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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.

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.

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., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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.

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.

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.

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., (Copyright © 2011 Wiley Periodicals, Inc.)

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.

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.

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.

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.

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.

The status of the 66-kDa human estrogen receptor-alpha (hER-alpha66) is a critical determinant in the assessment of the prognosis and in the design of treatment strategies of human breast cancer. Recently, we cloned the cDNA of an alternatively spliced variant of hER-alpha66, termed hER-alpha36; the predicted protein lacks both transcriptional activation domains of hER-alpha66 but retains its DNA-binding domain, partial dimerization, and ligand-binding domains and three potential myristoylation sites located near the N terminus. These findings thus predict that hER-alpha36 functions very differently from hER-alpha66 in response to estrogen signaling. We now demonstrate that hER-alpha36 inhibits the estrogen-dependent and estrogen-independent transactivation activities of hER-alpha66 and hER-beta. We further demonstrate that hER-alpha36 is predominantly associated with the plasma membrane where it transduces both estrogen- and antiestrogen-dependent activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway and stimulates cell growth. We conclude that hER-alpha36 is a predominantly membrane-based, unique alternatively spliced variant of hER-alpha66 that acts as a dominant-negative effector of both estrogen-dependent and estrogen-independent transactivation functions signaled through hER-alpha66 and ER-beta; it also transduces membrane-initiated estrogen-dependent activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase mitogenic signaling pathway. The estrogen and antiestrogen signaling pathways mediated by hER-alpha36 provide an alternative explanation for why some human breast cancers are resistant to and others are worsened by antiestrogen therapy; the data suggest that hER-alpha36 also may be an important marker to direct therapy in human breast cancers, and perhaps hER-alpha36 also may transduce estrogen-dependent signaling in other estrogen target tissues.

The identification and subsequent cloning of the 66-kDa human estrogen receptor (here termed hER-alpha66), its 46-kDa splice variant hER-alpha46, and the closely related hER-beta have had a profound impact on the generation of new understanding of estrogen-mediated functions and led to progress in diagnosis and treatment of human breast cancer. However, a persistent problem has been that not all findings previously reported in estrogen-stimulated cell proliferation can be explained through the known properties of the different estrogen receptors described. As the consequence of a search for alternative mechanisms to account for these different findings, we have now identified, cloned, and expressed in HEK 293 cells a previously unrecognized 36-kDa variant of hER-alpha66, termed hER-alpha36. hER-alpha36 differs from hER-alpha66 since it lacks both transcriptional activation domains (AF-1 and AF-2) but it retains the DNA-binding domain, and partial dimerization and ligand-binding domains of hER-alpha66. It also contains three myristoylation sites postulated to direct ER-alpha36 to the plasma membrane. It is concluded that ER-alpha36 is a unique variant of ER-alpha66; ER-alpha36 is predicted to function as a dominant-negative effector of hER-alpha66-mediated estrogen-responsive gene pathways and has the potential to trigger membrane-initiated mitogenic estrogen signaling.

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.

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.

Background: Cytoreductive surgery (CS) and intraperitoneal hyperthermic chemotherapy (IPHC) are efficacious in patients with disseminated mucinous tumors of the appendix. We reviewed our experience using this approach for nonappendiceal colorectal cancer (NACC)., Methods: We performed a retrospective chart review of a prospective database for patients undergoing CS and IPHC with mitomycin C for peritoneal carcinomatosis from colorectal primary lesions between December 1991 and April 2002., Results: There were 77 patients, with a median age of 54 years. Peritoneal carcinomatosis was synchronous and metachronous in 27% and 73% patients, respectively. Seventy-five percent of patients (n = 58) had received chemotherapy prior to IPHC. Complete resection of all gross disease was accomplished in 37 patients (48%). The mean carcinoembryonic antigen level decreased from a preoperative value of 31.2 to a postoperative value of 6.9 (P <.0001). Overall survival (OS) at 1, 3, and 5 years was 56%, 25%, and 17%, respectively. With a median follow-up of 15 months, the median OS was 16 months. Perioperative morbidity and mortality were 30% and 12%, respectively. Hematologic toxicity occurred in 15 patients (19%). Cox regression analysis identified poor performance status (P =.018), bowel obstruction (P =.001), malignant ascites (P =.001), and incomplete resection of gross disease (P =.011) as independent predictors of decreased survival. Patients with complete resection of all gross disease had a 5-year OS of 34%, with a median OS of 28 months., Conclusions: CS and IPHC with mitomycin C can improve outcomes for select patients with peritoneal spread from NACC. One third of patients who undergo complete resection of gross disease have long-term survival.

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.

Background: Patients have traditionally been considered candidates for sentinel node biopsy (SNBx) only at the time of wide local excision (WLE). We hypothesized that patients with prior WLE may also be staged accurately with SNBx., Methods: Seventy-six patients, including 18 patients from the University of Virginia and 58 from a multicenter study of SNBx led by investigators at the University of Vermont, who had previous WLE for clinically localized melanoma underwent lymphoscintigraphy with SNBx. Median follow-up time was 38 months., Results: Intraoperative identification of at least 1 sentinel node was accomplished in 75 patients (98.6%). The mean number of sentinel nodes removed per patient was 2.0. Eleven patients (15%) had positive sentinel nodes. Among the 64 patients with negative SNBx, 3 (4%) developed nodal recurrences in a sentinel node-negative basin simultaneous with systemic metastasis, and 1 (1%) developed an isolated first recurrence in a lymph node., Conclusions: This multicenter study more than doubles the published experience with SNBx after WLE and provides much-needed outcome data on recurrence after SNBx in these patients. These outcomes compare favorably with the reported literature for patients with SNBx at the time of WLE, suggesting that accurate staging of the regional lymph node bed is possible in patients after WLE.

Background: Cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy with mitomycin C for peritoneal carcinomatosis is used as a palliative treatment for a variety of malignancies. The purpose of this study was to measure the quality of life (QOL) of survivors (>3 years) after treatment., Methods: Patients were interviewed by telephone with the following tools: (1) the Functional Assessment of Cancer Therapy-Colon (FACT-C), (2) the Short Form of the Medical Outcomes Study Questionnaire, (3) the Center for Epidemiologic Studies-Depression scale, (4) the Life Appreciation scale, (5) the Psychosocial Concerns Questionnaire, and (6) performance status rating., Results: Seventeen (10 appendix, 5 large intestine, 1 ovarian, and 1 peritoneum) of 109 patients were interviewed from 3.1 to 8.0 years after treatment. Ten patients (62.5%) described their health as excellent or very good. No limitations on moderate activity were reported in 94% of cases. Paired t-tests were used to compare 10 patients who had baseline QOL data. FACT mean difference scores and P values (positive difference scores indicate improved QOL) were functional well-being: 4.9, P =.01; physical well-being: 3.3, P =.05; and FACT total: 14.3, P =.02., Conclusions: Long-term survival with good QOL is possible for selected patients with peritoneal carcinomatosis after cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy.

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.

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.

The use of hyperthermia as an adjunct to chemotherapy in the treatment of peritoneal carcinomatosis is a promising technique for patients who otherwise have a poor prognosis for survival. We, herein, report an overview and description of our technique for the safe conduct of this treatment. Included in these data are a total of 71 patients who underwent an intraoperative treatment with Mitomycin C at temperatures of 41-42 degrees C for a 90- to 120-min time period. The treatment protocol, perfusion system description, technical considerations, and potential complications are also included. The prognosis for intraabdominal carcinomatosis is poor with conventional treatments and modalities. We believe that the use of this technique offers a very positive clinical alternative for patients undergoing treatment for laparoscopic palliation of malignant ascites and/or surgical debulking for intraoperative treatment and prevention of metastasis.

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.

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.

This paper summarizes the author's thoughts about the use of cytoreductive surgery combined with intraperitoneal hyperthermic chemotherapy (CS-IPHC) for treatment of peritoneal malignant mesothelioma. Pleural malignant mesotheliomas are by far more common (about ten- to thirty-fold) than the peritoneal variants (2.2 cases per 1 million in the US). Other locations (pericardium, tunica vaginalis) are very rare. It is well known that chemotherapy for mesothelioma is largely unsatisfactory, and measurement of treatment responses can be difficult. Single agent responses are all less than 20% with currently available agents for systemically administered drugs. Multiple drug combinations are typically more toxic, and have yielded little consistent demonstrable benefit with major studies reporting median survivals consistently under a year. There is currently more attention being paid to the response category of "stable" or absence of disease progression in concert with quality of life measurements; all regimens show poor durability. With peritoneal malignant mesothelioma, malignant ascites is a common presentation and a major factor in disease-related morbidity and mortality. Interperitoneal administration of agents is attractive, but drug distribution is an issue, as are response rates and durability. Multiple treatments are required; further, all neoplasms with peritoneal dissemination are typically understaged by current radiologic tests (CT, MRI), and the variable uptake of sugar by the small bowel limits the use of positron-emission tomography (PET) imaging for peritoneal malignant mesothelioma. Also, symptoms of bowel obstruction are not uncommon, and any mechanical component of obstruction will not improve with any form of chemotherapy. The author's approach relies on surgery to achieve the following: 1) accurate staging; 2) tumor debulking, as possible, and treatment of mechanical obstruction as well as prevention of impending obstruction by resection or bypass; and 3) preparation for the use of intra-operative hyperthermic chemotherapy perfusion. This approach has been associated with rapid clinical symptom improvement, as well as a reliable and durable resolution of ascites with a single therapy. Morbidity and mortality have been acceptable with about 27-month median survival. The inability to provide effective systemic therapy to maintain or consolidate these gains is problematic.

Malignant peritoneal mesothelioma (MPM) is a rare and often rapidly fatal disease with median survival of 5 to 12 months for untreated cases and 16 months reported after multimodality treatment. We report a prospective clinical treatment study using cytoreductive surgery combined with intraoperative intraperitoneal heated chemotherapy (IPHC) perfusion using mitomycin C for MPM. Twelve patients (11 male with a mean age 51 years) were treated. Seven patients presented with bulky disease and seven with ascites. All underwent exploratory laparotomy with histologically confirmed diagnosis of MPM. Surgical debulking as feasible was performed. Complete gross tumor removal was possible in only one patient. Cytoreduction was followed by a 2-hour closed low-volume IPHC using mitomycin C. One patient died 50 days postoperatively from complications relating to small bowel perforation. Hematologic toxicity of the procedure was minimal. Ascites was controlled in all patients and permanently in 86 per cent of patients presenting with ascites. To date median survival is 34.2 months with median follow-up of 45.2 months. One patient was re-explored for ventral hernia 2 years post-IPHC, had negative peritoneal biopsies, and remains disease-free at 5 years. Given the dismal prognosis associated with MPM the results of treatment with cytoreductive surgery combined with IPHC perfusion are encouraging. The rarity of MPM makes appropriately powered prospective randomized trials unlikely. Therefore, we now offer this approach off protocol; however, further study of this combined modality therapy is warranted.

Background: Pseudomyxoma peritonei (PMP) is a rare condition characterized by gelatinous ascites. Although the histologic attributes of PMP have been well studied, the cytologic features remain ill defined., Methods: We reviewed the peritoneal washings (PW) in 67 patients with PMP to identify cytomorphologic features useful in classifying cases as either disseminated peritoneal adenomucinosis (DPAM) or peritoneal mucinous carcinomatosis (PMCA). Histologic specimens were correlated with the cytologic diagnoses. Correlation between cytologic diagnosis and patient outcome was investigated., Results: Neoplastic epithelial cells were identified in 63 of 67 PW (94%). Concordance with the histologic diagnosis was obtained in 61 of 63 cases. Of these 36.5% were cytologically classified as DPAM with primary appendiceal neoplasms in 19 cases. Thirty-four of 63 cases (53.9%) were cytologically diagnosed as PMCA based on PW cytology. Most were of appendiceal or colonic origin. Four cases displayed cytologic features of both DPAM and PMCA. Two discordant cases each with a cytologic diagnosis of PMCA had an appendiceal adenoma. Acellular mucin alone was identified in the PW in four cases. Analysis of follow-up data revealed that cases diagnosed as DPAM had a better prognosis than those diagnosed as PMCA., Conclusions: Cytomorphologic features of epithelial cells in PW material can accurately categorize cases of PMP as either DPAM or PMCA. Furthermore, this categorization appears to have important prognostic implications.

Disseminated peritoneal adenomucinosis (DPAM) is a relatively rare cause of pseudomyxoma peritonei, marked by peritoneal lesions with abundant extracellular mucin and little cytologic atypia among exfoliated tumor cells, and usually associated with appendiceal adenomas. Peritoneal mucinous carcinomatosis (PMCA) also causes diffuse peritoneal tumor but is marked by neoplastic mucinous epithelium with cytologic features of carcinoma and associated with appendiceal, colon, gastric, or small bowel carcinoma. Compared with PMCA, DPAM has a different distribution of disease and a significantly better prognosis. DPAM is characterized by the lack of lymph node involvement, with primarily superficial peritoneal involvement, and a relatively benign, relapsing course over many years. Dominant primary masses may not be evident in DPAM. Despite considerable overlap in the two main causes of pseudomyxoma peritonei, there are features of the two that may help differentiate between them. We present the computed tomographic appearance of DPAM in a series of seven cases and emphasize characteristics of the disease.

Sentinel lymph node biopsy was attempted in 336 patients with clinically node-negative cutaneous melanoma. All patients were injected with technetium-99m labelled radiocolloid, with 108 patients simultaneously receiving vital blue dye for sentinel node identification. Sentinel lymph nodes were identified in 329 patients, giving a technical success rate of 97.9%. Metastatic disease was identified in 39 (11.9%) of the patients in whom sentinel nodes were found. Patients with negative sentinel nodes were observed and patients with positive sentinel nodes underwent comprehensive lymph node dissection. The presence of metastatic disease in the sentinel nodes and primary tumour depth by Breslow or Clark levels were joint predictors of survival based on Cox proportional hazards modelling. Disease recurrences occurred in 26 (8.8%) patients with negative sentinel lymph nodes, with isolated regional recurrences as the first site in 10 (3.4%). No patients with Clark level II primary tumours were found to have positive sentinel nodes or disease recurrences. One patient with a thin (<0.75 mm) Clark level III primary had metastatic disease in a sentinel node. Patients with metastases confined to the sentinel nodes had similar survival rates regardless of the number of nodes involved.

Aims: This study assessed the functional status and quality of life (QOL) of patients with disseminated peritoneal cancer (DPC) before and after cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy (IPHC)., Methods: Patients with confirmed or suspected diagnosis of gastro-intestinal cancer including stomach, pancreas, hepatobiliary and colorectal cancer with peritoneal implants were enrolled in the study. Sixty-four patients completed the Functional Assessment of Cancer Therapy-Colon (FACT-C) scale and several other instruments at baseline. Forty-eight, 40, 39 and 31 patients were assessed at approximately 2 weeks post-surgery, and 3, 6 and 12 months respectively., Results: There was a significant overall effect on the physical (P=0.0025), emotional (P<0.0001) and functional well-being (P=0.0044) subscales and the FACT-C (P=0.0076). Physical and functional well-being scores decreased at post-surgery follow-up and increased relative to baseline at 3, 6 and 12 months. Nineteen per cent, 46%, 59% and 74% of patients resumed greater than 50% of their normal activities post-operatively at 3, 6 and 12 months respectively. A percentage of patients reported depressive symptoms: baseline (28%), post-operatively (33%), 3 months (23%), 6 months (21%) and 12 months (29%)., Conclusions: Cytoreductive surgery followed by IPHC was well tolerated. Most patients returned to baseline or better levels of functioning within 3 months post-treatment., (Copyright Harcourt Publishers Limited.)

Sentinel lymph node (SLN) mapping has evolved into the standard of care for melanoma and may replace routine node dissection in the treatment of breast cancer. There are few data evaluating sentinel node mapping in patients with cancer of the colon. This trial represents our initial experience with SLN mapping for carcinoma of the colon. SLN mapping was performed in 22 patients most of whom had biopsy-proven adenocarcinoma of the colon. One milliliter of isosulfan blue was injected with a 25-gauge needle into the subserosa at four sites around the edge of the palpable tumor. The SLN was identified visually and excised. A standard lymphadenectomy was then performed. The SLN was analyzed with standard hematoxylin and eosin evaluation. Immunohistochemical techniques for carcinoembryonic antigen and cytokeratin (Imm) were performed if the H&E was negative. The mapping added approximately 5 minutes to the total operative time and no adverse reactions to the dye occurred. A SLN was identified in 20 of 22 cases. In cases with negative lymph nodes the SLN was predictive of all the regional nodes by both H&E and Imm (14 of 14). In patients with positive lymph nodes the SLN was predictive in all cases (six of six). In one case the only node with disease was the SLN, and in this case the diease was identified by only Imm; thus this patient was upstaged. SLN mapping is feasible and safe and can readily be performed in patients with colonic cancer. In conjunction with SLN mapping, Imm techniques may upstage a subset of patients likely to be at increased risk for metastatic disease. Consequently SLN mapping of colon cancer should be evaluated in large prospective trials.

No standard effective treatment exists for peritoneal carcinomatosis of gastrointestinal origin. The pharmacokinetic advantage of intraperitoneal chemotherapy and the synergy of heat and certain anticancer agents have prompted researchers to investigate intraperitoneal hyperthermic chemotherapy in treating disseminated peritoneal cancers. We have conducted a large Phase II trial to determine the safety and efficacy of aggressive cytoreductive surgery and intraperitoneal hyperthermic chemotherapy (IPHC) in treating peritoneal carcinomatosis of gastrointestinal origin. Patients with disseminated peritoneal carcinomatosis of gastrointestinal origin with or without malignant ascites were eligible. After aggressive surgical debulking, patients were administered a 2-hour heated (40.5 degrees C) intraperitoneal perfusion with mitomycin C. The major response variable monitored was overall survival. Patients were assessed for toxicity after IPHC administration using the National Cancer Institute Common Toxicity Criteria. Eighty-four patients with peritoneal carcinomatosis of gastrointestinal origin were evaluated for survival and toxicity (colon, n = 38; appendix, n = 22; stomach, n = 19; other gastrointestinal, n = 5). Thirty-nine (46%) patients had malignant ascites at the time of therapy. The operative mortality (30-day) was 6 per cent. Hematologic toxicity was the most common toxicity but was of mild to moderate severity (7 and 4% of patients had grade 3/4 white blood cell or platelet toxicity, respectively). The overall median survival was 14.3 months. The median survival of patients with peritoneal carcinomatosis of appendiceal, colorectal, and gastric origins were 31.1+, 14.6, and 10.1 months, respectively. Significant differences in median survival were seen in patients without and with malignant ascites (27.7 vs 7.6 months; P = 0.0004) and R0/R1 (complete gross tumor resection) versus R2 (gross residual tumor) surgical resection status (28.5+ vs 10.8 months, P = 0.0002). These data suggest that aggressive cytoreductive surgery with IPHC using mitomycin C is safe and effective in treating peritoneal carcinomatosis of gastrointestinal origin. Additional studies and broader applications of this treatment are encouraged.

Objective: To report atypical cytomorphologic features in fine needle aspiration biopsies (FNABs) from two cases of Merkel cell carcinoma (MCC), a primary neuroendocrine neoplasm of skin., Study Design: Retrospective review of FNABs with histologic correlation from six patients with MCC and a report of findings from two whose smears showed atypical features., Results: Typically the aspirates produce highly cellular smears of loosely clustered and individual, relatively monomorphic, small tumor cells with round to oval, regularly contoured nuclei. In two of our cases, the tumor cell nuclei exhibited a spectrum of pleomorphism ranging from moderately complex nuclear membranes with cleaves, indentations and protrusions in one case to large, markedly bizarre, convoluted nuclei and multinucleate tumor cells in the extreme case. Both cases were primary neoplasms, and the diagnosis was based on clinical, histologic and immunohistochemical data. Additionally, electron microscopy was performed on the tumor with bizarre nuclei and demonstrated rare, dense core neurosecretory granules and paranuclear bundles of intermediate filaments.

The management of lymph nodes in melanoma patients who have no clinical evidence of nodal disease has changed dramatically with the development of selective lymph node biopsy. This procedure localizes the node in a regional basin most likely to contain a metastasis (the sentinel node) and averts the morbidity of unnecessary elective node dissection. This update reviews the rationale for this procedure and describes the methodology used by the surgeon and the pathologist. A progress report highlights the promise and limitation of this procedure. Sentinel node biopsy is currently the standard for staging select groups of melanoma patients, but the field is rapidly evolving and may eventually be surpassed by even newer molecular diagnostic techniques.

Objectives: To study the efficacy of gamma-probe radiolocalization of the first draining (sentinel) lymph node (SLN) in stage N0 melanoma of the head and neck and to evaluate its potential role in the staging and treatment of this disease., Design: Gamma-probe radiolocalization, a new alternative to blue-dye lymphatic mapping, uses a scintillation (gamma) probe to identify radiolabeled SLNs. In a consecutive sample clinical trial, gamma-probe radiolocalization of the SLN is compared with lymphoscintigraphy and blue-dye lymphatic mapping. Follow-ups ranged from 1.7 years to 4 years, with a mean follow-up of 2.5 years., Setting: Tertiary and private care teaching hospital., Patients: Between June 1993 and November 1995, 23 patients with stage N0 intermediate-thickness melanoma of the head and neck were enrolled in this volunteer sample., Interventions: Twenty-four hours prior to surgery, a radioactive tracer was intradermally injected around the circumference of a primary melanoma. Twelve patients also had blue dye injected just prior to surgical resection. Using a handheld gamma probe, radiolabeled lymph nodes were identified and selectively removed with minimal dissection. In patients with nodes with histologic evidence of metastases, a regional lymphadenectomy was performed., Main Outcome Measures: The successful identification of radiolabeled SLNs, the correlation of SLN radiolabeling to lymphoscintigraphy and blue-dye mapping, and the long-term development of regional metastases., Results: Surgeons successfully resected the radiolabeled SLNs in 22 (96%) of 23 patients. The success rate of blue-dye lymphatic mapping was 8 (75%) of 12 patients and lymphoscintigraphy was 20 (91%) of 22 patients. One hundred percent of blue-stained lymph nodes were radiolabeled. The one patient in whom no SLN could be identified developed regional disease at 17 months., Conclusions: Gamma-probe radiolocalization and resection of the radiolabeled SLN is a simple and reliable method of staging regional lymph nodes and determining the need for elective lymphadenectomy.

Some patients presenting with cutaneous malignant melanoma without palpable adenopathy have regional metastatic disease. We have applied the technique of gamma probe-directed selective lymph node biopsy and used the results to direct further therapy. The results of a prospective nonrandomized clinical study are presented. Between November 1993 and December 1996, 63 patients with a diagnosis of primary cutaneous malignant melanoma underwent lymphoscintigraphy with technetium sulfur colloid followed by gamma probe-guided lymph node biopsy. There were 32 (51%) women and 31 (49%) men with a mean age of 51.1 years (median, 50; range, 13-87). Mean Breslow thickness was 2.13 mm (range, 0.5-15.0 mm; median, 1.56 mm). Primary locations were head and neck in 8 (13%), trunk in 24 (38%), upper extremity in 13 (21%), and lower extremity in 18 (29%). Selective lymph node biopsy was done on an outpatient basis with local anesthesia in 49 cases (78%) and in the operating room with general anesthetic in 14 patients (22%). One lymph node site was biopsied in 46 patients (73%), two sites in 16 (25%), and three in 1 (2%), for a total of 81 selective lymph node biopsy sites, mean 1.29 per patient. The mean number of labeled lymph nodes removed per site per patient was 1.64 (range, 1-5). Seroma or infection occurred in 6 patients (10%). Micrometastatic disease was identified in nine selective lymph node biopsy sites in eight patients. Of eight patients undergoing lymph node dissection, 5 (63%) had no additional pathological lymph node involvement. With a mean follow-up of 579 days from selective lymph node biopsy (median, 594; range, 36-1157), 59 (94%) have no evidence of disease. Three patients have died, 2 with systemic disease (475 and 1149 days) and 1 from a myocardial infarction (380 days). No patient has failed with regional-only recurrence. Gamma probe-directed selective lymph node biopsy is a straightforward procedure that can be done in the outpatient setting and facilitates management of patients with cutaneous malignant melanoma.

Background: The purpose of this study was to determine the incidence and severity of thoracic reactions in patients undergoing intraperitoneal heated chemotherapy (IPHC)., Methods: Forty-two patients who had intraperitoneal disseminated malignancies were treated with cytoreductive surgery (CS) and IPHC. The primary malignancies included carcinoma of the colon (n = 17), stomach (n = 6), appendix (n = 6), pseudomyxoma peritonei (n = 3), mesothelium (n = 2), ovaries (n = 2), jejunum (n = 2), gallbladder (n = 1), urachus (n = 1), and peritoneal carcinomatosis (n = 2). After CS, IPHC with mitomycin (MMC) was administered by perfusion at 40.5 degrees C. After IPHC, multiple radiographs of the chest were reviewed in comparison to the control group., Results: Thoracic complications occurred in 36 patients (86%), including atelectasis in 32 patients (76%), pleural effusions in 27 (64%), pulmonary edema in 10 (24%), pneumonia in 2 (5%), and pneumothorax in 2 (5%). The incidence of thoracic complications in the IPHC group was significantly higher than that of patients in the control group (P < .05). Correlations between the prevalence of pleural effusion and the dose of MMC, duration of procedure, and presence of thrombocytopenia were not significant (P > .05)., Conclusions: Bibasilar atelectasis and pleural effusions are common findings after IPHC with MMC, but most of them do not necessarily warrant intervention.

Urachal adenocarcinoma is an uncommon clinicopathologic entity associated with a dismal prognosis. We report a case of peritoneal carcinomatosis from urachal adenocarcinoma (signet cell type) treated with cytoreductive surgery and intraperitoneal hyperthermic chemotherapy (IPHC). Prior to treatment, disease had progressed with systemic chemotherapy. The patient remained free of symptomatic peritoneal disease or local recurrence but eventually died 23 months after IPHC and 31 months after diagnosis due to widespread bone metastases.

Percutaneous endoscopic gastrostomy (PEG) is a relatively safe procedure and is an important supportive treatment adjunct for patients with head and neck cancer. We report a case in which squamous cell carcinoma of the larynx implanted at a PEG exit site. This was resected for cure. In this case, and in five others reviewed in the literature, the PEG placement method was the "pull" technique. It is unknown whether other methods of PEG placement may reduce metastatic implants at the PEG exit site, but the possibility of this complication must be considered.

Background: The preoperative assessment of depth of invasion of rectal carcinoma is increasingly important as new treatment methodologies are developed. Accuracy of preoperative endorectal MR imaging was therefore compared with that of the endoscopic rectal sonography in determining depth of invasion of rectal carcinomas., Method: From March 1993 to April 1994, 10 consecutive patients with biopsy-proven rectal carcinomas were imaged with both endorectal MR imaging and endoscopic rectal sonography. These two studies were performed an average of 2.7 days apart in each patient. All 10 patients had surgical resection of the rectal carcinoma within days of imaging studies. TNM staging of each malignant lesion was correlated with the imaging reports., Result: Staging accuracy was 80% for endorectal MR imaging and 70% for endoscopic rectal sonography. With MR imaging, one T2 lesion was overstaged and one T3 lesion was understaged. With sonography, two T2 lesions were overstaged and one T3 lesion was understaged. One MR error resulted from misinterpretation. All other staging errors occurred in patients with tumor spread into, but not through, the muscularis propria or with microscopic spread through this layer., Conclusions: Endorectal MR imaging and endoscopic rectal sonography have similar accuracy for assessing depth of invasion of rectal carcinoma.

Hemangiopericytomas, first described in 1942, are rare, highly vascular neoplasms that arise from capillary pericytes. They are seen most commonly as a painless mass arising from the lower extremity but can also originate in the pelvic retroperitoneum and on the head, neck, chest, and abdomen. An unusual case is reported here of a patient presenting with recurrent massive upper gastrointestinal (GI) bleeding in whom a large hemangiopericytoma was found arising in the perisplenic soft tissues. Precedence exists in the literature for the association of hemangiopericytoma with GI bleeding. In prior reports, however, a mural origin of the tumor and subsequent bleeding into the GI lumen was demonstrated. In the case presented here, marked dilatation of the gastric and splenic vessels was noted, but there was no direct pathologic involvement of the stomach wall. It is proposed that superficial gastric erosions combined with the tumor-associated increased vascularity within the stomach wall led to recurrent major bleeding. Diagnosis of these tumors roentgenographically is nonspecific, but angiography is helpful. Morphological characteristics allow accurate histopathological diagnosis and provide prognostic information. The treatment of choice remains wide surgical excision, with the addition of radiation or chemotherapy in selected cases.

No satisfactory treatment exists to treat or prevent malignant ascites secondary to nonovarian intraperitoneal (IP) disseminated malignancies. A Phase I/II clinical trial combining radical cytoreductive surgery (CS) and IP hyperthermic chemotherapy (IPHC) with mitomycin C is presented. Between December 9, 1992 and July 31, 1995, 39 patients (pts) were explored for IP cancer. Five pts with known liver metastases were excluded, leaving 34 pts (15 female, 19 male) of median age 53 (range, 17-76). The majority of pts had disseminated IP cancers of gastrointestinal origin (80%). Prior therapy included the following: chemotherapy, 20 pts (59%); surgery, 29 pts (85%); and radiation, 2 pts (6%). Following CS, IPHC with mitomycin C was done. At surgery, 12 pts (35.3%) had frank ascites, and 12 pts (35.3%) had positive IP cytology without ascites. The median hospital stay was 9 days (range, 5-65) with no 30-day mortality. Complications for 36 treatments included: thrombocytopenia Eastern Cooperative Oncology Group grade 3 or 4, two cases (5.6%); neutropenia requiring granulocyte colony-stimulating factor, seven cases (19.4%); sepsis, four cases (11.1%); bowel leak, two cases (5.6%); and serous wound leak, two cases (5.6%). Ascites correlated with worse resection status (P = 0.025). Ascites was controlled in 9 of 12 (75.0%) pts, with failures at 1, 4, and 14 months (median follow-up, 7.5 months). No cytology-positive ascites-negative pts developed clinical ascites (median follow-up, 9.4 months). The median survival time in pts with ascites was 10.1 months versus 32.7 for patients without ascites (P = 0.013). For the entire study population, the 1- and 2-year survival rates were 74.6 and 48.5 per cent, respectively (median follow-up, 18.2 months). In this study, malignant ascites was controlled in 75 per cent of cases and prevented in all pts with positive IP cytology. CS plus IPHC appears to be relatively well tolerated and may be effective for the treatment and prevention of malignant ascites.

Exenterative pelvic surgery is commonly performed for advanced carcinoma of the cervix and selected cases of locally advanced colorectal cancers. Low-lying lesions that are locally invasive in contiguous organs require resection of the perineal body en bloc with the resected specimen. The resulting defect, both in the pelvis and the perineum, creates a difficult management problem. Dead space in the pelvis, especially with adjunctive irradiation, leads to delayed wound healing and prolapse of small bowel into the pelvis. Small bowel obstruction and/or fistula formation are the greatest sources of morbidity in the operative group. Fifteen patients underwent exenterative pelvic procedures (total exenteration, 1 patient; posterior exenteration, 8 patients; abdominoperineal resection, 6 patients). All patients were reconstructed by transpelvic placement of the rectus abdominis muscle (muscle only, 4 patients; muscle with skin grafting, 8 patients; musculocutaneous, 3 patients). Eighty-seven percent received radiation therapy. One patient had Crohn's disease and all others had carcinoma. Healing was complete in 12 of 15 patients at discharge. There were no complications related to pelvic dead space (i.e., bowel obstruction, perineal fistula), with a mean follow-up time of 24.3 months. Small bowel was effectively excluded from the pelvis to the level of the acetabular roof by computerized axial tomography scan. The transpelvic rectus abdominis muscle flap is effective in preventing major morbidity after exenterative pelvic surgery.

Objective: A phase I/II clinical trial of surgical cytoreduction combined with intraperitoneal hyperthermic chemotherapy (IPHC) for patients with disseminated peritoneal carcinoma was begun in December 1991. The use of peritoneal cytology to assess this treatment modality was the objective of this study., Study Design: Adult patients with primary intraabdominal cancer with peritoneal dissemination underwent surgical debulking and intraoperative, two-hour, heated abdominopelvic perfusion with mitomycin C (MMC). Peritoneal washings were sent before and after IPHC, and the use of peritoneal cytology in this setting was reviewed retrospectively., Results: Twenty patients (9 female, 11 male) with adenocarcinoma (19) and one with epithelial mesothelioma, all with bulky peritoneal disease, were treated. Pre- and post-IPHC cytologic specimens were available for 18 cases. Cytology was tumor negative in three cases before and after IPHC. Conversion to negative post-IPHC cytology was seen in 6 of 15 cases and correlated with total or near-total tumor debulking (Fisher's exact test, P = .002). For 13 patients with follow-up > or = 6 months, 6 patients with both negative post-IPHC cytology and tumor < or = 1 g were alive at 6 months; of 7 patients with residual gross tumor or positive post-IPHC cytology, 5 had died within 6 months (P = .02)., Conclusion: Some patients undergoing IPHC with tumor-positive peritoneal cytology will convert to negative cytology following IPHC. This correlates with total or near-total tumor debulking and is associated with improved survival.

We conducted a combined biochemical modulation trial of N-(phosphonacetyl)-L-aspartate (PALA), dipyridamole (DP), and fluorouracil (5-FU) in patients with cancer. Eighty-eight patients with advanced cancer were entered into this Phase I trial. During the first part of the study, four doses of PALA (125, 250, 500, and 1000 mg/m2, administered on day 1) were evaluated to determine the PALA dose with maximal suppression of aspartate transcarbamylase (ATCase) activity that was clinically tolerable. Patients were randomized to receive DP (or no DP), 50 mg/m2, p.o. every 6 h on days 1-6, and all patients received 5-FU, 400 mg/m2, by bolus administration on days 2-5. Prior to and during therapy, WBCs were collected and assayed for ATCase activity. After the maximally tolerated PALA dose with 400 mg/m2 5-FU +/- 50 mg/m2 DP was defined, the 5-FU dose was escalated using the same administration schedule of 5-FU, PALA, and DP. The dose of 5-FU was escalated by 25% in each of the DP cohorts until dose-limiting toxicity was reached. ATCase activity was inhibited in a dose-dependent manner with PALA doses of 125, 250, 500, and 1000 mg/m2, resulting in 0, 13, 17, and 49% inhibition of ATCase activity. Only at the higher PALA doses (i.e., 500 and 1000 mg/m2) was ATCase activity suppressed during days 2-5, but the activity returned to pretreatment levels by day 15. Based on the clinical tolerance and significant suppression of ATCase activity, a PALA dose of 500 mg/m2 was selected for the 5-FU dose escalation phase. At a 5-FU dose of 625 mg/m2, dose-limiting toxicity (leukopenia, stomatitis, and diarrhea) occurred in both DP cohorts. We recommend that for this monthly treatment schedule, 500 mg/m2 PALA and 500 mg/m2 5-FU, with or without 50 mg/m2 DP, be used in subsequent Phase II trials.