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The best management of patients who have unresectable mucinous appendiceal cancer (MAC) with peritoneal spread after a failed attempt at cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is unclear. This study aimed to assess outcomes after systemic chemotherapy (SCT) for patients with unresectable peritoneal metastases from high-grade MAC.A single-center retrospective cohort study was conducted using a prospective CRS/HIPEC database. The study included high-grade MAC patients with peritoneal carcinomatosis who were deemed surgical candidates, but had an aborted CRS/HIPEC or only palliative HIPEC due to unresectable disease. Overall survival (OS) was compared.Of 72 identified patients, 20 received SCT and 52 did not (NoCT). The groups were balanced by age (p = 0.299), sex (p = 0.930), histopathologic subtype (p = 0.096), preoperative chemotherapy (p = 0.981), and postoperative major complication rates (p = 0.338). Both groups had extensive disease (median peritoneal cancer index at exploration, 39 vs 39). The median number of cycles was 12 (interquartile range [IQR], 6-15), and the median time between the procedure and SCT was 7 weeks (IQR, 5-10 weeks). The median follow-up period was 65 months. The median OS was significantly higher for the SCT group (26 months; 95 % confidence interval [CI], 10.8-41.5 months) than for the NoCT group (12 months; 95 % CI, 9.6-14.4 months) (p0.001), with hazard ratio (HR) of 0.22 (95 % CI, 0.08-0.66; p = 0.007) after adjustment for other factors.Systemic chemotherapy is associated with improved OS for high-grade MAC patients with unresectable peritoneal metastases who are deemed surgical candidates but underwent an unsuccessful CRS/HIPEC attempt. Further prospective studies with a larger sample are required to identify patient subgroups who benefit the most from SCT.

Purpose: Pseudomyxoma peritonei is an understudied cancer in which an appendiceal neoplasm invades the peritoneum and forms tumor foci on abdominal organs. Previous studies have shown that bacteria reside within pseudomyxoma peritonei tumors and mucin. Thus, we sought to analyze the effect of antibiotics on bacterial density and β-catenin expression within pseudomyxoma peritonei samples.Experimental Design: The study included 48 patients: 19 with disseminated peritoneal adenomucinosis (DPAM) and 29 with peritoneal mucinous carcinomatosis (PMCA). Fourteen patients were given antibiotics (30 mg lansoprazole, 1 g amoxicillin, and 500 mg clarithromycin) twice a day for 14 days. One week after completion of therapy, surgery was conducted and specimens were harvested for pathology, bacterial culture, ISH, and immunohistochemistry.Results: ISH showed the presence of bacteria in 83% of the patient samples, with a higher Helicobacter pylori density observed in PMCA versus DPAM. PMCA patients treated with antibiotics had a significantly lower bacterial density and decreased β-catenin levels in the cytoplasm, the cell nuclei, and mucin-associated cells. Although not significant, similar trends were observed in DPAM patients. Cell membrane β-catenin was significantly increased in both DPAM and PMCA patients receiving antibiotics.Conclusions: Bacteria play an important role in pseudomyxoma peritonei. Antibiotic treatment improved the histopathology of tissue, particularly in PMCA patients. In PMCA, antibiotics decreased bacterial density and were associated with a significant β-catenin decrease in the cytoplasm, cell nuclei, and mucin along with a small membrane increase. These results suggest that antibiotics offer potential protection against cell detachment, cellular invasion, and metastasis. Clin Cancer Res; 19(14); 3966–76. ©2013 AACR.

Live Dead Staining Figure S1 - PDF file 142K, Live Dead Staining of bacteria

Live Dead Staining Legend - PDF file 75K, Legend to Figure S1

Supplementary Materials - PDF file 297K, Additional methods for studies described within the manuscript

Diaphragmatic resection (DR) is often required during cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) to achieve complete cytoreduction (CC). While CC provides the best survival, requiring a DR may indicate unfavorable tumor biology. We assessed how DR during CRS/HIPEC affects outcomes. A retrospective cohort study was conducted using a prospective single-center database from October 1994–May 2020. Peritoneal surface malignancy patients who underwent CRS/HIPEC with CC-0/1/2 were assigned to DR and NoDR groups. Survival was measured using the Kaplan–Meier method. Subgroup analysis was performed for patients with peritoneal cancer index (PCI) ≥ 20 to eliminate confounding of more extensive disease in DR. Of 824 CRS/HIPECs, 774 were included: 134 DR and 640 NoDR. PCI was significantly higher in DR: 29 versus 21, p < 0.001. CC-0/1 rate was 89% in DR and 95% in NoDR (p = 0.003). Neither 100-day morbidity nor mortality differed between the groups (p = 0.355 and p = 1.000). Median follow-up was 64 months. Median overall survival (OS) was significantly lower in DR (32 vs. 96 months, p < 0.001). Subgroup analysis by tumor type in patients with PCI ≥ 20 showed significantly shorter OS in DR than NoDR in appendiceal (40 vs. 196 months, p < 0.001) and colorectal (14 vs. 23 months, p = 0.003), but not in ovarian tumors (32 vs. 42 months, p = 0.893), whereas median PCI did not differ among subgroups. DR during CRS/HIPEC does not increase morbidity and mortality. It is associated with worse survival in appendiceal and colorectal tumors, even after adjusting for tumor burden but does not appear to impact ovarian cancer survival.

Surgeons may hesitate to perform nephrectomy (NE) during cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) due to a potential increase in morbidity. However, no data are available regarding the impact of NE on outcomes, so the authors decided to assess its safety during CRS/HIPEC.A single-center propensity score-matched study was conducted using a prospective database (1994-2021). The study included patients who underwent NE during CRS/HIPEC with completeness of cytoreduction (CC) of 0, 1, or 2. Control subjects (no-NE) were selected in a 1:3 ratio using propensity score-matching weighted by age, histology, peritoneal cancer index (PCI), CC-0 or CC-1 rate, and length of surgery.Among 828 patients, 13 NE and 39 no-NE control subjects were identified. The indications for NE included tumor involvement of the ureter, hilum, and/or kidney with preserved (n = 8), decreased (n = 2), or absent (n = 3) function. NE patients received more intraoperative intravenous (IV) fluids (16,000 vs 11,500 mL; p = 0.045) and had a greater urine output (3200 vs 1913 mL; p = 0.008). NE patients received mitomycin C (40 mg for 90 min) or melphalan (50 mg/mNephrectomy performed during CRS/HIPEC does not seem to increase postoperative morbidity or to delay adjuvant chemotherapy, and NE can be performed if required for complete cytoreduction. The NE patients in our cohort did not have a reduction of mitomycin C or melphalan dose or perfusion time.

Women 65 years of age or older with epithelial ovarian cancer (EOC) are thought to have a worse prognosis than younger patients. However, no consensus exists concerning the best treatment for ovarian cancer in this age group. This report presents outcomes for patients treated with cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC). A prospective database of EOC patients treated with CRS/HIPEC (1998–2019) was analyzed. Perioperative variables were compared by treatment including upfront CRS/HIPEC, neoadjuvant chemotherapy plus CRS/HIPEC (NACT + CRS/HIPEC), and salvage CRS/HIPEC, and by age at surgery (

Background. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) after neoadjuvant chemotherapy (NACT) showed promise as initial treatment for stage IIIC (SIII) epithelial ovarian cancer (EOC); however, stage IV (SIV) outcomes are rarely reported. We assessed our experience and outcomes treating newly diagnosed SIV EOC with NACT plus CRS/HIPEC compared to SIII patients. Methods. Advanced EOC from 2015–2018 managed with NACT (carboplatin/paclitaxel) due to unresectable disease or poor performance status followed by interval CRS/HIPEC were reviewed. Perioperative factors were assessed. Overall survival (OS) and progression-free survival (PFS) were analyzed by stage. Results. Twenty-seven FIGO stage IIIC (n = 12) and IV (n = 15) patients were reviewed. Median NACT cycles were 3 and 4, respectively. Post-NACT omental caking, ascites, and pleural effusions decreased/resolved in 91%, 91%, and 100% of SIII and 85%, 92%, and 71% of SIV. SIII/SIV median PCI was 21 and 20 obtaining 92% and 100% complete cytoreduction (≤0.25 cm), respectively. Median organ resections were 6 and 7, respectively. Grade III/IV surgical complications were 0% SIII and 23% SIV, without hospital mortality. Median time to adjuvant chemotherapy was 53 and 74 days, respectively ( p = 0.007 ). SIII OS at 1 and 2 years was 100% and 83% and 87% and 76% in SIV ( p = 0.269 ). SIII 1-year PFS was 54%; median PFS: 12 months. SIV 1- and 2- year PFS was 47% and 23%; median PFS: 12 months ( p = 0.944 ). Conclusion. Outcomes in select initially diagnosed and unresectable SIV EOC are similar to SIII after NACT plus CRS/HIPEC. SIV EOC may benefit from CRS/HIPEC, and further studies should explore this treatment approach.

Low-grade appendiceal mucinous neoplasms (LAMN) are tumors that frequently present with peritoneal spread of either acellular mucin (AM) or cellular mucin (CM). We aim to determine how mucin types and distribution affect survival. PATIENTS AND METHODS: A retrospective cohort study was conducted using a prospective database. Newly diagnosed LAMN patients with AM versus CM treated with cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) were compared. Postoperative pathology reports were reviewed to assess each involved abdominal zone. Survival was analyzed using the Kaplan-Meier method.Of 121 identified patients, 50 (41%) had peritoneal lesions with AM and 71 (59%) with CM. Peritoneal cancer index was lower in AM versus CM (mean: 19 ± 13 vs 28 ± 10, p = 0.004), but complete cytoreduction (CC) rates were similar (98% vs 96%, p = 0.642). The 5-year progression-free survival (PFS) was higher in AM versus CM (96% vs 69.8%, p = 0.002). CM patients had zones with both types of lesions: with and without cells. The CM subgroup analysis showed significant differences in 5-year progression-free survival (PFS) among patients with 1-3, 4-7, and 8-10 zones with cells (95.2%, 68.4%, and 35.7%, respectively, p 0.001), but PFS was not affected by the number of zones with any lesion type. There was no difference in overall survival (OS) between groups.Despite comparable CC rates after CRS/HIPEC, CM patients have shorter PFS than AM patients. In CM patients, more zones with cells, but not the total number of involved zones, negatively impact PFS. Mucin type does not impact OS. It is important to assess and report mucin cellularity in LAMN specimens.

Pseudomyxoma peritonei (PMP) is a subtype of peritoneal carcinomatosis that is traditionally treated by cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC). A growing body of evidence suggests that microbes are associated with various tumor types and have been found in organs and cavities that were once considered sterile. Prior and ongoing research from our consortium of PMP researchers strongly suggests that bacteria are associated with PMP tumors. While the significance of this association is unclear, in our opinion, further research is warranted to understand whether these bacteria contribute to the development, maintenance and/or progression of PMP. Elucidation of a possible causal role for bacteria in PMP could suggest a benefit for supplementation of antibiotics to current treatment protocols.

MD Anderson Cancer Center developed a computed tomography (CT)-based preoperative assessment tool simplified preoperative assessment for appendix tumor (SPAAT) for predicting incomplete cytoreduction (IC) in low-grade mucinous adenocarcinoma (LGMA) of the appendix, based on preoperative CT scans. This study independently evaluates the tool’s performance. Seventy-six preoperative CT scans of LGMA patients were evaluated by two surgeons unfamiliar with the patients’ medical history. Scores were assigned based on SPAAT criteria, with a SPAAT ≥3 predictive of IC. Binary regression analyses and area under the receiver operating characteristic (AUROC) curve analyses were performed. Patients with splenic resection were excluded due to the structure of the SPAAT assessment tool. Seventy-six LGMA patients underwent attempted cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Of 68 patients, 58 had complete cytoreduction and 10 had IC; 8 patients were ineligible due to prior splenectomy. The mean SPAAT score was 0.8, with six patients having SPAAT scores ≥3. SPAAT scores ≥3 were predictive of IC, with a hazard ratio (HR) of 19 (95% confidence interval 2.8–124.1) (p = 0.002). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value were 40, 97, 50, and 90%, respectively. A SPAAT score ≥3 was not associated with worse survival prognosis. Median follow-up was 2.4 years and AUROC curve was 71%. SPAAT components with respective HR and p-values were foreshortening of the bowel mesentery (29.5; p = 0.004), and scalloping of the pancreas (9; p = 0.008), spleen (4.3; p = 0.04), portal vein (3.1; p = 0.4), and liver (2.1; p = 0.3). A SPAAT score ≥3 predicted IC based on a binary regression model. The clinical value of this score is controversial due to low sensitivity and PPV.

Survival in peritoneal dissemination from appendiceal cancer after complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) varies within each histopathologic subtype. Analyzing patients with unique responses may uncover the mechanisms behind their extreme outcomes. We proposed a method to identify retrospectively and to characterize patients who responded exceptionally well or very poorly within each histopathologic subtype. Retrospective review of patients with low-grade mucinous carcinoma peritonei (LGMCP), high-grade MCP (HGMCP), and HGMCP with signet ring cells (HGMCP-S) with complete CRS/HIPEC (CC-0/1) was performed. Patients were divided by recurrence status. Median follow-up was calculated for each. Exceptional responders (ExR) were defined as alive without recurrence after median follow-up of the nonrecurrent group. Poor responders (PoR) were defined as disease recurrence before median follow-up of the recurrent group. Perioperative characteristics were analyzed. LGMCP, HGMCP, and HGMCP-S had 48 (41%), 19 (23%), and 7 (14%) ExR and 11 (10%), 20 (24%), and 20 (39%) PoR, respectively. All ExR had lower median PCI (26 vs. 36 [p = 0.004]; 13 vs. 33.5 [p

Background. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is debated. Melphalan as a perfusion agent has also demonstrated survival benefit in other recurrent and chemoresistant malignancies. Thus, we hypothesize that melphalan as a HIPEC agent may improve overall survival (OS) and progression-free survival (PFS) in patients with PC from CRC. Methods. A retrospective review of a prospective database of 48 patients who underwent optimal CRS (CC-0/1) and HIPEC from 2001-2016 was performed. Nineteen had CRS/HIPEC with melphalan (group I) and 29 with mitomycin-C (group II). Survival was estimated using the Kaplan-Meier method. Cox regression was used for multivariate analysis. Perioperative variables were compared. Results. Mean age at CRS/HIPEC was 53±10 years. Median peritoneal cancer index (PCI) was 17 vs 13 in groups I and II, respectively (p=0.86). PCI≥20 occurred in 9 (47%) and 13 (45%) patients in groups I and II, respectively. Positive lymph nodes were identified in 8/19 (42%) vs 12/29 (41%) in groups I and II, respectively (p=0.73). Multivariate analysis identified PCI≥20 as a predictive factor of survival (HR: 7.5). Median OS in groups I and II was 36 and 28 months, respectively (p=0.54). Median PFS in groups I and II was 10 and 20 months, respectively (p=0.05). Conclusions. CRS/HIPEC with MMC had longer median PFS in PC from CRC. PCI≥20 was the only independent predictive factor for survival. Until longer follow-up is available, we recommend using MMC in CRS/HIPEC for PC from CRC. Further prospective randomized studies are necessary.

We evaluated the 7th edition of the American Joint Committee on Cancer (AJCC) staging classification in terms of overall survival (OS) in patients with PMP treated with cytoreductive surgery (CRS)/hyperthermic intraperitoneal chemotherapy (HIPEC). A total of 208 PMP patients treated with CRS/HIPEC were identified from a prospective database. Patients with peritoneal mucinous carcinomatosis (PMCA) were retrospectively staged at time of diagnosis according to AJCC staging classification. Patients with disseminated peritoneal adenomucinosis (DPAM) were evaluated in a separate group. Median follow-up was 5.2 years. Of 208 patients, 124 had PMCA and 84 patients had DPAM. According to the AJCC staging classification 47 lymph node (LN) negative patients with well-differentiated PMCA, were classified as a stage IVA. 77 patients with either moderately or poorly differentiated PMCA irrespective of LN status, or well-differentiated PMCA with positive LN were classified as stage IVB. 84 patients with DPAM, constituted a separate group. OS of stage IVA and IVB patients was 100, 90, 67, and 91, 50, and 27 for 1, 3, and 5 years, respectively (p

Background Patients with PMCA commonly undergo surgery before CRS/HIPEC. We evaluated the role of extensive surgical treatment before CRS/HIPEC in terms of overall survival (OS). Methods 105 patients with PMCA who underwent a CRS/HIPEC procedure were identified from a prospective database. Patients were divided into two groups based on Prior Surgery Score (PSS): PSS ≤1 limited surgery group (LSG), PSS >1 extensive surgery group (ESG). Survival of lymph node (LN) negative and positive patients was analyzed separately. Results 40 patients were in LSG and 65 in ESG. Mean time from diagnosis to CRS/HIPEC was 6 and 17 months for LSG and ESG, respectively (p = 0.004). Groups were well balanced in peritoneal cancer index, complete cytoreduction rate, and LN status. One, 3, and 5-year OS among LN negative patients was 95, 83, and 75% for the LSG (n = 22) group and 87, 55, and 32% for the ESG (n = 35), group respectively (p = 0.026). One, 3, and 5-year OS among LN positive patients was 69, 50, and 17% for the LSG (n = 18) group and 80, 21, and 14% for the ESG (n = 30), group respectively (p = 0.613). For all patients 1, 3, and 5-year OS was 84, 65, and 54% for the LSG (n = 40) group and 86, 43, and 26% for the ESG (n = 65) group, respectively (p = 0.029). Conclusion Extensive surgical treatment before CRS/HIPEC is associated with delay of CRS/HIPEC and poorer OS overall, especially among LN negative patients. We recommend early referral of PMCA patients to a peritoneal surface malignancy center.

Background The role of SC before CRS/HIPEC for patients with PMCA is unclear. This study explores the effect of SC prior to CRS/HIPEC on overall survival (OS) in patients with PMCA. Methods 72 patients with recently diagnosed PMCA who underwent CRS/HIPEC were identified from a prospective database. Thirty patients had SC before CRS/HIPEC (Group 1) and 42 did not (Group 2). Patients who were referred to our center after multiple lines of SC were excluded from this analysis. OS was estimated. Results Median follow-up was 3.2 years. Groups were similar regarding lymph node positivity, postoperative SC and rate of complete cytoreduction. Twenty-four (80%) patients in Group 1 and 21 (50%) in Group 2 had high grade histology (HG) (p = 0.01). OS from CRS/HIPEC at 1, 2, and 3 years was 93, 68, 51% in Group 1 and 82, 64, 60% in Group 2, respectively (p = 0.74). Among HG patients 3-year survival was 36% in the SC group vs. 35% in the group without SC (p = 0.67). The 3-year OS for patients with low grade (LG) tumors was 100% in the SC group vs. 79% in the group with no prior SC (p = 0.26). Among patients with signet ring cell (SRC) histology, 1, 2 and 3-year survival was 94, 67 and 22% in the SC group vs. 43, 14, 14% in the group with no SC, respectively (p = 0.028). There were only 6 patients with LG PMCA who received prior SC. Conclusions Preoperative SC could improve the prognosis of patients with high-grade PMCA with SRC histology.

Port-site metastases (PSMs) have been reported after laparoscopy in patients with peritoneal carcinomatosis (PC). We hypothesize that PSM is an independent negative predicting factor of survival in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). A retrospective review of a prospective database was conducted to search patients who underwent laparoscopy prior to CRS/HIPEC. Most of the tumors were of appendiceal origin. All previous laparoscopy port sites were excised regardless of macroscopic tumor involvement. Patients were divided into two groups: patients with PSM [PSM (+)] and patients without PSM [PSM (−)]. Overall survival (OS) was estimated by Kaplan–Meier curves and the log-rank test. Cox regression [hazard ratios (HRs) and 95 % confidence intervals (CIs)] was used to test for independent effects of the PSM (+) and the associated clinicopathological variables. Sixty-five patients had laparoscopy before CRS/HIPEC. One hundred and forty-four port-sites were resected; 41 (29 %) ports were positive for malignancy in a total of 22 (34 %) patients. Mean OS at 1, 3, and 5 years was 88, 66, and 63 %, respectively. Survival in patients with PSM was 73, 35, and 23 %, respectively, compared with 95, 82, and 82 %, respectively, in patients without PSM (p ≤ 0.001). Positive lymph nodes (LNs) were detected in 13/22 patients with PSM and 11/43 patients without PSM. Independent effects on survival shows an HR of 3.136, 95 % CI 1.150–8.549 (p = 0.026) for LN metastases, and an HR of 3.462, 95 % CI 1.198–10.006 (p = 0.022) in patients with positive PSM. PSMs are common in patients with PC undergoing CRS/HIPEC and are independently associated with a worse prognosis. Resection of previous laparoscopy port sites is advocated in patients with PC to ensure complete cytoreduction.

CRS/HIPEC has evolved as a therapeutic option for selected patients with peritoneal surface malignancies. To achieve complete cytoreduction (CC), some patients require extensive abdominal-wall resection (AWR) and subsequent complex reconstructions, which may be associated with wound complications (WC) and delay of postoperative cancer therapy. Review of a prospective database of 350 patients revealed 213 patients with peritoneal carcinomatosis who underwent AWR due to suspected or proven wound/port site metastases during CRS/HIPEC. Tumor origin included: appendix, colon, ovarian, peritoneal mesothelioma, primary peritoneal, and others. WC were related to peritoneal carcinomatosis index (PCI), CC score, length of surgery, type of AWR and closure, blood transfusion, and albumin levels using binary logistic regression (odds ratios (OR) and 95 % CIs) analysis. PCI ≥ 20 was found in 151 (71 %), CC was achieved in 178 (84 %). Mean length of surgery was 613 min. Postoperative WC were detected in 49 of 213 (23 %) patients, 13 (6 %) had Grade III (according to Clavien–Dindo’s classification) WC, and led to delay of postoperative chemotherapy. WC occurred in 21 of 64 (32.8 %) patients with excision of port sites (odds ratio [OR] = 2.11, confidence interval [CI] = 1.09–4.10, p = 0.026). Primary fascial closure was performed in 191 of 213 (89.7 %) patients, 40 (21 %) of whom had WC. Mesh-assisted abdominal wall reconstruction was required in 22 of 213 (10.3 %) patients, of whom 9 (40.9 %) had WC (OR = 2.61, CI = 1.04–6.55, p = 0.035). Port-site excision and mesh-assisted abdominal wall reconstruction were associated with higher incidence of postoperative WC following CRS/HIPEC. The implications of these preliminary findings may need to be considered during surgical planning for these patients.

Background Vascular endothelial growth factor (VEGF) is a prognostic factor and target treatment for metastatic colorectal and ovarian cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has improved survival on peritoneal carcinomatosis (PC) from appendiceal cancer. We hypothesize that tumoral high expression of VEGF receptor 2 (VEGFR-2) is a negative prognostic factor for survival in patients with PC from appendiceal cancer. Methods A retrospective study of a prospective database revealed 89 patients with PC from appendiceal cancer who underwent 127 CRS/HIPECs. Surgical specimens from 59 patients were tested to identify high vs. low VEGFR-2 expression. Patient outcomes and survival were analyzed. Results There were 26 males and 33 females. Mean age was 51 years. Forty-seven VEGFR-2 high expressers and 15 low expressers were identified. Mean follow-up of high and low expressers was 25.1 and 26.6 months, respectively (p = 0.806). At follow-up, 33 (70%) high expressers were alive and 14 (30%) deceased, while 11 (92%) low expressers were alive and 1 (8%) deceased. Recurrence, use of bevacizumab, CC score, PCI, and LN status showed no differences between high and low expressers. OS for high expressers was 90.5%, 59.8%, and 47.1% at 1-, 3-, and 5-years, respectively, while OS for low expressers remained stable at 91.7% at 1-, 3-, and 5-years (p = 0.133). Conclusion There is a trend towards better outcomes and survival in patients with PC from appendiceal cancer who have low expression of VEGFR-2 compared to high expression. More studies are encouraged to confirm this trend.

Background Cytoreductive surgery (CRS)/hyperthermic intraperitoneal chemotherapy (HIPEC) is the procedure of choice in patients with peritoneal dissemination from appendiceal cancer. Although recurrence rates are 26%–44% after first CRS/HIPEC, the role of repeated CRS/HIPEC has not been well defined. We hypothesize that patients undergoing multiple CRS/HIPEC's have meaningful long term survival. Methods A retrospective study of a prospective database of 294 patients with peritoneal carcinomatosis (PC) was conducted, of these 162 had PC of appendiceal origin. Twenty-six of these patients underwent 56 CRS/HIPEC. Survival and outcomes was analyzed. Results The percentage of patients with pre-surgical PCI scores ≥20 for the first, second, and third CRS/HIPEC was 65, 65, and 25%, respectively. Complete cytoreduction (CC 0-1) at first, second, and, third surgeries was 96, 65 and 75%, respectively. The mean operating time was 10.1 h. There was no 30-day peri-operative mortality. Following the first, second, and third CRS/HIPEC 27, 42, and 50% experienced grade III complications, respectively. Mean follow up was 51, 28, and 16 months from the first, second, and third CRS/HIPEC, respectively. Overall survival rate for the first CRS/HIPEC was 100, 83, 54, and 46% at years 1, 3, 5 and 10, respectively; from the second CRS/HIPEC 91, 53, and 34% at 1, 3, and 5 years, respectively; and from the third CRS/HIPEC was 75% at one year. Conclusion Repeat CRS/HIPEC can lead to meaningful long term survival rates in patients with appendiceal peritoneal carcinomatosis with morbidity and mortality similar to those of the initial CRS/HIPEC.

Purpose: Pseudomyxoma peritonei is an understudied cancer in which an appendiceal neoplasm invades the peritoneum and forms tumor foci on abdominal organs. Previous studies have shown that bacteria reside within pseudomyxoma peritonei tumors and mucin. Thus, we sought to analyze the effect of antibiotics on bacterial density and β-catenin expression within pseudomyxoma peritonei samples. Experimental Design: The study included 48 patients: 19 with disseminated peritoneal adenomucinosis (DPAM) and 29 with peritoneal mucinous carcinomatosis (PMCA). Fourteen patients were given antibiotics (30 mg lansoprazole, 1 g amoxicillin, and 500 mg clarithromycin) twice a day for 14 days. One week after completion of therapy, surgery was conducted and specimens were harvested for pathology, bacterial culture, ISH, and immunohistochemistry. Results: ISH showed the presence of bacteria in 83% of the patient samples, with a higher Helicobacter pylori density observed in PMCA versus DPAM. PMCA patients treated with antibiotics had a significantly lower bacterial density and decreased β-catenin levels in the cytoplasm, the cell nuclei, and mucin-associated cells. Although not significant, similar trends were observed in DPAM patients. Cell membrane β-catenin was significantly increased in both DPAM and PMCA patients receiving antibiotics. Conclusions: Bacteria play an important role in pseudomyxoma peritonei. Antibiotic treatment improved the histopathology of tissue, particularly in PMCA patients. In PMCA, antibiotics decreased bacterial density and were associated with a significant β-catenin decrease in the cytoplasm, cell nuclei, and mucin along with a small membrane increase. These results suggest that antibiotics offer potential protection against cell detachment, cellular invasion, and metastasis. Clin Cancer Res; 19(14); 3966–76. ©2013 AACR.

Cytoreductive surgery/heated intraperitoneal chemotherapy (CRS/HIPEC) has been shown to be effective for selected patients with advanced appendiceal cancer. We propose that delaying CRS/HIPEC leads to disease progression and affects outcome. A retrospective analysis of a prospective database was carried out. Patients were divided into two groups based on time from diagnosis to CRS/HIPEC (less than 6 months = early, greater than 6 months = delayed). Comparison was made of Peritoneal Cancer Index (PCI), Prior Surgery Score (PSS), complete cytoreduction (CC), and lymph node status. Overall survival (OS) was calculated using Kaplan-Meier estimates. Of 127 patients, 50 had disseminated peritoneal adenomucinosis and 77 had peritoneal mucinous carcinomatosis (PMCA). Of patients with PMCA, 41 had early CRS/HIPEC and 36 delayed. PCI was less than 20 in 46 and 17 per cent ( P = 0.007) of the early and delayed groups, respectively. CC was achieved in 88 and 61 per cent ( P = 0.009) of the early and delayed groups, respectively. PSS was (2 of 3) in 51 and 91 per cent ( P = 0.001) of the early and delayed groups, respectively. Five-year OS was 54 per cent for the early group and 45 per cent for the delayed group ( P = 0.2). Delaying CRS/HIPEC was associated with higher tumor load and lower chance for complete cytroreduction. Longer follow-up and larger numbers are needed to determine if OS difference will reach statistical significance.

Although essential hypertension (HTN) is the most common type of HTN, nearly 10% of patients have a secondary cause. Primary hyperaldosteronism (PHA) accounts for up to 23% of secondary HTN depending on criteria, screening methods, and the population studied.1 Aldosterone-producing adenomas, known as Conn’s syndrome, represent nearly 30% of PHA cases. Symptoms of PHA are nonspecific and may be easily missed, leading instead to the diagnosis of essential HTN. Two patients with a long history of HTN, hypokalaemia, and vague symptoms were followed by multiple specialties (internal medicine, cardiology, and endocrinology), but had not been diagnosed with Conn’s syndrome. Two cases are presented here as a means to raise awareness of this condition (Conn’s syndrome) among primary care practitioners (PCPs), because it is a potentially curable cause of HTN. A 46-year-old white female with a 6-year history of presumed essential HTN presented to her PCP with fatigue, myalgias, migraines, generalised anxiety, decreased libido, paresthesias, polydipsia, polyuria, trace peripheral oedema, heart palpitations, and shortness of breath over the previous 2 years, as well as a 1-month unexplained weight gain (3 kg). Fluctuating serum potassium levels (with the lowest of 2.1 mEq/L) were reported. Antihypertensive medications (nifedipine and hydrochlorothiazide) were deemed the cause of hypokalaemia. Oral potassium supplements and spironolactone were prescribed. A chest CT scan was unremarkable, but, incidentally, a 1.8 × 1.2 cm …

Patients with peritoneal mucinous carcinomatosis (PMCA) of appendiceal origin and extensive disease are commonly advised against CRS/HIPEC. We hypothesize that CRS/HIPEC is a beneficial treatment for this group. Retrospective analysis of 134 patients with appendiceal cancer treated with CRS/HIPEC was performed from a prospective database. Extent of disease, measured by peritoneal cancer index (PCI), was related to completeness of cytoreduction (CC), lymph node (LN) status, and prior surgery score (PSS). Overall survival (OS) was estimated by Kaplan-Meier curves. Test differences were calculated using log-rank test. A total of 77 patients (57%) had PMCA. Mean follow-up was 22 months with a median of 18 months. OS was 88%, 56%, and 40% for 1, 3, and 5 years, respectively. 68% had PCI ≥ 20. LN metastasis was found in 44% of patients in PCI ≥ 20 and PCI

Pseudomyxoma peritonei (PMP) is characterized by peritoneal tumors arising from a perforated appendiceal adenoma or adenocarcinoma, but associated entry of enteric bacteria in the peritoneum has not been considered as a cofactor. Because Gram-negative organisms can upregulate MUC2 mucin gene expression, we determined whether bacteria were detectable in PMP tissues.In situ hybridization was performed on resection specimens from five control subjects with noninflamed, nonperforated, non-neoplastic appendix and 16 patients with PMP [six with disseminated peritoneal adenomucinosis (DPAM) and 10 with peritoneal mucinous carcinomatosis (PMCA)]. Specific probes were designed to recognize: (1) 16S rRNA common to multiple bacteria or specific to H. pylori; (2) H. pylori cagA virulence gene; or (3) MUC2 or MUC5AC apomucins. Specimens from one patient with PMCA were examined by ultrastructural immunohistochemistry. Bacterial density and apomucin expression were determined in four histopathological compartments (epithelia, inflammatory cells, stroma, and free mucus).Enteric bacteria were detected in all specimens. Bacterial density and MUC2 expression were significantly (p0.05) higher in PMCA than in DPAM and controls and were highest in free mucin. MUC2 was also expressed in dysplastic epithelia and in associated inflammatory cells. MUC2 expression was significantly correlated with bacterial density.Multiple enteric bacteria are present in PMP, and bacterial density and MUC2 expression is highest in the malignant form of PMP. Based on these observations, we propose that the bacteria observed in PMP may play a role in the mucinous ascites and perhaps promote carcinogenesis.

Diffuse malignant peritoneal mesothelioma (DMPM) is an uncommon malignancy, which can be difficult to treat. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have evolved as the treatment of choice when complete cytoreduction is to be achieved. This study reports the outcomes of CRS/HIPEC for peritoneal mesothelioma performed in a center for peritoneal surface malignancy. A retrospective analysis of a prospective database of 389 CRS/ HIPEC procedures identified 23 patients who underwent CRS/HIPEC for DMPM from 1999 to 2014. Gender, age at diagnosis, age at surgery, previous surgeries, follow-up time, peritoneal cancer index (PCI) score, completeness of cytoreduction (CC), pathology, and overall survival (OS) were analyzed. The univariate analysis was used to determine the prognostic value of age, gender, neoadjuvant chemotherapy, histopathology of the tumor, PCI, CC, and lymph node status on survival. Mean follow-up time from surgery was 31 months (range = 0.5–124). The median PCI score was 28, and 77 per cent had PCI ≥20. CC 0–1 was achieved in 65 per cent of cases. One- and 5-year actuarial OS rates from diagnosis were 86 per cent and 60 per cent, respectively. One- and 5-year actuarial OS from HIPEC was 70 per cent and 64 per cent, respectively. The univariate analysis showed that the CC was the only significant prognostic factor. Patients with DMPM may achieve long-term survival when treated with CRS/HIPEC. The CC is the most significant prognostic factor for long-term survival.

4098 Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) have become standard of care for patients with peritoneal carcinomatosis (PC) from appendiceal cancer (AC). We reviewed our experience and outcomes. Methods: A retrospective review of 614 CRS/HIPEC procedures from 1998-2016 was performed. Patient characteristics, surgical variables, and postoperative outcomes of first CRS/HIPEC were analyzed. Results: Two hundred ninety patients with PC from AC underwent 334 CRS/HIPEC’s. Median age at diagnosis and surgery was 52 (22-79) and 53 (23-81) years, respectively; 65% (187) were female. Prior surgical score was 0, 1, 2, and 3 in 20%, 38%, 37%, and 5%, respectively. Prior systemic chemotherapy was reported in 30% of patients. Median time from diagnosis to CRS/HIPEC was 4 months (0-182). Pre-operative tumor markers (CEA, CA-125, CA-19-9) were positive in 48% with one, two, and three positive markers in 21%, 15%, and 13% patients, respectively. Median Peritoneal Cancer Index was 29. Mitomycin-C was the HIPEC agent of choice. Mean operative time was 10 hours (R: 4-19) and median length of stay was 10 days (R: 4-93). Histology included 59% (171) peritoneal mucinous carcinomatosis (PMCA), 41% (119) disseminated peritoneal adenomucinosis (DPAM). Lymph nodes were positive in 47% PMCA. Complete cytoreduction rate was 87% (84% PMCA, 92% DPAM [p = 0.048]). Grade III-V complications occurred in 21%, with one 30-day mortality (0.3%). Overall, median progression-free survival (PFS) was 84 months with 5-year PFS of 56%. Median PFS was 43 months in PMCA and not reached in DPAM. Five year PFS was 40% PMCA and 82% DPAM (p < 0.001). Median overall survival (MOS) was 139 months with 61% 5-year OS. MOS was 53 months in PMCA and not reached in DPAM. Five year OS was 47% PMCA and 85% DPAM (p < 0.001). At 42-month median follow-up, 68% were alive (92 PMCA/103 DPAM) with 84% disease free (72 PMCA/92 DPAM), 28% died of disease (73 PMCA/7 DPAM). Conclusions: CRS/HIPEC is an effective treatment for patients with PC from AC providing meaningful long term survival in low and high grade tumors and should be considered the standard of care.

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has survival benefit in the treatment of selected patients with peritoneal carcinomatosis (PC) from appendiceal cancer (AC). We evaluated factors affecting the survival of patients with PC from AC after CRS/HIPEC. A retrospective analysis of 387 CRS/HIPEC procedures performed between February 1998 and February 2013 identified 202 patients with PC from AC. Tumor histopathology, complete cytoreduction (CC 0–1), Peritoneal Cancer Index (PCI), and lymph node (LN) status were related to overall survival (OS) and progression-free survival (PFS) using the Kaplan–Meier method. Overall, 129 women (64 %) and 73 men (36 %), mean age 54 years (range 25–81), with a mean follow-up of 36 months were included in the study. Seventy-seven low-grade tumors (disseminated peritoneal adenomucinosis [DPAM]; 38 %) and 125 high-grade tumors (peritoneal mucinous carcinomatosis [PMCA]; 62 %) were identified. Five- and 10-year OS was 56 % and 47 %, respectively, with PFS of 44 % at 5 and 10 years. Five-year OS in DPAM patients was 83 %, with a 5-year OS significant difference related to CC 0–1 versus CC 2–3 (incomplete cytoreduction) [p = 0.021]. Five-year OS in PMCA patients was 41 %, with a 5-year OS significant difference related to CC 0–1 versus CC 2–3 (p

Surgery, the most effective treatment for colon and rectal cancer, is based on empirical knowledge of the patterns of tumor spread, gross findings at laparotomy, and histologic confirmation of tumor-free margins. In spite of the many technical improvements in surgery, there has not been a significant change in cure rates for colon and rectal cancers. In fact, one-half of affected patients will not survive 5 years. It is in this arena of treatment for primary colon and rectal cancer patients that radioimmunoguided surgery (RIGS) technology may provide the most benefit. RIGS is an intraoperative procedure for detection of carcinoma lesions that are targeted with a radiolabeled monoclonal antibody (MAb) to provide the surgeon with immediate intraoperative definition of tumor margins and identification of occult disease. To optimize this technique, our studies were designed to increase tumor uptake by higher affinity CC-49 (a second-generation MAb) and to increase tumor antigen expression using biological response modifiers (BRMs). The ability of BRMs, such as interferons (IFNs), to enhance the expression of tumor-associated antigens, may play an important role in an adjuvant setting for MAb-based treatment. Preclinical and clinical data provided evidence for the use of IFN as an adjuvant to enhance MAb-targeting of human carcinoma lesions. A combination protocol with IFN and RIGS is ongoing at our institution.

PURPOSE: An accurate determination of the extent or staging of a disease is critical, because it provides the basis for making therapeutic decisions. Staging is a collaborative effort by the surgeon and the pathologist. Radioimmunoguided surgery has been evaluated for its ability to help surgeons determine the extent of disease during surgery, when management decisions have the most impact on patient care. This study was done to compare radioimmunoguided surgery “biostaging” with traditional pathologic staging (TNM) as predictors of survival in patients undergoing curative resections for colorectal cancer. METHODS: Ninety-seven patients with colorectal cancer were prospectively enrolled in radioimmunoguided surgery protocols. Evaluation of follow-up survival data was performed. All patients underwent exploratory laparotomy and radioimmunoguided surgery with resection of their primary colorectal tumor. Survival data were analyzed with the Kaplan-Meier method with log-rank comparisons. RESULTS: Of 97 patients enrolled in the study, 59 were evaluable and completely resectable by radioimmunoguided surgery. Mean follow-up was 62 months, with a range of 34 to 89 months. By traditional staging 13 patients were pStage I, 18 patients were pStage II, and 28 patients were pStage III. By radioimmunoguided surgery biostaging, 24 patients were radioimmunoguided surgery-negative whereas 35 patients were radioimmunoguided surgery-positive. Survival rates by pathologic stage approached a significant difference, but did not, as of the conclusion of the study period, reach it (P=0.12). Survival rates based on radioimmunoguided surgery status demonstrated a highly significant difference (P=0.0002). CONCLUSIONS: Radioimmunoguided surgery biostaging provides new information intraoperatively on cancer staging that has not been available before. This may lead to new strategies for therapy that can be individualized and optimized for each patient with cancer.

Bei ca. 50 % der Patienten mit lokalisiertem colorectalem Carcinom werden im Verlauf der Erkrankung Rezidive gesichert. Diese Rezidive werden als Manifestation von, bei der Erstoperation nicht entfernten, regionalen oder extraregionalen Mikrometastasen aufgefast (peripheres Blut oder Knochenmark). In unserer Arbeitsgruppe wurde ein Verfahren zur Entdeckung nicht sichtbarer, abdomineller Metastasen entwickelt. Dazu wird vor der Operation ein radioaktiv markierter Antitumorzellen-Antikorper injiziert („radioimmunoguided surgery“, RIGS). Trotz Einsatz fortschrittlicher Technologien ist es nicht moglich, im Falle einer hamatogenen Dissemination alle Mikrometastasen zu entfernen. Ausgehend von dem Wissen um die gestorte humorale Immunantwort, die gegen die freigesetzten tumorassoziierten Antigene (TAA), gerichtet ist, haben wir eine neue Methodik entwickelt, um die Immunantwort der B-Zellen und die Rekrutierung aller B-Zellen, verursacht durch die chronische TAA-Immunkomplexprasentation auf den follicularen dentritischen Zellen, zu reduzieren und zu korrigieren („immune corrective surgery“, ICS). Diese Methode basiert auf einer selektiven Lymphadenektomie. Die Ziellymphknoten sind die, welche mit TAA-Immunkomplexen beladen sind. Als Detektionsmethode wahlten wir die Injektion von radioaktiv markierten Antikorpern, die fahig sind, die Immunkomplexe zu erkennen. Von 20 Patienten (Stadium I, II und III), die mit ICS therapiert wurden, uberlebten 17 mehr als 5 Jahre. Wenn diese Patientengruppe mit einer historischen Gruppe verglichen wird, zeigt sich ein signifikanter Uberlebensvorteil. Zusammenfassend zeigen diese Daten, das die Chirurgie des colorectalen Carcinoms selektiv auf spezifische anatomische Regionen ausgedehnt werden sollte, um bisher verborgen gebliebene Mikrometastasen zu entfernen. Ein weiterer, noch wichtigerer Vorteil ist es, das die postoperative Immunantwort korrigiert wird, die die T-Zellantwort gegen residuale Tumorzellen supprimieren konnte.

The survival of patients with recurrent or metastatic colorectal cancer usually is less than 12 months. In an attempt to improve this dismal prognosis, we investigated the role of intraoperative high dose rate brachytherapy (IOHDR) in the management of these patients.From April 1992 to December 1996, 26 patients with locally recurrent or metastatic colorectal carcinoma were treated with maximal surgical resection and IOHDR. Intraoperative radiation dose ranged from 10 to 20 Gy, prescribed at 0.5 cm depth. The residual tumor irradiated was microscopic in 16 patients (62%) and gross residual in 10 patients (38%). Six patients received postoperative external beam radiation therapy.After a median follow-up of 28 months (range 6 to 54 months), seven of 15 evaluable patients (47%) failed in the area treated with IOHDR. The median time to local failure was 21 months (range 4 to 52 months). The median survival was 23 months (microscopic 24 months; gross 17 months), with a 4-year actuarial survival rate of 36%. Major morbidity was observed in 7 patients (47%) and usually was surgery-related.The use of IOHDR in association with radical resection increases local control in patients with recurrent or metastatic colorectal cancer. Patients with microscopic residual disease achieved a better result than do those with gross residual disease. Future strategies include the addition of limited EBRT dose to IOHDR, even for previously irradiated patients.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has become an option for peritoneal carcinomatosis (PC). Frequently, these patients have failed systemic chemotherapies and surgeries, including CRS/HIPEC with traditional regimens (mitomycin-C or platinum based). An alternative agent for failed or repeated CRS/HIPEC is unknown. We hypothesize that melphalan is an alternative agent in patients with PC from aggressive primaries, including recurrences following failed regional therapies.A retrospective review of a prospective database of 247 patients revealed 25 patients (9 male and 16 female) who received intraperitoneal melphalan (50 mg/m(2)) in 31 CRS/HIPEC procedures, of which 19 were repeated. Primary malignancies included 17 appendiceal, one colorectal, two ovarian, two uterine sarcomas, two primary peritoneal and one mesentery sarcoma.PC index (PCI) was ≥20 in 76 % of patients (19/25). 88 % of patients (22/25) had complete cytoreduction. Seventeen patients were alive, with mean survival of 63.6 months, and eight patients are deceased. Overall survival (OS) for the entire group since diagnosis was 95.8, 84.5, 50.9, and 38.2 % at 1, 3, 5, and 10 years, respectively; OS since melphalan HIPEC was 89.4, 45, and 30 % at 1, 3, and 5 years, respectively; and OS in patients with appendiceal malignancies was 91.7, 48.1 and 32.1 % at 1, 3 and 5 years, respectively. There was no postoperative mortality. Grade III-IV morbidity was 23 % (7/31). Nine patents had neutropenia, controlled with filgrastim.Melphalan is an efficacious alternative agent in patients undergoing CRS/HIPEC for aggressive and recurrent peritoneal surface malignancies. Its postoperative significant myelosuppression effect should be addressed.

Background Pseudomyxoma peritonei (PMP) is a malignancy characterized by dissemination of mucus-secreting cells throughout the peritoneum. This disease is associated with significant morbidity and mortality and despite effective treatment options for early-stage disease, patients with PMP often relapse. Thus, there is a need for additional treatment options to reduce relapse rate and increase long-term survival. A previous study identified the presence of both typed and non-culturable bacteria associated with PMP tissue and determined that increased bacterial density was associated with more severe disease. These findings highlighted the possible role for bacteria in PMP disease. Methods To more clearly define the bacterial communities associated with PMP disease, we employed a sequenced-based analysis to profile the bacterial populations found in PMP tumor and mucin tissue in 11 patients. Sequencing data were confirmed by in situ hybridization at multiple taxonomic depths and by culturing. A pilot clinical study was initiated to determine whether the addition of antibiotic therapy affected PMP patient outcome. Main results We determined that the types of bacteria present are highly conserved in all PMP patients; the dominant phyla are the Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes. A core set of taxon-specific sequences were found in all 11 patients; many of these sequences were classified into taxonomic groups that also contain known human pathogens. In situ hybridization directly confirmed the presence of bacteria in PMP at multiple taxonomic depths and supported our sequence-based analysis. Furthermore, culturing of PMP tissue samples allowed us to isolate 11 different bacterial strains from eight independent patients, and in vitro analysis of subset of these isolates suggests that at least some of these strains may interact with the PMP-associated mucin MUC2. Finally, we provide evidence suggesting that targeting these bacteria with antibiotic treatment may increase the survival of PMP patients. Conclusions Using 16S amplicon-based sequencing, direct in situ hybridization analysis and culturing methods, we have identified numerous bacterial taxa that are consistently present in all PMP patients tested. Combined with data from a pilot clinical study, these data support the hypothesis that adding antimicrobials to the standard PMP treatment could improve PMP patient survival.

In treating high-grade appendiceal cancer, appropriate patient selection for cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) is essential. The effect of lymph node (LN) status on survival is not clear. We hypothesize that LN metastases negatively affect long-term survival.Retrospective analysis of peritoneal mucinous carcinomatosis (PMCA) patients from a prospective database was conducted. Using Kaplan-Meier survival curves and Cox proportional hazards ratio analysis, the effect of LN status, completeness of cytoreduction (CC), and peritoneal cancer index (PCI) was studied.Of 134 patients with appendiceal cancer who underwent CRS/HIPEC, 77 (57%) had PMCA. Mean follow-up was 22 (range, 3-90) months. Overall survival (OS) was 88, 56, and 40% for 1, 3, and 5-year, respectively. Thirty-four patients (44%) had LN metastases, 23 of whom (68%) had CC, whereas in LN negative patients 35 of 43 (81%) had CC (p = 0.191). PCI ≥ 20 was seen in 23 of 34 patients (68%) with LN metastases and 29 of 43 (67%) without metastases (p = 0.191). Five-year OS for patients with LN metastases was 11% compared with 76% for LN negative (p 0.001). Among patients with complete cytoreduction, 5-year OS for LN positive vs. negative was 21 and 73%, respectively (p = 0.002). On multivariate regression analysis of LN status, CC score and PCI, the following hazard ratios were obtained: 3.4 (95% confidence interval (CI), 1.3-9.0), 2.6 (95% CI, 1.03-6.7), and 2.8 (95% CI, 0.8-10.4), respectively.Patient selection for CRS/HIPEC should take into consideration LN status, but it should not be a contraindication if preoperative evaluation revealed a high likelihood of complete cytoreduction.

Nude mice bearing CX-1 colon tumors were injected with 50 microCi 125I-labeled monoclonal antibody (MAb) B72.3. Radioactivity in tumors was studied with the gamma detecting probe (GDP) on days 1, 3, 7, and 10 after MAb injection. On each day, two mice were sacrificed and sections were examined with autoradiography (ARG), immunoperoxidase methods (IMP), and routine stains. Mean probe counts showed increasing tumor to background ratios and ARG demonstrated a progressive increase in radionuclide in the tumors. The distribution of 125I was primarily around the vascular spaces on day 1, but by day 3 and progressively it appeared in tumor gland lumina and necrotic areas. A regional correlation was shown between radionuclide in vascular spaces and its sequestration in tumor elements.

Objective Peritoneal sarcomatosis from primary uterine sarcoma (US) is a rare condition. Conventional therapeutic modalities have failed to improve survival and outcomes among patients with high-grade US with extrapelvic spread. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has shown improved outcomes for peritoneal carcinomatosis from other epithelial primaries with similar clinical presentation. We report our experience applying this treatment in 3 patients with recurrent high-grade US with peritoneal dissemination. Study Design This retrospective review of a prospective database of 378 patients with peritoneal dissemination of cancer treated with CRS/HIPEC identified 3 patients with recurrent high-grade US. Follow-up for disease progression was carried out by physical examination and computed tomography scan of the chest, abdomen, and pelvis. Results Two leiomyosarcomas and 1 adenosarcoma with sarcomatous overgrowth were identified. Two of the 3 had failed standard treatment with surgery and systemic chemotherapy before CRS/HIPEC was performed. Follow-up ranged from 34 to 140 months. All 3 patients are alive, 2 with no evidence of disease (NED), and 1 alive with disease. Adramycin/cisplatin was used for HIPEC in 1 case (140 months with NED), whereas melphalan was used in the other 2 cases (53 months alive with disease, 34 months with NED). Two patients underwent 1 CRS/HIPEC, whereas 1 required 3 CRS/HIPEC due to disease recurrence. Conclusion CRS/HIPEC shows promise as a treatment modality for the management of selected patients with recurrent high-grade US with peritoneal dissemination. Further studies are warranted.

Purpose: The clinical target volume (CTV) to be irradiated by intraoperative radiation therapy (IORT) after resection is generally based on the surgeon's estimation of close margins. We have developed a new technique, radioimmunoguided-intraoperative radiation therapy (RIG-IORT), that uses an intraoperative hand-held gamma-detecting probe to define areas of residual microscopic disease containing radiolabeled monoclonal antibodies to tumor associated antigen, to more precisely delineate the CTV for IORT. Methods and Materials: Patients were injected i.v. with 2 mCi 125 I- radiolabeled CC49 antibody approximately 3 weeks before surgery. They then underwent radioimmunoguided surgery (RIGS) with maximal resection of tumor. A hand-held gamma-detecting probe (Neoprobe 1000) was used intraoperatively to detect and resect areas of high radioactivity, representing tumor. Areas with persistently high probe counts after resection were the areas of occult residual disease, and represented the CTV to be irradiated. The IORT was given with either 6–9 MeV electron beam from a dedicated linear accelerator, or with high-dose-rate brachytherapy from a remote afterloader. If all RIGS-positive tissue had been resected, or if widely disseminated disease remained, the patient was not considered for IORT. Result: This technique was used in 31 patients with colorectal adenocarcinoma recurrent into the pelvis ( n = 23) or paraortic nodes ( n = 8). The CTV for IORT was delineated by increased RIGS count in 13 of 19 patients (68%) with microscopic residual, and in 11 of 12 patients (92%) with gross residual. In the other 7 patients, the tumor area did not accumulate the radiolabeled antibody; therefore, these tumor beds were irradiated based on the surgeon's estimation of close margins. Hence, overall, the RIG-IORT technique was used to define the tumor bed for IORT in 24 of 31 patients (77%). This technical report focuses on the development of the RIG-IORT technique and does not address the outcome results of the treated patients. Conclusion: A new technique, RIG-IORT, which uses radiolabeled monoclonal antibodies to precisely determine the CTV for IORT, is described. Whether the use of this technique will lead to improved tumor control will only be known upon the outcome analysis of RIG-IORT-treated patients compared with those obtained using traditional IORT techniques.

Background: Protein antigens are presented to cytotoxic T lymphocytes as small peptides (approximately 9-10 amino acids long) bound to class I molecules of the major histocompatibility complex. The identification of tumor-associated antigens and specific peptide epitopes (i.e., antigenic determinants) may be useful in the development of anticancer vaccines. The generation of a cytotoxic T-cell response to one peptide epitope (amino acids 146-154) of human prostate-specific antigen (PSA) has been reported. Purpose: Our aim was to identify novel PSA peptides capable of eliciting specific cytotoxic T-cell responses. Methods: Candidate peptides were identified on the basis of the following criteria: 1) they contained consensus amino acid motifs for binding to HLA-A2, which is the most common type of class I molecule; 2) they lacked strong homology with PSA-related kallikrein proteins; and 3) they were capable of stabilizing HLA-A2 class I molecules on the surface of human T2 (transport deletion mutant) cells, which are defective in antigen presentation. T-cell lines capable of killing (i.e., lysing) T2 target cells that had been pulsed with specific PSA peptides were generated from three different males (two disease-free individuals and one patient with prostate cancer) by incubating peripheral blood mononuclear cells with the peptides and interleukin 2. Specific cell lysis was monitored by the release of radioactivity from target cells that had been labeled with [ 111 In]oxyquinoline. Results: Two novel PSA peptides capable of eliciting cytotoxic T-cell responses were identified ; these peptides were designated PSA-1 (amino acids 141-150) and PSA-3 (amino acids 154-163). Four different cytotoxic T-cell lines were generated in response to these peptides-three against PSA-3 and one against PSA-1. Specific lysis of peptide-pulsed T2 cells by the T-cell lines was blocked by the addition of a monoclonal antibody directed against class I molecules. The T-cell lines were also capable of lysing PSA-positive, HLA-A2-positive LNCaP cells (human prostate carcinoma cells). The specificity of LNCaP cell lysis was shown by the following: 1) the inability of added human K562 (chronic myelogenous leukemia) cells to inhibit it, 2) the ability of added anti-HLA-A2 antibodies to block it, and 3) the inability of the T-cell lines to induce substantial lysis of PSA-negative, HLA-A2-positive human cancer cells. Implications: Our studies form a rational basis for the use of PSA peptides or recombinant vectors encoding PSA in the development of anticancer vaccine immunotherapy protocols for patients with prostate cancer.