these tumors is less than a year, and like other peritoneal surface malignancies, this is due primarily to intra-abdominal recurrence and progression. Currently there is a paucity of information about the biology of these tumors and molecular perturbations that are involved in tumor formation. Elucidation of mutations and biological pathways active in these tumors may identify valuable prognostic markers, as well as facilitate the development of novel therapies. In this study, we investigate the predictive value of epidermal growth factor receptor (EGFR) mutations in achieving optimal resectability. Twenty-nine patients with MPM were evaluated at a single tertiary care center and their tumors were probed for point mutations in the catalytic TK domain of epidermal growth factor receptor (mut+). All specimens were examined for somatic mutations by polymerase chain reaction amplification, and all variants were confirmed by multiple independent amplifications. Twenty-five patients were treated with cytoreductive surgery with or without intraperitoneal hyperthermic chemotherapy and complete clinical data including age, sex, cytoreductive score, mutation, and survival were available for comparison of the mut+ and mut- groups. The median age was 56 years, 71% of the patients were male, and the median follow-up time was 14.5 months. Mutations were found in 31% (9 of 29) of the tumors. Seven of these mutations were novel, and one was the L858R mutation described in non-small-cell lung cancer. Of the 25 patients managed surgically, 7 had mut+ and 18 wild type (mut-) disease. Optimal resectability was achieved in 7 (100%) of 7 of mut+ group and 9 (50%) of 18 mut- (p = .026). All mut+ patients are alive with a mean follow-up time of 24 months, whereas 5 (28%) of 18 of the mut- group are dead of disease with a mean follow-up time of 7 months (p = .27). In an analysis of covariance model, only optimal resectability (p = .04) was found to be predictive of survival. EGFR-TK seems to be a common site for mutation in MPM, with mutations being identified in 31% of patients. The EGFR mutations identified included the L858R activating mutation, as well as eight novel EGFR-TK catalytic domain point mutations. These mutations were predictive of optimal resectability, which was the only variable found to be predictive of survival. With longer follow-up, mut+ may not only be predictive of survival but may represent a subset of patients whose disease may be responsive to TK-inhibitor therapy. Experiments confirming the activating properties of the novel mutations are warranted.

Peritoneal surface disease from colorectal cancer: comparison with the hepatic metastases surgical paradigm in optimally resected patients.

BACKGROUND: Surgical resection is the treatment of choice for colorectal hepatic metastases (HM). In contrast, metastatic disease to the peritoneum is treated with systemic therapy. We examined our experience with cytoreductive surgery (CS) and intraperitoneal hyperthermic chemotherapy (IPHC) for peritoneal surface disease (PSD) compared with liver resection for HM. METHODS: A review of prospective databases of colorectal cancer patients undergoing surgery for metastatic disease to the peritoneum or liver (1992-2005) was carried out. RESULTS: One hundred and twenty-one patients underwent CS + IPHC and 101 patients underwent hepatic resection with median follow-up of 86 and 56 months, respectively. Fifty-five (45%) patients in the IPHC group had complete resection of all gross tumor. Ninety-five (94%) of the HM patients had negative surgical margins. Comparison of the R0/R1 PSD and margin-negative HM group demonstrated significant differences in age, performance status, and preoperative chemotherapy. The 1-, 3-, and 5-year overall survival for the R0/R1 PSD patients was 91, 48, and 26%; while it was 87, 59, and 34% for the HM patients (P = 0.32). Perioperative morbidity was 42% versus 34% (P = 0.38) and mortality was 5.5% versus 4.2% (P = 0.71) between the PSD and HM patients, respectively. CONCLUSION: R0/R1 resection during CS + IPHC compared with margin-negative hepatic resection demonstrated no significant difference in overall survival and for select patients should be considered a viable treatment option. Further studies to improve the resectability of PSD patients and define the role of neoadjuvant and adjuvant drug strategies are needed.

Low grade peritoneal mucinous carcinomatosis associated with human papilloma virus infection: case report.

Pseudomyxoma peritonei is a clinical syndrome characterized by peritoneal dissemination of a mucinous tumor with mucinous ascites. The vast majority of the pseudomyxoma peritonei are associated with mucinous neoplasms of the appendix. We describe a case of pseudomyxoma peritonei associated with mucinous adenocarcinoma of the cervix in a 60-year-old woman. The patient developed low grade mucinous peritoneal carcinomatosis 8 years after hysterectomy for cervical adenocarcinoma. No other primary mucinous tumor was identified and peritoneal carcinomatosis tested positive for high-risk human papilloma virus (HPV), showing both integrated and episomal pattern. HPV has been previously associated with development of cervical carcinomas (both squamous and mucinous) but neither has cervical adenocarcinoma nor HPV been implicated in development of pseudomyxoma peritonei. To the best of our knowledge, this is the first description of HPV-associated malignancy presenting as pseudomyxoma peritonei.

Bilateral blockade of MEK- and PI3K-mediated pathways downstream of mutant KRAS as a treatment approach for peritoneal mucinous malignancies.

Mucinous colorectal adenocarcinomas (MCAs) are clinically and morphologically distinct from nonmucinous colorectal cancers (CRCs), show a distinct spectrum of genetic alterations (higher KRAS mutations, lower p53, high MUC2), exhibit more aggressive behavior (more prone to peritoneal dissemination and lymph node involvement) and are associated with poorer response to chemotherapy with limited treatment options. Here, we report the effectiveness of combinatorial targeting of two KRAS-mediated parallel pathways in reducing MUC2 production and mucinous tumor growth in vitro and in vivo. By knockdown of mutant KRAS we show that, mutant KRAS (a) is necessary for MUC2 production in vitro and (b) synergistically engages PI3K/AKT and MEK/ERK pathways to maintain MUC2 expression in MCA cells. These results define a novel and a previously undescribed role for oncogenic KRAS in mucinous cancers. MCA cells were sensitive to MEK inhibition suggesting cellular dependence ('addiction') of KRAS-mutant MCA cells on hyperactivation of the MEK-driven pathway. Interestingly, MCA cells, though initially sensitive, were later resistant to PI3K single agent inhibition. Our studies suggest that this resistance involves dynamic rewiring of signaling circuits mediated through relief of RTK inhibition and MEK-ERK rebound activation. This resistance however, could be overcome by co-targeting of PI3K and MEK. Our studies thus provide a rational basis for MEK- and PI3K-targeted combination therapy for not only KRAS mutant MCA but also for other related mucinous neoplasms that overproduce MUC2 and have a high rate of KRAS mutations such as pseudomyxoma peritonei.

Patient-derived xenograft mouse models of pseudomyxoma peritonei recapitulate the human inflammatory tumor microenvironment.

Pseudomyxoma peritonei (PMP) is a neoplastic syndrome characterized by peritoneal tumor implants with copious mucinous ascites. The standard of care for PMP patients is aggressive cytoreductive surgery performed in conjunction with heated intraperitoneal chemotherapy. Not all patients are candidates for these procedures and a majority of the patients will have recurrent disease. In addition to secreted mucin, inflammation and fibrosis are central to PMP pathogenesis but the molecular processes that regulate tumor-stromal interactions within the peritoneal tumor microenvironment remain largely unknown. This knowledge is critical not only to elucidate PMP pathobiology but also to identify novel targets for therapy. Here, we report the generation of patient-derived xenograft (PDX) mouse models for PMP and assess the ability of these models to replicate the inflammatory peritoneal microenvironment of human PMP patients. PDX mouse models of low- and high-grade PMP were generated and were of a similar histopathology as human PMP. Cytokines previously shown to be elevated in human PMP were also elevated in PDX ascites. Significant differences in IL-6 and IL-8/KC/MIP2 were seen between human and PDX ascites. Interestingly, these cytokines were mostly secreted by mouse-derived, tumor-associated stromal cells rather than by human-derived PMP tumor cells. Our data suggest that the PMP PDX mouse models are especially suited to the study of tumor-stromal interactions that regulate the peritoneal inflammatory environment in PMP as the tumor and stromal cells in these mouse models are of human and murine origins, respectively. These mouse models are therefore, likely to be useful in vivo surrogates for testing and developing novel therapeutic treatment interventions for PMP.

Caveolin-1 down-regulation activates estrogen receptor alpha expression and leads to 17beta-estradiol-stimulated mammary tumorigenesis.

Constitutive activation of estrogen receptor alpha (ER-alpha) expression is an early event in breast cancer tumorigenesis. However, the mechanism whereby ER-alpha is constitutively activated during transformation of normal mammary cells has not been well established. Previously, we reported that haploinsufficiency of caveolin-1, a major structural protein that forms caveolae, resulted in anchorage-independent growth of a normal mammary epithelial cell line, MCF10A. Here, we further demonstrated that ER-alpha but not ER-beta expression was constitutively activated in these caveolin-1 haploinsufficient cells. Transient treatment of MCF10A cells with beta-methyl-cyclodextrin, a chemical that can displace caveolin-1 from the plasma membrane, also stimulated ER-alpha expression. We further found that the 17beta-estradiol (E2) accelerated anchorage-independent growth of these cells in vitro and promoted their tumorigenesis in nude mice. These results suggest that dysregulation of caveolin-1 is one of the mechanisms by which ER-alpha expression is activated during initiation of breast tumorigenesis.

Clinical significance of a NAD(P)H: quinone oxidoreductase 1 polymorphism in patients with disseminated peritoneal cancer receiving intraperitoneal hyperthermic chemotherapy with mitomycin C.

Recent data indicate that NAD(P)H: quinone oxidoreductase 1 (NQO1) is important in the activation of mitomycin C. A polymorphism in human NQO1 (609C>T) is associated with diminished NQO1 activity. The purpose of our study was to determine the effect of the 609C>T polymorphism on tumor NQO1 activity and overall survival in patients with disseminated peritoneal cancer receiving intraperitoneal mitomycin C therapy. Patients with disseminated peritoneal cancer of gastrointestinal or other origin were eligible. Following aggressive surgical debulking, patients were administered a 2-h heated (40.5 degrees C) intraperitoneal perfusion with mitomycin C. NQO1 activity was determined in tumor tissue obtained during surgery and patients were genotyped for the NQO1 C609T polymorphism using a polymerase chain reaction-based method. The major response variable monitored during the trial was overall survival. Of the 117 patients genotyped for the NQO1 609C>T polymorphism, 67% were wild-type (WT), 31% were heterozygous (HE), and 2% were homozygous mutant (HM). In tumor tissue, the mean NQO1 activities from WT (n = 14) and HE (n = 5) patients were 794 +/- 603 and 70 +/- 133.1 nmol/min/mg protein respectively (P = 0.006). Significant differences in survival between WT versus HE/HM genotypes were noted in optimally debulked patients (R0/R1) (43.6+ months, median not yet reached versus 23 months respectively, P = 0.037) and in patients with peritoneal carcinomatosis of colonic origin (18.2 versus 11.5 months respectively, P = 0.050). These data indicate that the NQO1 609C>T polymorphism results in significantly reduced tumor NQO1 activity and reduced survival in subsets of patients receiving intraperitoneal hyperthermic mitomycin C therapy.

The roles of sex steroid receptor coregulators in cancer.

Sex steroid hormones, estrogen, progesterone and androgen, play pivotal roles in sex differentiation and development, and in reproductive functions and sexual behavior. Studies have shown that sex steroid hormones are the key regulators in the development and progression of endocrine-related cancers, especially the cancers of the reproductive tissues. The actions of estrogen, progesterone and androgen are mediated through their cognate intracellular receptor proteins, the estrogen receptors (ER), the progesterone receptors (PR) and the androgen receptor (AR), respectively. These receptors are members of the nuclear receptor (NR) superfamily, which function as transcription factors that regulate their target gene expression. Proper functioning of these steroid receptors maintains the normal responsiveness of the target tissues to the stimulations of the steroid hormones. This permits the normal development and function of reproductive tissues. It can be inferred that factors influencing the expression or function of steroid receptors will interfere with the normal development and function of the target tissues, and may induce pathological conditions, including cancers. In addition to the direct contact with the basal transcription machinery, nuclear receptors enhance or suppress transcription by recruiting an array of coactivators and corepressors, collectively named coregulators. Therefore, the mutation or aberrant expression of sex steroid receptor coregulators will affect the normal function of the sex steroid receptors and hence may participate in the development and progression of the cancers.

Factors predicting survival after intraperitoneal hyperthermic chemotherapy with mitomycin C after cytoreductive surgery for patients with peritoneal carcinomatosis.

HYPOTHESIS: Certain clinicopathologic factors predict improved survival after cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis. DESIGN: Prospective clinical trial. SETTING: Surgical oncology service at a university academic hospital. PATIENTS: A population of 109 consecutive patients with peritoneal carcinomatosis treated between December 1991 and November 1997. INTERVENTION: All patients underwent resection of gross disease followed by 2-hour intraoperative perfusion of mitomycin C (20-40 mg) into the peritoneal cavity at a temperature of 40.5 degrees C. MAIN OUTCOME MEASURES: Clinicopathologic factors that independently predicted improved overall survival rates. RESULTS: Overall survival at 1 and 3 years was 61% and 33%, respectively. With median follow-up of 52 months, median overall survival was 16 months. Four factors were significant independent predictors of improved survival by multivariate analysis: nonadenocarcinoma histologic features (P =.001), the appendix as a primary site (P =.003), the absence of hepatic parenchymal metastases (P =.01), and complete resection of all gross disease (R1/0 resection) (P<.001). Patients with an R1/0 resection vs an incomplete resection of gross disease (R2 resection) had 3-year overall survival of 68% vs 21% (P<.001). CONCLUSIONS: Patients with peritoneal carcinomatosis have a uniformly poor prognosis. However, in select patients, the natural history of this disease condition may be altered by using the multimodality approach of cytoreductive surgery and intraperitoneal hyperthermic chemotherapy. These results require confirmation in prospective randomized studies.

Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for advanced gastric cancer.

Peritoneal carcinomatosis is a common and universally fatal sequelae of gastric carcinoma. Treatment of peritoneal carcinomatosis from appendiceal and colorectal sources with intraperitoneal hyperthermic chemotherapy (IPHC) combined with aggressive cytoreductive surgery has been shown to be effective. There are few data on this treatment modality for carcinoma of the stomach. This study evaluates cytoreductive surgery and IPHC with peritoneal carcinomatosis from gastric carcinoma. Thirty-four patients with peritoneal carcinomatosis due to gastric carcinoma underwent gastric resection with cytoreductive surgery followed by IPHC with mitomycin C. A control group consisting of 40 contemporaneous patients, who underwent radical gastrectomy without extended nodal resection, was identified through the tumor registry. Despite more advanced disease in the IPHC group compared to the control group (P < 0.001), overall survival in the two groups was similar. Proportional-hazards regression analysis shows that only resection status is significantly correlated with improved survival (P=0.0068). Within the IPHC group, patients who underwent an R0/R1 resection had increased survival times (11.2 vs. 3.3 months, P=0.015) vs. those who underwent R2 resection. The group who had an R0/R1 resection had 1- and 2-year survival rates of 45% and 45% compared to 16% and 8%, respectively, in the R2 group. Cytoreductive surgery and IPHC is a modality with limited potential for the treatment of peritoneal carcinomatosis from gastric carcinoma. Careful patient selection for this procedure is imperative, and patients in whom an R0/R1 resection can be achieved are the best candidates.

Inducible expression of RbAp46 activates c-Jun NH2-terminal kinase-dependent apoptosis and suppresses progressive growth of tumor xenografts in nude mice.

BACKGROUND: The retinoblastoma (Rb) suppressor-associated protein 46 (RbAp46) is a member of the WD-repeat protein family and a component of histone modifying and remodeling complexes. Previously, we demonstrated that RbAp46 inhibits cell growth and suppresses the transformed phenotypes of tumor cell lines. MATERIALS AND METHODS: We established a tetracycline-inducible RbAp46 expression system in Saos-2 cells to test the effects of RbAp46 induction on cell growth in vitro and on tumor formation in vivo. RESULTS: We found that inducible expression of RbAp46 activated the c-Jun N-terminal kinase (JNK) signaling pathway and triggered apoptosis in Saos-2 cells. A dominant-negative mutant of JNK1, which can inhibit RbAp46-induced JNK activity, blocked RbAp46-mediated apoptosis. We also found that the induction of RbAp46 expression strongly suppressed the formation of tumors grafted in nude mice and drastically reduced growth of established tumor xenografts. CONCLUSION: These results revealed a novel proapoptotic activity for RbAp46 via the JNK pathway and demonstrated that induction of RbAp46 expression inhibits progressive growth of tumor grafts in vivo.

Cryosurgery of close or positive margins after hepatic resection for primary and metastatic hepatobiliary malignancies.

Obtaining a one-centimeter negative margin is an important factor in preventing disease recurrence after surgery for hepatic tumors. Cryotherapy of the resected edge has been used to achieve optimal margin clearance in cases in which the alternative would be an extended high-risk liver resection. The effect of this technique on margin recurrence was examined. Between 1994 and 2001 a total of 56 patients underwent cryosurgery with or without resection for primary and metastatic hepatobiliary malignancies. A 5-cm cryotherapy lollipop probe was used to ablate surgical margins less than one centimeter in 13 of these patients. There were seven colorectal metastases, three hepatocellular carcinomas, and three gallbladder carcinomas. The median size of the colorectal and hepatocellular lesions was 3 cm (range 2-14 cm), and all gallbladder primaries were T2 tumors. All tumors except three were located centrally in the liver requiring cryoablation of margins at segments 4, 5, and 8. Most patients had one site frozen (n = 9) with a median target temperature of -190 degrees C and a median of two freeze-thaw cycles. Final pathological analysis of the resected specimens revealed nine close (<1 cm) and four positive margins. With a median follow-up of 16 months seven patients are alive with no evidence of disease and six have developed recurrences with three of them dying of their disease. Only one (8%) of the initial recurrences was at the cryoablated margin. Cryosurgery of the resection edge facilitates liver resection for malignant tumors when margins are close or positive. Because disease recurrence at the cryoablated margin is low this technique may allow more patients to undergo effective surgical treatment of their hepatobiliary cancers.

Comparison of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with mitomycin or carboplatin for diffuse malignant peritoneal mesothelioma.

Diffuse malignant peritoneal mesothelioma is a rare, aggressive disease. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have improved outcomes where systemic chemotherapy has not succeeded. In this study, we compare outcomes of patients treated with mitomycin or carboplatin as perfusate. In this retrospective study, 47 procedures (CRS + HIPEC) were conducted on 44 patients between March 2003 and August 2010 with either mitomycin or carboplatin. χ(2) and Student's t test were used for comparison of clinicopathological variables and Kaplan-Meier curves and log rank test were used to compare overall survival. Median survival of the mitomycin group was 18 months with 1- and 5-year survivals of 72.3 and 27.3 per cent, respectively. Median survival of the carboplatin group was not reached and 1- and 5-year survivals were 89.7 and 62.5 per cent, respectively (P = 0.014). Mean hospital and intensive care unit length of stay was 18.9 and 8.7 days in the mitomycin group and 12.5 and 2.3 days in the carboplatin group (P = 0.0069). Mean number of packed red blood cell units transfused was higher in the mitomycin group compared with the carboplatin group (3.54 vs 0.83, P < 0.05). There was no postoperative mortality. HIPEC with carboplatin in diffuse malignant peritoneal mesothelioma is associated with improved overall survival and shorter hospital stay compared with HIPEC with mitomycin.

Right hemicolectomy is not routinely indicated in pseudomyxoma peritonei.

Pseudomyxoma peritonei (PMP) is primarily the result of a ruptured mucinous appendix neoplasm (MAN). Often MAN is lumped with but biologically distinct from intestinal appendiceal adenocarcinoma. Nodal and systemic dissemination are rare with the peritoneal cavity being the primary site of recurrence. Routine performance of right hemicolectomy (RHC) for PMP/MAN has been extensively debated without consensus. Our objective was to ascertain whether RHC has a survival advantage over appendectomy. We hypothesize if RHC is mandatory, then increased tumor recurrence and mortality should be observed in appendectomy only. Retrospective chart review was carried out in patients with tumors that met the Ronnett classification for PMP/MAN. Demographics, tumor grade, extent, recurrence, and progression were recorded. We report the rate of nodal involvement/recurrence in patients treated with RHC versus appendectomy as well as the rate of systemic and peritoneal recurrence and survival. Multivariate logistic regression was done to identify factors that impact survival. Of 120 patients, 48 had appendectomy and 72 had RHC. Seven per cent of patients undergoing RHC had positive lymph nodes and no nodal failures (0%) in patients undergoing appendectomy. Appendectomy versus RHC recurrence rates (21 vs. 28%, P = 0.12) and death resulting from disease (8 vs. 22%, P = 0.27) were similar. Logistic regression revealed that the type of surgery had no impact on recurrence and mortality, only optimal resection score and performance status. There was no difference in tumor recurrence or survival based on treatment by appendectomy or RHC. Performance status and complete cytoreduction are the only factors associated with survival. Lymph node involvement is rare and selective RHC is safe in PMP/MAN.