Distance Traveled and Disparities in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: The impact of distance traveled on cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) outcomes needs further investigation. METHODS: This retrospective study reviewed a prospectively managed single-center CRS/HIPEC 1992-2022 database. Zip codes were used to calculate distance traveled and to obtain data on income and education via census data. Patients were separated into three groups based on distance traveled in miles (local: ≤50 miles, regional: 51-99 miles, distant: ≥100 miles). Descriptive statistics, Kaplan-Meier method, and Cox regression were performed. RESULTS: The 1614 patients in the study traveled a median distance of 109.5 miles (interquartile range [IQR], 53.36-202.29 miles), with 23% traveling locally, 23.9% traveling regionally, and 53% traveling distantly. Those traveling distantly or regionally tended to be more white (distant: 87.8%, regional: 87.2%, local: 83.2%), affluent (distant: $61,944, regional: $65,014, local: $54,390), educated (% without high school diploma: distant: 10.6%, regional: 11.5%, local: 13.0%), less often uninsured (distant: 2.3%, regional: 4.6%, local: 5.2%) or with Medicaid (distant: 3.3%, regional: 1.3%, local: 9.7%). They more often had higher Peritoneal Carcinomatosis Index (PCI) scores (distant: 15.4, regional: 15.8, local: 12.7) and R2 resections (distant: 50.3%, regional: 52.2%, local: 40.5%). Median survival did not differ between the groups, and distance traveled was not a predictor of survival. CONCLUSION: More than 50% of the patients traveled farther than 100 miles for treatment. Although regionalization of CRS/HIPEC may be appropriate given the lack of survival difference based on distance traveled, those who traveled further had fewer health care disparities but higher PCI scores and more R2 resections, which raises concerns about access to care for the underserved, time to treatment, and surgical quality.

Quality-of-Life Outcomes for Patients Taking Opioids and Psychotropic Medications Before Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: The impact of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) on quality of life (QoL) for patients taking opioids and psychotropic medications preoperatively is unclear. METHODS: This study retrospectively reviewed a CRS-HIPEC single-center prospectively maintained database for 2012-2016. Demographics and clinical data on opioids/psychotropic medication use were collected via chart review. The study collected QoL outcomes at baseline, then 3, 6, and 12 months postoperatively via the Center for Epidemiologic Studies Depression Scale (CES-D), Brief Pain Inventory, Functional Assessment of Cancer Therapy, and 36-Item Short-Form Health Survey. Differences in QoL between the groups were calculated using repeated measures analysis of variance regression. Descriptive statistics and Kaplan-Meier analyses were performed. RESULTS: Of 388 patients, 44.8% were taking opioids/psychotropic medications preoperatively. At baseline, those taking opioids/psychotropic medications preoperatively versus those not taking these medications had significantly worse QoL. By 1 year postoperatively, the QoL measures did not differ significantly except for emotional functioning (e.g., no medications vs. opioids/psychotropic medications: CES-D, 5.6 vs. 10.1). Median survival did not differ significantly (opioids/psychotropic medications vs. no medications: 52.3 vs. 60.6 months; p = 0.66). At 1 year after surgery, a greater percentage of patients were taking opioids, psychotropic medications, or both than at baseline (63.2% vs. 44.8%; p < 0.001). CONCLUSION: Despite worse baseline QoL, patients who took opioids/psychotropic medications had QoL scores 1 year postoperatively similar to the scores of those who did not except in the emotional domains. These data point to the potential utility of a timed psychosocial intervention to enhance emotional adaptation and further support the role of CRS-HIPEC in improving QoL.

Enhancing the Efficacy of HIPEC Through Bromelain: A Preclinical Investigation in Appendiceal Cancer.

INTRODUCTION: Appendiceal cancer (AC) excessive mucin production is a barrier to heated intraperitoneal chemotherapy (HIPEC) drug delivery. Bromelain is a pineapple stem extract with mucolytic properties. We explored bromelain treatment effects against mucinous AC in a patient-derived tumor organoid (PTO) model and an AC cell line. PATIENTS AND METHODS: PTOs were fabricated from tumor specimens obtained from patients with AC undergoing cytoreductive surgery with HIPEC. PTOs underwent HIPEC treatment with bromelain, cisplatin, and mitomycin C (MMC) at 37 °C and 42 °C with and without bromelain pretreatment. RESULTS: From October 2020 to May 2023, 16 specimens were collected from 13 patients with low-grade (12/16, 75%) and high-grade AC (4/16, 25%). The mucin-depleting effects of bromelain were most significant in combination with N-acetylcysteine (NAC) compared with bromelain (47% versus 10%, p = 0.0009) or NAC alone (47% versus 12.8%, p = 0.0027). Bromelain demonstrated > 31% organoid viability reduction at 60 min (p < 0.001) and > 66% in 48 h (p < 0.0001). Pretreatment with bromelain increased cytotoxicity of both cisplatin and MMC HIPEC conditions by 31.6% (p = 0.0001) and 35.5% (p = 0.0001), respectively. Ki67, CK20, and MUC2 expression decreased after bromelain treatment; while increased caspase 3/7 activity and decreased Bcl-2 (p = 0.009) and Bcl-xL (p = 0.01) suggest induction of apoptosis pathways. Furthermore, autophagy proteins LC3A/B I (p < 0.03) and II (p < 0.031) were increased; while ATG7 (p < 0.01), ATG 12 (p < 0.04), and Becline 1(p < 0.03), expression decreased in bromelain-treated PTOs. CONCLUSIONS: Bromelain demonstrates cytotoxicity and mucolytic activity against appendiceal cancer organoids. As a pretreatment agent, it potentiates the cytotoxicity of multiple HIPEC regimens, potentially mediated through programmed cell death and autophagy.

Detection of Residual Peritoneal Metastases Following Cytoreductive Surgery Using Pegsitacianine, a pH-Sensitive Imaging Agent: Final Results from a Phase II Study.

BACKGROUND: For patients with peritoneal carcinomatosis, extent of disease and completeness of cytoreductive surgery (CRS) are major prognostic factors for long-term survival. Assessment of these factors could be improved using imaging agents. Pegsitacianine is a pH-sensitive polymeric micelle conjugated to the fluorophore indocyanine green. The micelle disassembles in acidic microenvironments, such as tumors, resulting in localized fluorescence unmasking. We assessed the utility of pegsitacianine in detecting residual disease following CRS. PATIENTS AND METHODS: NCT04950166 was a phase II, non-randomized, open-label, multicenter US study. Patients eligible for CRS were administered an intravenous dose of pegsitacianine at 1 mg/kg 24-72 h before surgery. Following CRS, the peritoneal cavity was reexamined under near-infrared (NIR) illumination to evaluate for fluorescent tissue. Fluorescent tissue identified was excised and evaluated by histopathology. The primary outcome was the rate of clinically significant events (CSE), defined as detection of histologically confirmed residual disease excised with pegsitacianine or a revision in the assessment of completeness of CRS. Secondary outcomes included acceptable safety and pegsitacianine performance. RESULTS: A total of 53 patients were screened, 50 enrolled, and 40 were evaluable for CSE across six primary tumor types. Residual disease was detected with pegsitacianine in 20 of 40 (50%) patients. Pegsitacianine showed high sensitivity and was well tolerated with no serious adverse events (SAEs). Transient treatment-related, non-anaphylactic infusion reactions occurred in 28% of patients. CONCLUSIONS: Pegsitacianine was well tolerated and facilitated the recognition of occult residual disease following CRS. The high rate of residual disease detected suggests that the use of pegsitacianine augmented surgeon assessment and performance during CRS.

Correlation of Morphological Appearance of Peritoneal Lesions at Laparotomy and Disease at Pathological Assessment in Patients Undergoing Cytoreductive Surgery for Peritoneal Malignancy: Results of Phase I of the PRECINCT Study in 707 Patients.

BACKGROUND: The PRECINCT (Pattern of peritoneal dissemination and REsponse to systemic Chemotherapy IN Common and uncommon peritoneal Tumors) is a prospective, multicenter, observational study. This report from phase I of PRECINCT outlines variations in recording the surgical peritoneal cancer index (sPCI) at experienced peritoneal malignancy centers and the incidence of pathologically confirmed disease in morphologically different peritoneal lesions (PL). METHODS: The sPCI was recorded in a prespecified format that included the morphological appearance of PL. Six prespecified morphological terms were provided. The surgical and pathological findings were compared. RESULTS: From September 2020 to December 2021, 707 patients were enrolled at 10 centers. The morphological details are routinely recorded at two centers, structure bearing the largest nodule, and exact size of the largest tumor deposit in each region at four centers each. The most common morphological terms used were normal peritoneum in 3091 (45.3%), tumor nodules in 2607 (38.2%) and confluent disease in 786 (11.5%) regions. The incidence of pathologically confirmed disease was significantly higher in 'tumor nodules' with a lesion score of 2/3 compared with a lesion score of 1 (63.1% vs. 31.5%; p < 0.001). In patients receiving neoadjuvant chemotherapy, the incidence of pathologically confirmed disease did not differ significantly from those undergoing upfront surgery [751 (47.7%) and 532 (51.4%) respectively; p = 0.069]. CONCLUSIONS: The sPCI was recorded with heterogeneity at different centers. The incidence of pathologically confirmed disease was 49.2% in 'tumor nodules'. Frozen section could be used more liberally for these lesions to aid clinical decisions. A large-scale study involving pictorial depiction of different morphological appearances and correlation with pathological findings is indicated.

A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 ocular retardation J mice.

BACKGROUND: A goal of developmental genetics is to identify functional interactions that underlie phenotypes caused by mutations. We sought to identify functional interactors of Vsx2, which when mutated, disrupts early retinal development. We utilized the Vsx2 loss-of-function mouse, ocular retardation J (orJ), to assess interactions based on principles of positive and negative epistasis as applied to bulk transcriptome data. This was first tested in vivo with Mitf, a target of Vsx2 repression, and then to cultures of orJ retina treated with inhibitors of Retinoid-X Receptors (RXR) to target Rxrg, an up-regulated gene in the orJ retina, and gamma-Secretase, an enzyme required for Notch signaling, a key mediator of retinal proliferation and neurogenesis. RESULTS: Whereas Mitf exhibited robust positive epistasis with Vsx2, it only partially accounts for the orJ phenotype, suggesting other functional interactors. RXR inhibition yielded minimal evidence for epistasis between Vsx2 and Rxrg. In contrast, gamma-Secretase inhibition caused hundreds of Vsx2-dependent genes associated with proliferation to deviate further from wild-type, providing evidence for convergent negative epistasis with Vsx2 in regulating tissue growth. CONCLUSIONS: Combining in vivo and ex vivo testing with transcriptome analysis revealed quantitative and qualitative characteristics of functional interaction between Vsx2, Mitf, RXR, and gamma-Secretase activities.

Exposure to Neoadjuvant Oxaliplatin-Containing Chemotherapy, Does it Effect Intraperitoneal Hyperthermic Chemotherapy Perfusion?

INTRODUCTION: Patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) are commonly exposed to oxaliplatin neoadjuvant chemotherapy (NAT) regimens. The impact of systemic exposure to oxaliplatin prior to HIPEC with oxaliplatin is unknown. METHODS: We conducted a retrospective review of our institutional registry of CRS/HIPEC cases who received oxaliplatin-containing NAT, and compared patients who underwent HIPEC with oxaliplatin versus cases perfused with mitomycin C. The primary outcome was survival, defined by overall survival (OS) and disease-free survival (DFS). Subgroup analysis was performed based on primary tumor etiology and completeness of cytoreduction. RESULTS: A total of 333 cases satisfied the selection criteria-159 appendiceal primaries (all high-grade disease) and 174 colorectal cases. Thirty-one cases (9.3%) underwent HIPEC with oxaliplatin, with the remaining 302 cases (90.7%) receiving mitomycin C. Both cohorts were identical in regard to baseline characteristics, and both groups were alike in regard to NAT regimens and oxaliplatin exposure. There was no difference in survival outcomes. OS times were 2.9 (± 2.8) and 2.8 ( ± 3.6) years for oxaliplatin and mitomycin C perfusions, respectively (p = 0.94), and the 5-year OS rates were also similar at 9.7 and 18.5% (odds ratio [OR] 0.49, 95% confidence interval [CI] 0.14-1.67, p = 0.24) for oxaliplatin and mitomycin cases, respectively. Likewise, DFS findings were similar, with survival of 2.5 (± 4.5) and 1.8 (± 2.4) years for oxaliplatin and mitomycin perfusions, respectively (p = 0.21). There was no difference in 5-year DFS rates, at 10.5 and 7.8% (OR 1.39, 95% CI 0.30-6.56, p = 0.68) for oxaliplatin and mitomycin C, respectively. Subgroup analysis found minimal discordant findings from the main results. CONCLUSION: This analysis found no discernable association with NAT oxaliplatin exposure in regard to survival outcomes following CRS/HIPEC stratified out by perfusion agent.

Switching Perfusion Agents for Repeat Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy: Surgical Dogma or Evidence-Based Practice?

BACKGROUND: A common practice is to switch chemotherapy perfusion agents for repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). However, there is a paucity of objective benefit with this practice. METHODS: A retrospective review of our institutional registry involving repeat CRS-HIPEC cases was conducted, comparing cases that underwent a perfusion agent switch versus those cases with no switch. The primary outcome of this study was survival, measured by overall survival (OS) and disease-free survival (DFS). A subgroup analysis was performed on the basis of primary etiology. RESULTS: A total of 101 cases met selection criteria. Mitomycin C was used as the index perfusion agent in 84% of cases, while oxaliplatin was utilized in the remaining 16% of cases. In total, 66 cases underwent a perfusion switch, with 35 cases using the same agent. Analysis revealed no survival benefit with HIPEC perfusion switch. For OS, there were similar mean survival times of 5.2 (± 4.1) years and 5.1 (± 3.6) years for cases with perfusion switch and no perfusion switch, respectively (P = 0.985). The 5-year OS rates were also similar at 61.4% and 53.3% for switch and non-switch cases, respectively [odds ratio (OR) 0.41, 95% confidence interval (CI) 0.54-3.56, P = 0.49]. Mean DFS was 4.0 (± 4.2) years and 3.6 (± 3.8) years for switch and non-switch cases, respectively (P = 0.74). The 5-year DFS rates had a greater difference with statistical trend, with rates of 53% versus 28% for switch and non-switch cases, respectively (OR 2.91, 95% CI 0.86-9.86, P = 0.081). Subgroup analysis had a similar trend to the main results. CONCLUSIONS: The study findings revealed no survival benefit with switching perfusion agents. Analysis suggests that the practice of perfusion switch is ineffective.

Does Preoperative MRI Reduce Positive Margins after Breast-Conserving Surgery?

BACKGROUND: Breast-conserving surgery (BCS) is a mainstay for breast cancer management, and obtaining negative margins is critical. Some have advocated for the use of preoperative magnetic resonance imaging (MRI) in reducing positive margins after BCS. We sought to determine whether preoperative MRI was associated with reduced positive margins. PATIENTS AND METHODS: The SHAVE/SHAVE2 trials were multicenter trials in ten US centers with patients with stage 0-3 breast cancer undergoing BCS. Use of preoperative MRI was at the discretion of the surgeon. We evaluated whether or not preoperative MRI was associated with margin status prior to randomization regarding resection of cavity with shave margins. RESULTS: A total of 631 patients participated. Median age was 64 (range 29-94) years, with a median tumor size of 1.3 cm (range 0.1-9.3 cm). Patient factors included 26.1% of patients (165) had palpable tumors, and 6.5% (41) received neoadjuvant chemotherapy. Tumor factors were notable for invasive lobular histology in 7.0% (44) and extensive intraductal component (EIC) in 32.8% (207). A preoperative MRI was performed in 193 (30.6%) patients. Those who underwent preoperative MRI were less likely to have a positive margin (31.1% versus 38.8%), although this difference was not statistically significant (p = 0.073). On multivariate analysis, controlling for patient and tumor factors, utilization of preoperative MRI was not a significant factor in predicting margin status (p = 0.110). Rather, age (p = 0.032) and tumor size (p = 0.040) were the only factors associated with margin status. CONCLUSION: These data suggest that preoperative MRI is not associated margin status; rather, patient age and tumor size are the associated factors.

Long-Term Survival in Patients Treated with Cytoreduction and Heated Intraperitoneal Chemotherapy for Peritoneal Mesothelioma at a Single High-Volume Center.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare diagnosis with a dismal prognosis if untreated. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is shown to significantly improve survival. Our institution is uniquely positioned to report long-term outcomes in MPM with CRS-HIPEC, due to our robust peritoneal surface disease program existing over the past three decades. METHODS: Our prospectively maintained, single-institution database of CRS-HIPEC cases was reviewed, identifying 111 consecutive patients with MPM over 28 years (1993-2021). Prognostic, operative, and pathologic factors were reviewed. Overall survival (OS) and conditional survival (CS) analyses were performed. RESULTS: The average age was 55.1 years; 58.6% of patients were male; 17 of 111 patients (15.3%) had a second CRS-HIPEC. At first CRS-HIPEC, the average PCI score was 18.7, and the perfusate drugs were platinum-based (72.1%) and mitomycin C (27.9%). The resection status at first CRS-HIPEC was R2a (46.4%), followed by R0-1 (29.1%), and R2b-c (24.5%). Median OS was 3.3 years for the entire cohort, with 75th and 25th percentiles at 10.7 months and 10.6 years. Median CS was improved if patients survived to the 1-year postoperative mark (4.9 years, p < 0.01) and trended toward further improvement with each passing year. If 3-year postoperative survival was achieved, the median CS improved to 6.1 years. CONCLUSIONS: This represents one of the largest and lengthiest, single-center, longitudinal, case series of peritoneal mesothelioma treated with CRS-HIPEC. The OS suggests efficacy for CRS-HIPEC for MPM. Long-term survival improves significantly after patients achieve the 1-year, postoperative mark.

Survival Outcomes of Optimally Treated Colorectal Metastases: The Importance of R0 Status in Surgical Treatment of Hepatic and Peritoneal Surface Disease.

BACKGROUND: Although colorectal hepatic metastases (HM) and peritoneal surface disease (PSD) are distinct biologic diseases, they may have similar long-term survival when optimally treated with surgery. METHODS: This study retrospectively reviewed prospectively managed databases. Patients undergoing R0 or R1 resections were analyzed with descriptive statistics, the Kaplan-Meier method, and Cox regression. Survival was compared over time for the following periods: 1993-2006, 2007-2012, and 2013-2020. RESULTS: The study enrolled 783 HM patients undergoing liver resection and 204 PSD patients undergoing cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). Compared with PSD patients, HM patients more often had R0 resections (90.3% vs. 32.4%), less often had pre-procedure chemotherapy (52.4% vs. 92.1%), and less often were functionally independent (79.7% vs. 95.6%). The 5-year overall survival for HM was 40.9%, with a median survival period of 45.8 months versus 25.8% and 33.4 months, respectively, for PSD (p < 0.05). When stratified by resection status, R0 HM and R0 PSD did not differ significantly in median survival (49.0 vs. 45.4 months; p = 0.83). The median survival after R1 resection also was similar between HM and PSD (32.6 vs. 26.9 months; p = 0.59). Survival between the two groups again was similar over time when stratified by resection status. The predictors of survival for HM patients were R0 resection, number of lesions, intraoperative transfusion, age, and adjuvant chemotherapy. For the PSD patients, the predictors were peritoneal cancer index (PCI) score, estimated blood loss (EBL), and female gender. CONCLUSION: The study showed that R0 resections are associated with improved outcomes and that median survival is similar between HM and PSD patients when it is achieved. Surveillance and treatment strategies that facilitate R0 resections are needed to improve results, particularly for PSD.

Plasma Exosome Gene Signature Differentiates Colon Cancer from Healthy Controls.

BACKGROUND: Liquid biopsies have become an integral part of cancer management as minimally invasive options to detect molecular and genetic changes. However, current options show poor sensitivity in peritoneal carcinomatosis (PC). Novel exosome-based liquid biopsies may provide critical information on these challenging tumors. In this initial feasibility analysis, we identified an exosome gene signature of 445 genes (ExoSig445) from colon cancer patients, including those with PC, that is distinct from healthy controls. METHODS: Plasma exosomes from 42 patients with metastatic and non-metastatic colon cancer and 10 healthy controls were isolated and verified. RNAseq analysis of exosomal RNA was performed and differentially expressed genes (DEGs) were identified by the DESeq2 algorithm. The ability of RNA transcripts to discriminate control and cancer cases was assessed by principal component analysis (PCA) and Bayesian compound covariate predictor classification. An exosomal gene signature was compared with tumor expression profiles of The Cancer Genome Atlas. RESULTS: Unsupervised PCA using exosomal genes with greatest expression variance showed stark separation between controls and patient samples. Using separate training and test sets, gene classifiers were constructed capable of discriminating control and patient samples with 100% accuracy. Using a stringent statistical threshold, 445 DEGs fully delineated control from cancer samples. Furthermore, 58 of these exosomal DEGs were found to be overexpressed in colon tumors. CONCLUSIONS: Plasma exosomal RNAs can robustly discriminate colon cancer patients, including patients with PC, from healthy controls. ExoSig445 can potentially be developed as a highly sensitive liquid biopsy test in colon cancer.

Impact of myometrium invasion on survival outcomes following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC).

INTRODUCTION: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is an effective surgical intervention for peritoneal surface malignancy. The effect of myometrium invasion on outcomes is unknown. METHODS: Retrospective review of our institutional registry with analysis of CRS-HIPEC cases involving a hysterectomy. Compared cases with myometrium invasion versus those without invasion. Primary outcome was survival as measured by overall survival (OS) and disease-free survival (DFS). Secondary outcome was the evaluation of risk factors for myometrium invasion based on multivariate analysis. RESULTS: A total of 126 cases of CRS-HIPEC involving a hysterectomy were identified. Ninety-seven cases (76.9%) had no myometrium invasion and the remaining 29 cases (23.1%) had malignant invasion. The presence of myometrial invasion was a significant negative survival prognostic factor. The OS was halved with mean survival times of 2.8 (±2.3) versus 5.8 (±4.7) years for cases with and without invasion, respectively (p = 0.002). Five-year OS rates were also inferior with myometrium invasion at 17.4% versus 53.8% (odds ratio [OR] = 0.181, 95% confidence interval [CI]: 0.057-0.580, p = 0.002). A similar trend was present with DFS with mean survival times of 1.4 (±0.9) versus 3.7 (±3.9) years for noninvasion and invasion cases (p = 0.009). The 5-year DFS rates were 0% versus 34.8% (OR = 0.652, 95% CI: 0.549-0.775, p = 0.004). Secondary analysis significantly associated several risk factors with myometrium invasion to include lymph node positivity (OR = 2.539, 95% CI: 1.074-6.003, p = 0.012), colorectal primary tumors (OR = 2.248, 95% CI: 1.094-5.161, p = 0.035), and high-grade tumors (OR = 2.160, 95% CI: 1.080-4.820, p = 0.038). CONCLUSION: Myometrium invasion is a significant negative prognostic factor for survival following CRS-HIPEC. Several risk factors are potentially predictive of identifying those at high-risk for myometrium invasion.

Incidence, Risk Factors, and Outcomes from Conversion of Low-Grade to High-Grade Appendiceal Neoplasms for Patients Undergoing Multiple Cytoreductive Surgeries with Hyperthermic Intraperitoneal Chemotherapy.

INTRODUCTION: Conversion from low-grade to high-grade disease is known to occur following repeat cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC); however, the incidence rate, risk factors, and outcomes have not been studied. METHODS: We conducted a retrospective review of multiple CRS/HIPEC cases for patients originally diagnosed with low-grade appendiceal neoplasms, and compared converted cases with non-converters. Primary outcomes were the incidence rate and risk factors for conversion, while secondary outcomes were effect on cytoreduction, overall survival (OS), and disease-free survival (DFS). RESULTS: Overall, 65 patients undergoing 134 cases of repeat CRS/HIPEC were identified; 11 patients converted to high-grade disease, an incidence rate of 16.92%. Converted cases averaged 4.4 years between CRS/HIPEC, versus 3.7 years for non-converters. Elevated baseline carcinoembryonic antigen (CEA) level, splenectomy at index CRS/HIPEC, and adjuvant chemotherapy utilization were statistically significant with conversion. Conversion had no impact on specific cytoreductive scores at repeat CRS/HIPEC (p = 0.435). Evaluating the effect on OS from the index CRS/HIPEC conversion had no impact. Mean OS was 9.5 and 8.8 years for cases that remained low-grade compared with those that converted, respectively (p = 0.668); however, when comparing OS from the time of conversion at repeat CRS/HIPEC, patients who progressed to high-grade disease had decreased survival at 4.4 versus 5.8 years (p = 0.0317). There was no difference in DFS between non-converters and converters at 4.1 and 3.6 years, respectively (p = 0.671). CONCLUSION: Conversion had no impact on OS from the index CRS/HIPEC but resulted in inferior survival from repeat surgery. Conversion was insignificant in regard to DFS, and should not be considered a contraindication to repeat CRS/HIPEC. Adjuvant chemotherapy should be avoided.

Utility of Neoadjuvant Chemotherapy for Peritoneal Carcinomatosis Secondary to High-Grade Appendiceal Neoplasms for Patients Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy.

INTRODUCTION: Neoadjuvant chemotherapy (NAT) is frequently utilized before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for high-grade appendiceal neoplasms. The proposed benefits of NAT do not correlate with the limited literature. METHODS: Retrospective review of our CRS-HIPEC registry. Primary outcomes were the effect of NAT on disease burden, cytoreduction scores, overall survival (OS), disease-free survival (DFS), and recurrence patterns. RESULTS: A total of 126 cases of high-grade disease met selection criteria; 73 cases received NAT before referral, and 53 cases received no therapy before referral and went directly to CRS-HIPEC. For those cases who received NAT 89% received a FOLFOX-based regimen. Mean PCI scores were 16.47 and 16.07 (P = 0.843) with complete cytoreductions rates of 79.5% and 75% (P = 0.556) for NAT and non-NAT cases, respectively. NAT cases were associated with significantly decreased OS and DFS rates. Mean OS was 3.6 and 2.5 years (P = 0.005) with actual 5-year OS rates of 24.2% versus 5% (P = 0.017) for non-NAT and NAT cases respectively. Mean DFS was 2.8 and 1.7 years (P = 0.015) with actual 5-year DFS rates of 18.6% versus 5.7% (P = 0.048) for non-NAT and NAT cases respectively. Lastly, the use of NAT had no impact on recurrence patterns (P = 0.221). CONCLUSIONS: This is the largest study to evaluate high-grade appendiceal neoplasms in regard to CRS-HIPEC and NAT. NAT had no impact in regard to disease burden, cytoreduction, or recurrence patterns. Utilization of NAT was associated with decreased OS and DFS.

Patient-Specific Sarcoma Organoids for Personalized Translational Research: Unification of the Operating Room with Rare Cancer Research and Clinical Implications.

INTRODUCTION: Sarcoma clinical outcomes have been stagnant for decades due to heterogeneity of primaries, lack of comprehensive preclinical models, and rarity of disease. We hypothesized that engineering hydrogel-based sarcoma organoids directly from the patient without xenogeneic extracellular matrices (ECMs) or growth factors is routinely feasible and allows rare tumors to remain viable as avatars for personalized research. METHODS: Surgically resected sarcomas (angiosarcomas, leiomyosarcoma, gastrointestinal stromal tumor, liposarcoma, myxofibrosarcoma, dermatofibrosarcoma protuberans [DFSP], and pleiomorphic abdominal sarcoma) were dissociated and incorporated into a hyaluronic acid and collagen-based ECM hydrogel and screened for chemotherapy efficacy. A subset of organoids was enriched with a patient-matched immune system for screening of immunotherapy efficacy (iPTOs). Response to treatment was assessed using LIVE/DEAD staining and metabolic assays. RESULTS: Sixteen sarcomas were biofabricated into three-dimensional (3D) patient-specific sarcoma organoids with a 100% success rate. Average time from organoid development to initiation of drug testing was 7 days. Enrichment of organoids with immune system components derived from either peripheral blood mononuclear cells or lymph node cells was performed in 10/16 (62.5%) patients; 4/12 (33%) organoids did not respond to chemotherapy, while response to immunotherapy was observed in 2/10 (20%) iPTOs. CONCLUSIONS: A large subset of sarcoma organoids does not exhibit response to chemotherapy or immunotherapy, as currently seen in clinical practice. Routine development of sarcoma hydrogel-based organoids directly from the operating room is a feasible platform, allowing for such rare tumors to remain viable for personalized translational research.

Timing of Repeat Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy for Recurrent Low-Grade Appendiceal Mucinous Neoplasms.

BACKGROUND: Low-grade appendiceal mucinous neoplasm (LAMN) with peritoneal involvement is a common indication for cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC). With peritoneal recurrence, patients are increasingly being offered repeat CRS/HIPECs, however optimal timing for a second CRS/HIPEC remains unknown. METHODS: A prospectively maintained 30-year database at our high-volume HIPEC center was analyzed retrospectively for patients with LAMNs and peritoneal recurrence receiving one or two CRS/HIPECs. Kaplan-Meier survival analysis, linear regression modeling, and Cox proportional hazards regression analyses were performed. RESULTS: Overall, 143 patients with LAMNs who underwent CRS/HIPECs had confirmed postoperative peritoneal recurrence. Of these patients, 85 underwent one CRS/HIPEC and 58 underwent two CRS/HIPECs. The groups had significant differences in age, with younger patients more likely to undergo a second CRS/HIPEC (48.5 vs. 58.0 years; p < 0.001). The median overall survival (OS) for the group undergoing two CRS/HIPECs was approximately four times longer compared with the group undergoing one CRS/HIPEC (227.1 vs. 54.5 months; p < 0.0001). The time from recurrence to the second CRS/HIPEC was not significantly associated with OS from the time of the first operation. Instead, a shorter time between the first CRS/HIPEC and recurrence was significantly associated with shorter OS from the time of the first operation (p = 0.037). CONCLUSION: In peritoneal LAMNs with recurrence, receiving two CRS/HIPECs was associated with better OS compared with receiving one CRS/HIPEC. Longer time to recurrence was a good prognostic factor. Delay between recurrence and second CRS/HIPEC had no apparent impact on OS from the first CRS/HIPEC; thus, immediate or delayed reoperative intervention are both reasonable approaches.

Repeat Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy for Cancers with Peritoneal Metastasis: A 30-year Institutional Experience.

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) improves survival in abdominal cancer patients with metastatic disease limited to the peritoneal cavity. Patients are increasingly being offered repeat CRS-HIPECs for peritoneal recurrence. However, in this rare clinical scenario, the survival benefit of performing repeat CRS-HIPEC operations remains unclear. METHODS: A retrospective review of the CRS-HIPEC database at Wake Forest Baptist Medical Center was performed over a 30-year timespan. From 1547 patients with appendix cancers, colorectal cancers, mesotheliomas, and other miscellaneous cancers, 156 received more than one CRS-HIPEC. Kaplan-Meier survival analysis was performed using overall survival (OS) from the time of surgery as the primary endpoint. Multi-variable Cox proportional hazards regression modelling was performed on pertinent clinical variables. RESULTS: Patients who received multiple CRS-HIPECs had significantly better median OS (10.7 years) versus those who received one CRS-HIPEC (2.5 years), with appendix cancers faring best (12.9 years). Resection status R2a or better was achieved in 76.4% of repeat CRS-HIPECs. There were no significant changes in complication rates after repeat CRS-HIPEC. On multivariate analysis of repeat CRS-HIPEC, patients with appendix and colorectal cancers, heart disease, and poor functional status were independently associated with poor OS. Factors not independently associated with OS were age, sex, body mass index, race, diabetes, lung disease, smoking history, and systemic chemotherapy between CRS-HIPECs. CONCLUSIONS: Performing multiple CRS-HIPEC operations on appropriate surgical candidates may significantly prolong survival. Appendix cancers derived the greatest benefit. Satisfactory resection margins and complication rates are comparable to first cases and achievable in repeat CRS-HIPEC procedures.

Development of a Prognostic Nomogram and Nomogram Software Application Tool to Predict Overall Survival and Disease-Free Survival After Curative-Intent Gastrectomy for Gastric Cancer.

BACKGROUND: We sought to derive and validate a prediction model of survival and recurrence among Western patients undergoing resection of gastric cancer. METHODS: Patients who underwent curative-intent surgery for gastric cancer at seven US institutions and a major Italian center from 2000 to 2020 were included. Variables included in the multivariable Cox models were identified using an automated model selection procedure based on an algorithm. Best models were selected using the Bayesian information criterion (BIC). The performance of the models was internally cross-validated via the bootstrap resampling procedure. Discrimination was evaluated using the Harrell's Concordance Index and accuracy was evaluated using calibration plots. Nomograms were made available as online tools. RESULTS: Overall, 895 patients met inclusion criteria. Age (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.17-1.84), presence of preoperative comorbidities (HR 1.66, 95% CI 1.14-2.41), lymph node ratio (LNR; HR 1.72, 95% CI 1.42-2.01), and lymphovascular invasion (HR 1.81, 95% CI 1.33-2.45) were associated with overall survival (OS; all p < 0.01), whereas tumor location (HR 1.93, 95% CI 1.23-3.02), T category (Tis-T1 vs. T3: HR 0.31, 95% CI 0.14-0.66), LNR (HR 1.82, 95% CI 1.45-2.28), and lymphovascular invasion (HR 1.49; 95% CI 1.01-2.22) were associated with disease-free survival (DFS; all p < 0.05) The models demonstrated good discrimination on internal validation relative to OS (C-index 0.70) and DFS (C-index 0.74). CONCLUSIONS: A web-based nomograms to predict OS and DFS among gastric cancer patients following resection demonstrated good accuracy and discrimination and good performance on internal validation.

HIPEC after neoadjuvant chemotherapy is associated with acceptable toxicity and favorable quality of life in newly diagnosed advanced ovarian cancer patients.

OBJECTIVE: To evaluate toxicity, quality of life and PFS in patients with advanced ovarian cancer who underwent neoadjuvant chemotherapy (NAC) followed by CRS and HIPEC with carboplatin. METHODS: Patients with stage IIIC or IVA epithelial ovarian cancer, who were not candidates for primary CRS, were enrolled in this phase two trial. Patients received 3-6 cycles of NAC with an IV carboplatin doublet followed by CRS with HIPEC (carboplatin 800 mg/m2 for 90 min). They were followed for at least 12 months to assess for adverse events, quality of life (QOL) and disease progression. QOL was measured using the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaires prior to CRS and post-operatively at 6 weeks, 3 months, and 6 months after CRS. RESULTS: Twenty patients were enrolled. HIPEC was completed successfully in all twenty patients, and there was no peri-operative mortality. Twelve (70.6%) patients experienced a grade 3 or 4 toxicity; most commonly anemia (59%), thrombocytopenia (29%), and hypokalemia (24%). There was no significant change between the pre-operative and postoperative 6 weeks, 3 month, and 6 month FACT-O, NTX, and AD scores. Nine (45%) patients have experienced disease recurrence to date. The median progression free survival in this cohort is 11.2 months (2.5-23.7 months). CONCLUSION: The addition of HIPEC with carboplatin to interval CRS was well tolerated in patient population. Myelosuppression was the most common adverse event. CRS with HIPEC did not adversely impact these patients' QOL indices. The efficacy of this regimen should be further evaluated in a larger clinical trial.