Amplifying Curcumin's Antitumor Potential: A Heat-Driven Approach for Colorectal Cancer Treatment.

Introduction: Peritoneal metastases from colorectal cancer (CRC) present a significant clinical challenge with poor prognosis, often unresponsive to systemic chemotherapy. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment approach for select patients. The use of curcumin, a natural compound with antitumor properties, in HIPEC is of interest due to its lower side effects compared to conventional drugs and potential for increased efficacy through direct delivery to the peritoneal cavity. Methods: An in vitro hyperthermic model was developed to simulate clinical HIPEC conditions. Three colon cancer cell lines (SK-CO-1, COLO205, SNU-C1) representing different genetic mutations (p53, KRAS, BRAF) were treated with either curcumin (25 µM) or mitomycin-C (1 µM) for 1, 2, or 3 hours. Post-treatment, cells were incubated at 37°C (normothermia) or 42°C (hyperthermia). Cell viability and proliferation were assessed at 24, 48 and 72 hours post-treatment using Annexin V/PI, MTT assay, trypan blue exclusion, and Hoffman microscopy. Results: Hyperthermia significantly enhanced the antitumor efficacy of curcumin, evidenced by a two-fold reduction in cell viability compared to normothermia across all cell lines. In the SNU-C1 cell line, which harbors a p53 mutation, mitomycin-C failed to significantly impact cell viability, unlike curcumin, suggesting mutation-specific differences in treatment response. Discussion: The findings indicate that hyperthermia augments the antitumor effects of curcumin in vitro, supporting the hypothesis that curcumin could be a more effective HIPEC agent than traditional drugs like mitomycin-C. Mutation-associated differences in response to treatments were observed, particularly in p53 mutant cells. While further studies are needed, these preliminary results suggest that curcumin in HIPEC could represent a novel therapeutic strategy for CRC patients with peritoneal metastases. This approach may offer improved outcomes with fewer side effects, particularly in genetically distinct CRC subtypes.

Adoption of cytoreductive surgery in the management of peritoneal malignancies-Global trends.

Cytoreductive surgery (CRS) has now been accepted as an integral component in the management of gastrointestinal and gynecological cancers with peritoneal metastases. Since the adoption of CRS is influenced by access to advanced medical facilities, trained multidisciplinary teams, and funding, there is wide variability in incorporation of CRS into routine clinical practice between high- versus low- and middle-income countries. This review highlights the global trends in the adoption of CRS for peritoneal malignancies with a specific focus on the establishment of CRS programs and barriers to incorporate CRS into routine clinical care in low- and middle-income countries.

The role of cytoreductive surgery and intraperitoneal chemotherapy in gastric cancer.

Gastric cancer (GC) with peritoneal carcinomatosis (PC) progresses rapidly and has historically dismal survival rates. Given the aggressive tumor biology and poor survival outcomes of patients with GC/PC, additional treatments beyond systemic chemotherapy are needed. Cytoreductive surgery and intraperitoneal chemotherapy have been effective management options for peritoneal surface malignancies, with increasing data to support their use in GC/PC. This review highlights the evolution of the surgical treatment of GC/PC, and discusses critical studies supporting the role of cytoreductive surgery, appropriate patient selection, and various methods in the delivery of intraperitoneal chemotherapy for patients with GC/PC.

Factors Predictive of Outcomes after Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy for Colon and Appendiceal Carcinomatosis: A Single-Institution Experience.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), although considered an acceptable treatment option in the management of selected patients with colon and appendiceal peritoneal carcinomatosis (PC), concerns about morbidity have limited its acceptance. Our objective was to evaluate the short- and long-term outcomes of CRS/HIPEC for appendix and colon PC performed at our institution and to elucidate factors predictive of patient outcomes. All patients who underwent CRS/HIPEC for appendix or colon PC from 2011 to 2017 were identified from our institution's prospective database. Postoperative outcomes, overall survival, and recurrence-free survival were assessed. Of 125 patients who underwent CRS/HIPEC during the study period, 45 patients were eligible (appendix n = 26; colon n = 19). The median postoperative length of stay was nine days (5-28 days). Grade III/IV complications occurred in 4/45 (8.8%) patients. There were no postoperative mortalities. Median DFS and overall survival have not yet been reached, in both the colon and appendix groups. As of the study conclusion date, 37/45 (82.2%) patients were alive with or without disease. Lymph node status was predictive of recurrence in appendix PC. In our experience, CRS/HIPEC can be safely performed with acceptable short- and long-term outcomes. Lymph node status is an important predictor of recurrence.

Is Fecal Diversion Needed in Pelvic Anastomoses During Hyperthermic Intraperitoneal Chemotherapy (HIPEC)?

BACKGROUND: The role of fecal diversion with pelvic anastomosis during cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is not well defined. METHODS: A retrospective review of patients who underwent CRS and HIPEC between 2009 and 2016 was performed to identify those with a pelvic anastomosis (colorectal, ileorectal, or coloanal anastomosis). RESULTS: The study identified 73 patients who underwent CRS and HIPEC at three different institutions between July 2009 and June of 2016. Of these patients, 32 (44%) underwent a primary anastomosis with a diverting ileostomy, whereas 41 (56%) underwent a primary anastomosis without fecal diversion. The anastomotic leak rate for the no-diversion group was 22% compared with 0% for the group with a diverting ileostomy (p < 0.01). The 90-day mortality rate for the no-diversion group was 7.1%. The hospital stay was 14.1 ± 8.0 days in the diversion group compared with 17.9 ± 12.5 days in the no-diversion group (p = 0.12). Of those patients with a diverting ileostomy, 68% (n = 22) had their bowel continuity restored, 18% of which required a laparotomy for reversal. Postoperative complications occurred for 50% of those who required a laparotomy and for 44% of those who did not require a laparotomy (p = 0.84). CONCLUSION: Diverting ileostomies in patients with a pelvic anastomosis undergoing CRS and HIPEC are associated with a significantly reduced anastomotic leak rate. Reversal of the diverting ileostomy in this patient population required a laparotomy in 18% of the cases and had an associated morbidity rate of 50%.

Initial Results of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome.

Multigene panel testing for hereditary cancer risk has recently become commercially available; however, the impact of its use on patient care is undefined. We sought to evaluate results from implementation of panel testing in a multidisciplinary cancer center. We performed a retrospective review of consecutive patients undergoing genetic testing after initiating use of multigene panel testing at Loma Linda University Medical Center. From February 13 to August 25, 2014, 92 patients were referred for genetic testing based on National Comprehensive Cancer Network guidelines. Testing was completed in 90 patients. Overall, nine (10%) pathogenic mutations were identified: five BRCA1/2, and four in non-BRCA loci. Single-site testing identified one BRCA1 and one BRCA2 mutation. The remaining mutations were identified by use of panel testing for hereditary breast and ovarian cancer. There were 40 variants of uncertain significance identified in 34 patients. The use of panel testing more than doubled the identification rate of clinically significant pathogenic mutations that would have been missed with BRCA testing alone. The large number of variants of uncertain significance identified will require long-term follow-up for potential reclassification. Multigene panel testing provides additional information that may improve patient outcomes.

The American Society of Peritoneal Surface Malignancies evaluation of HIPEC with Mitomycin C versus Oxaliplatin in 539 patients with colon cancer undergoing a complete cytoreductive surgery.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are gaining acceptance as treatment for selected patients with colorectal cancer with peritoneal carcinomatosis (CRCPC). Tremendous variations exist in the HIPEC delivery. METHODS: The American Society of Peritoneal Surface Malignancies (ASPSM) examined the overall survival in patients with CRCPC who underwent a complete cytoreduction and HIPEC with Oxaliplatin vs. Mitomycin C (MMC), stratifying them by the Peritoneal Surface Disease Severity Score (PSDSS). RESULTS: Median overall survival (OS) of 539 patients with complete cytoreduction was 32.6 months, 32.7 months for the MMC group and 31.4 months for the Oxaliplatin group (P = 0.925). However, when stratified by PSDSS, median OS rates in PSDSS I/II patients were 54.3 months in those receiving MMC vs. 28.2 months in those receiving oxaliplatin (P = 0.012), whereas in PSDSS III/IV patients, median OS rates were 19.4 months in those receiving MMC vs. 30.4 months in those receiving Oxaliplatin (P = 0.427). CONCLUSION: These data suggest that MMC might be a better agent for HIPEC delivery than Oxaliplatin in patients with CRCPC, favorable histologies and low burden of disease (PSDSS I/II) undergoing complete cytoreduction. Prospective studies are warranted, which stratify patients by their PSDSS and randomize them to HIPEC with MMC vs. Oxaliplatin.

The American Society of Peritoneal Surface Malignancies (ASPSM) Multiinstitution Evaluation of the Peritoneal Surface Disease Severity Score (PSDSS) in 1,013 Patients with Colorectal Cancer with Peritoneal Carcinomatosis.

BACKGROUND: Extensive clinical experience suggests that hyperthermic intraperitoneal chemotherapy (HIPEC) may play an important role in the management of colorectal cancer patients with peritoneal carcinomatosis (CRCPC). However, there remains no established nonsurgical process to rationally select patients for this management, either for inclusion/stratification in clinical trials or as a component of standard of care. The Peritoneal Surface Disease Severity Score (PSDSS) was introduced as a basis to improve patient selection. METHODS: The American Society of Peritoneal Surface Malignancies conducted a retrospective review of 1,013 CRCPC patients. The PSDSS was evaluated on 3 specific criteria obtained before surgery (symptoms, extent of peritoneal dissemination, and primary tumor histology). Overall survival was analyzed according to four tiers of disease severity, and a comparison was made between patients who underwent cytoreductive surgery + HIPEC and those who did not. RESULTS: The PSDSS was calculated on 884 patients (87 %). The median survival of 275 patients not undergoing CRS/HIPEC based on their PSDSS-I (n = 8), II (n = 80), III (n = 55), and IV (n = 132)-was 45, 19, 8, and 6 months, respectively. The median survival of 609 patients who underwent CRS/HIPEC based on their PSDSS-I (n = 75), II (n = 317), III (n = 82), and IV (n = 135)-was 86, 43, 29, and 28 months, respectively. CONCLUSIONS: These data support that the PSDSS, undertaken before surgery, is capable of defining CRCPC populations who have a statistically defined high or considerably lower likelihood of long-term survival after CRS/HIPEC. The PSDSS can be quite useful in the decision to enter CRCPC patients into, and their stratification within, clinical trials.

Prediction of the adequacy of lymph node retrieval in colon cancer by hospital type.

BACKGROUND: Examination of 12 or more regional lymph nodes (LNs) is the accepted minimum for nodal staging in colon cancer and serves as a surrogate for adequate resection. OBJECTIVE: To determine the contributing role of the hospital in the number of LNs retrieved. Design/ SETTING: We retrospectively reviewed colon resections in 83 patients by 2 surgical oncologists at a National Comprehensive Cancer Network (NCCN) hospital or at community-based hospitals from January 1, 2002, through December 31, 2007. PATIENTS: We included all patients undergoing colectomy for primary colon cancer and excluded patients with recurrence, rectal cancer, or preoperative chemotherapy. MAIN OUTCOME MEASURES: Total number of LNs retrieved. We also analyzed clinical factors accounting for differences. RESULTS: The median number of LNs examined at the NCCN hospital (42 patients) vs the community hospitals (41 patients) were 17.8 vs 7.0 (P < .001), and the frequency of an inadequate number of LNs examined (<12) was 11 of 42 cases (26%) vs 35 of 41 cases (85%) (P < .001). Potential predictive factors for LNs retrieved were grouped into modifiable (hospital type, surgeon, and surgical approach [laparoscopic vs open]) and nonmodifiable (age, sex, and tumor location). On multivariate analysis of the factors, hospital type was the only modifiable factor predictive of LNs reported (P < .001). CONCLUSIONS: Our study is the first, to our knowledge, to demonstrate that the number of LNs removed in colectomies performed by the same 2 surgeons depends on the hospital type (NCCN vs community) in which the resection occurred. We postulate that the number of LNs retrieved may be related to the institution's pathological review in addition to the extent of surgical resection.

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

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