John H. Stewart

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: A consensus statement

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin : a consensus statement

Pseudomyxoma peritonei of appendiceal origin: a clinicopathologic analysis of 101 patients uniformly treated at a single institution, with literature review.

Pseudomyxoma peritonei is a clinical term for gelatinous ascites, usually secondary to an appendiceal tumor. The pathologic classification of pseudomyxoma peritonei and its associated appendiceal tumors has been plagued with controversy and confusing terminology. In an effort to clarify this, we reviewed the pathology of 101 patients, all treated at our institution from 1993 to 2005, with pseudomyxoma peritonei of appendiceal origin. All patients were uniformly treated with our standardized protocol. This is the largest pathologic series solely devoted to appendiceal neoplasia with gelatinous ascites.The cases were assigned, according to previously published criteria, to the categories of disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), or PMCA with intermediate (well differentiated) features (PMCA-I), with the exception that any case with a signet-ring cell component was considered as PMCA and not PMCA-I. By histologic category, 58 patients had DPAM, 23 were PMCA, and 20 were PMCA-I.One-year, 3-year, and 5-year survival outcomes were not significantly different between DPAM and PMCA-I. DPAM and PMCA-I also exhibited a roughly equal incidence of parenchymal (beyond the serosa) organ invasion. Survival outcomes were significantly worse for PMCA, compared with PMCA-I and DPAM. After reviewing our data and the literature, mucinous carcinoma peritonei-low grade was applied to the low-grade histology of pseudomyxoma peritonei, including those cases referred to by some as DPAM in the same category as PMCA-I. Cases that are moderately differentiated to poorly differentiated are classified as mucinous carcinoma peritonei-high grade.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: a consensus statement. Society of Surgical Oncology.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin : a consensus statement

Participation in Surgical Oncology Clinical Trials: Gender-, Race/Ethnicity-, and Age-based Disparities

ObjectiveTo characterize the representation of racial/ethnic minorities, women, and older persons among participants in surgical trials sponsored by the National Cancer Institute (NCI).MethodsThe NCI Clinical Trial Cooperative Group surgical oncology trials database was queried for breast, colorectal, lung, and prostate cancers treated during the period 2000–2002 (n=13,991). Data from the SEER program and the Census were used to estimate age-, gender-, and race/ethnicity-specific incidence of the same cancers among U.S. adults during the same period. Enrollment fraction (EF), defined as the number of trial enrollees divided by the estimated U.S. cancer cases in each demographic group, was the primary outcome measure. Logistic regression was used to compare the enrollment of racial/ethnic, gender and age subgroups in this analysis.ResultsRelative to white patients (EF=0.72%), lower EFs were noted in African-American (0.48%, odds ratio[OR] vs whites 0.67, P<0.001), Hispanic (0.54%, OR 0.76, P<0.001), and Asian/Pacific islander (0.59%, OR 0.82, P=0.001) patients. Overall, women were more likely to enroll in surgical trials (1.12%) than men (0.22%, OR 5.06, P<0.001). Patients 65–74 years of age (EF 0.45%) were less likely to be enrolled than those 20–44 years of age (EF=2.28%, OR 0.20, P=0.001).ConclusionsThe enrollment in surgical oncology trials is very low across all demographics. However, racial/ethnic minorities and older persons are less likely to be enrolled in cooperative group surgical oncology trials than are whites and younger patients. The high EF for women is due to the high availability of trials for women with breast cancer. Strategies to increase accrual to surgical trials and ameliorate disparities related to race/ethnicity, gender, and age are needed.

Appendiceal Neoplasms With Peritoneal Dissemination: Outcomes After Cytoreductive Surgery and Intraperitoneal Hyperthermic Chemotherapy

BackgroundAppendiceal neoplasms frequently present with peritoneal dissemination (PD) and have a clinical course marked by bowel obstruction and subsequent death. Few data have correlated outcome with appendiceal histology after cytoreductive surgery and intraperitoneal hyperthermic chemotherapy (IPHC). We have reviewed our experience with cytoreductive surgery and IPHC for PD from the appendix.MethodsA total of 110 cases of PD from proven appendiceal neoplasms treated with IPHC were identified from a prospectively managed database. Tumor samples were classified on pathologic review as disseminated peritoneal adenomucinosis (n = 55), peritoneal mucinous carcinomatosis (PMCA) with intermediate features (n = 18), PMCA (n = 29), or high-grade nonmucinous lesions (n = 8). A retrospective review was performed with long-term survival as the primary outcome measure.ResultsA total of 116 IPHCs were performed on 110 patients for appendiceal PD between 1993 and 2004. The 1-, 3-, and 5-year survival rates for all cases were 79.9% ± 4.1%, 59.0% ± 5.7%, and 53.4% ± 6.5%, respectively. When stratified by histology, disseminated peritoneal adenomucinosis and intermediate tumors had better 3-year survival rates (77% ± 7% and 81% ± 10%) than PMCA and high-grade nonmucinous lesions (35% ± 10% and 15% ± 14%; P = .0032 for test of differences between groups). Age at presentation (P = .0134), performance status (P < .0001), time between diagnosis and IPHC (P = .0011), resection status (P = .0044), and length of hyperthermic chemoperfusion (P = .0193) were independently associated with survival.ConclusionsThe data show that long-term survival is anticipated in most patients who are treated with cytoreduction and IPHC for appendiceal PD. The findings presented herein underscore the important prognostic characteristics that predict outcome after IPHC in patients with PD. In all, this work establishes a framework for the consideration of IPHC in future trials for appendiceal PD.

Intraperitoneal Hyperthermic Chemotherapy for Peritoneal Surface Malignancy: Current Status and Future Directions

Natural history studies have shown that peritoneal carcinomatosis is uniformly fatal, with a median survival in the range of approximately 6 months. For more than a decade, a handful of centers have pursued aggressive intraperitoneal cytoreductive surgery combined with intraperitoneal hyperthermic chemotherapy as an alternative approach to this disease. Strict selection criteria, variation in intraperitoneal chemotherapy, and the vagaries of what represents “cytoreductive surgery” make many of our colleagues, particularly those in medical oncology, reticent to refer patients for such an aggressive therapy. This article establishes a conceptual framework for understanding the role of intraperitoneal hyperthermic chemotherapy in the treatment of peritoneal surface malignancy. This procedure continues to make advancements in the oncological community despite formidable challenges. The advancement of centers of excellence and the initiation of further phase II trials will help to define the optimal treatment approach for peritoneal carcinomatosis.

Intraperitoneal Chemotherapy for Peritoneal Surface Malignancy: Experience with 1,000 Patients

BACKGROUND Peritoneal dissemination of abdominal malignancy (carcinomatosis) has a clinical course marked by bowel obstruction and death; it traditionally does not respond well to systemic therapy and has been approached with nihilism. To treat carcinomatosis, we use cytoreductive surgery (CS) with hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS A prospective database of patients has been maintained since 1992. Patients with biopsy-proven peritoneal surface disease were uniformly evaluated for, and treated with, CS and HIPEC. Patient demographics, performance status (Eastern Cooperative Oncology Group), resection status, and peritoneal surface disease were classified according to primary site. Univariate and multivariate analyses were performed. The experience was divided into quintiles and outcomes compared. RESULTS Between 1991 and 2013, a total of 1,000 patients underwent 1,097 HIPEC procedures. Mean age was 52.9 years and 53.1% were female. Primary tumor site was appendix in 472 (47.2%), colorectal in 248 (24.8%), mesothelioma in 72 (7.2%), ovary in 69 (6.9%), gastric in 46 (4.6%), and other in 97 (9.7%). Thirty-day mortality rate was 3.8% and median hospital stay was 8 days. Median overall survival was 29.4 months, with a 5-year survival rate of 32.5%. Factors correlating with improved survival on univariate and multivariate analysis (p ≤ 0.0001 for each) were preoperative performance status, primary tumor type, resection status, and experience quintile (p = 0.04). For the 5 quintiles, the 1- and 5-year survival rates, as well as the complete cytoreduction score (R0, R1, R2a) have increased, and transfusions, stoma creations, and complications have all decreased significantly (p < .001 for all). CONCLUSIONS This largest reported single-center experience with CS and HIPEC demonstrates that prognostic factors include primary site, performance status, completeness of resection, and institutional experience. The data show that outcomes have improved over time, with more complete cytoreduction and fewer serious complications, transfusions, and stomas. This was due to better patient selection and increased operative experience. Cytoreductive surgery with HIPEC represents a substantial improvement in outcomes compared with historical series, and shows that meaningful long-term survival is possible for selected carcinomatosis patients. Multi-institutional cooperative trials are needed to refine the use of CS and HIPEC.

Sentinel lymph node biopsy during pregnancy: initial clinical experience.

The diagnosis of breast cancer or melanoma in a pregnant patient presents some unique and difficult challenges for both patients and providers. Lymphatic mapping and sentinel lymph node (SLN) biopsy has become an attractive alternative to elective lymphadenectomy procedures for patients with breast cancer and melanoma. However, there is no data on the safety or utility of sentinel node mapping in pregnant patients. Therefore, we reviewed our experience with mapping in gravid patients. Academic institutions throughout North Carolina were asked to contribute cases of mapping performed during pregnancy. A total of nine women underwent sentinel node mapping during pregnancy. All nine were Caucasian with an average age of 32. SLN were found in all cases and mapping procedures were for breast cancer (three), and melanoma (six). There were no adverse reactions to the SLN procedures and one patient developed a seroma at a biopsy site. All went on to have term deliveries without known adverse effects.This limited experience shows that SLN mapping procedures are feasible in pregnant patients. However, this is not a general endorsement of such procedures in pregnant patients. We suggest that potential risks of vital dye or radioactive tracers be clearly explained to the parents when the mother is a candidate for a mapping procedure, and be balanced against the risk of delaying therapy or omitting nodal staging.

Rapid photothermal intracellular drug delivery using multiwalled carbon nanotubes.

Carbon nanotubes are unique materials that absorb infrared (IR) radiation, especially between 700 and 1100 nm, where body tissues are most transparent. Absorbed IR promotes molecular oscillation leading to efficient heating of the surrounding environment. A method to enhance drug localization for peritoneal malignancies is perfusion of warm (40-42 degrees C) chemotherapeutic agents in the abdomen. However, all tissues in the peritoneal cavity are subjected to enhanced drug delivery due to increased cell membrane permeability at hyperthermic temperatures. Here we show that rapid heating (within ten seconds) of colorectal cancer cells to 42 degrees C, using infrared stimulation of nanotubes as a heat source, in the presence of the drugs oxaliplatin or mitomycin C, is as effective as two hours of radiative heating at 42 degrees C for the treatment of peritoneal dissemination of colorectal cancer. We demonstrate increased cell membrane permeability due to hyperthermia from multiwalled carbon nanotubes in close proximity to cell membranes and that the amount of drug internalized by colorectal cancer cells heated quickly using carbon nanotubes equals levels achieved during routine application of hyperthermia at 42 degrees C. This approach has the potential to be used as a rapid bench to bedside clinical therapeutic agent with significant impact for localizing chemotherapy agents during the surgical management of peritoneal dissemination of colorectal cancer.

Gene expression profiling of peritoneal metastases from appendiceal and colon cancer demonstrates unique biologic signatures and predicts patient outcomes.

BACKGROUND Treatment of peritoneal metastases from appendiceal and colon cancer with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) shows great promise. Although long-term disease-free survival is achieved in some cases with this procedure, many patients have recurrence. Oncologists have treated such recurrences of appendiceal cancer similarly to colorectal carcinoma, which has been largely ineffective. This study uses gene expression analysis of peritoneal metastases to better understand these neoplasms. STUDY DESIGN From a prospectively maintained database and tissue bank, 41 snap frozen samples of peritoneal metastases (26 appendiceal, 15 colorectal) from patients undergoing HIPEC with complete cytoreduction and more than 3 years of follow-up underwent global gene expression analysis. Distinct phenotypes were identified using unsupervised hierarchical clustering based on differential gene expression. Survival curves restratified by genotype were generated. RESULTS Three distinct phenotypes were found, 2 consisting of predominantly low grade appendiceal samples (10 of 13 in Cluster 1 and 15 of 20 in Cluster 2) and 1 consisting of predominantly colorectal samples (7 of 8 in Cluster 3). Cluster 1 consisted of patients with good prognosis and Clusters 2 and 3 consisted of patients with poor prognosis (p = 0.006). Signatures predicted survival of low- (Cluster 1) vs high-risk (Cluster 2) appendiceal (p = 0.04) and low-risk appendiceal (Cluster 1) vs colon primary (Cluster 3) (p = 0.0002). CONCLUSIONS This study represents the first use of gene expression profiling for appendiceal cancer, and demonstrates genomic signatures quite distinct from colorectal cancer, confirming their unique biology. Consequently, therapy for appendiceal lesions extrapolated from colonic cancer regimens may be unfounded. These phenotypes may predict outcomes guiding patient management.