Phase I Safety and Feasibility Pilot of Hepatic Artery Infusion Chemotherapy in a Rural Catchment Area Using The Codman Vascular Catheter with The Medtronic SynchroMed II Pump for Intrahepatic Cancers.

BACKGROUND: Discontinuation of the Codman 3000 pump in 2018 left no Food and Drug Administration (FDA)-approved hepatic artery infusion (HAI) device for unresectable colorectal liver metastases (uCLM) and intrahepatic cholangiocarcinoma (uIHC). Historically, HAI has been performed at academic medical centers in large metropolitan areas, which are often inaccessible to rural patients. Consequently, feasibility of dissemination of HAI to rural populations is unknown. PATIENTS AND METHODS: Under an FDA investigational device exemption, we opened the only HAI program in Kentucky and enrolled patients with uCLM and uIHC in a phase I clinical trial. The trial examined the safety of the hybrid Codman catheter/Medtronic SynchroMed II pump (hCMP) combination, defined as successful completion of one cycle of HAI chemotherapy. Rural feasibility was assessed by number of missed pump fills appointments. RESULTS: A total of 21 patients (n = 17 uCLM, n = 4 uIHC) underwent hCMP implantation before accrual was stopped early owing to FDA approval of the Intera 3000 pump. 20/21 (95%) patients met the primary safety endpoint. Serious adverse events (AEs) included a grade 5 coronavirus disease 2019 (COVID-19) infection (n = 1) and a grade 3 catheter erosion into the bowel (n = 1). Biliary sclerosis developed in two patients (9.5%). Median distance to infusion center was 47.6 miles (2-138 miles), and 62% were from Appalachia, yet there were no missed pump fill appointments. The 2-year overall survival was 82.4% (uCLM) and 50% (uIHC). CONCLUSIONS: The hCMP device had an acceptable safety profile. Despite the complexity of starting a new HAI program, early results showed feasibility for HAI delivery in a rural catchment area and comparable outcomes to larger urban-based HAI centers.

A Retrospective Cohort Study to Evaluate Adding Biomarkers to the Risk Analysis Index of Frailty.

INTRODUCTION: The Risk Analysis Index (RAI) is a frailty assessment tool associated with adverse postoperative outcomes including 180 and 365-d mortality. However, the RAI has been criticized for only containing subjective inputs rather than including more objective components such as biomarkers. METHODS: We conducted a retrospective cohort study to assess the benefit of adding common biomarkers to the RAI using the Veterans Affairs Surgical Quality Improvement Program (VASQIP) database. RAI plus body mass index (BMI), creatinine, hematocrit, and albumin were evaluated as individual and composite variables on 180-d postoperative mortality. RESULTS: Among 480,731 noncardiac cases in VASQIP from 2010 to 2014, 324,320 (67%) met our inclusion criteria. Frail patients (RAI ≥30) made up to 13.0% of the sample. RAI demonstrated strong discrimination for 180-d mortality (c = 0.839 [0.836-0.843]). Discrimination significantly improved with the addition of Hematocrit (c = 0.862 [0.859-0.865]) and albumin (c = 0.870 [0.866-0.873]), but not for body mass index (BMI) or creatinine. However, calibration plots demonstrate that the improvement was primarily at high RAI values where the model overpredicts observed mortality. CONCLUSIONS: While RAI's ability to predict the risk of 180-d postoperative mortality improves with the addition of certain biomarkers, this only observed in patients classified as very frail (RAI >49). Because very frail patients have significantly elevated observed and predicted mortality, the improved discrimination is likely of limited clinical utility for a frailty screening tool.

Creation of EGD-Derived Gastric Cancer Organoids to Predict Treatment Responses.

Gastric adenocarcinoma (GAd) is the third leading cause of cancer-related deaths worldwide. Most patients require perioperative chemotherapy, yet methods to accurately predict responses to therapy are lacking. Thus, patients may be unnecessarily exposed to considerable toxicities. Here, we present a novel methodology using patient-derived organoids (PDOs) that rapidly and accurately predicts the chemotherapy efficacy for GAd patients. Methods:Endoscopic GAd biopsies were obtained from 19 patients, shipped overnight, and PDOs were developed within 24 h. Drug sensitivity testing was performed on PDO single-cells with current standard-of-care systemic GAd regimens and cell viability was measured. Whole exome sequencing was used to confirm the consistency of tumor-related gene mutations and copy number alterations between primary tumors, PDOs, and PDO single-cells. Results:Overall, 15 of 19 biopsies (79%) were appropriate for PDO creation and single-cell expansion within 24 h of specimen collection and overnight shipment. With our PDO single-cell technique, PDOs (53%) were successfully developed. Subsequently, two PDO lines were subjected to drug sensitivity testing within 12 days from initial biopsy procurement. Drug sensitivity assays revealed unique treatment response profiles for combination drug regimens in both of the two unique PDOs, which corresponded with the clinical response. Conclusions:The successful creation of PDOs within 24 h of endoscopic biopsy and rapid drug testing within 2 weeks demonstrate the feasibility of our novel approach for future applications in clinical decision making. This proof of concept sets the foundation for future clinical trials using PDOs to predict clinical responses to GAd therapies.

Starting a successful hepatic artery infusion pump program: A practical guide.

Implementation of a successful hepatic artery infusion pump program requires numerous factors to be in place, and the lack of any of these may lead to program failure. First and foremost, hepatic artery infusion pump programs must have adequate surgical expertise in the complex technical aspects of hepatic artery infusion pump implantation and postoperative management. Most new hepatic artery infusion pump programs are initiated by a surgeon and led in conjunction with a medical oncologist. Medical oncology experience in floxuridine dosing is critical in maximizing the treatment doses and the number of cycles administered while avoiding biliary toxicity. This is facilitated by collaboration with an engaged pharmacy team. To have adequate patient volume for a successful program, internal and external stakeholders must have buy-in, including surgical and medical oncology colleagues unfamiliar with hepatic artery infusion pumps, colorectal surgery, and other referring providers. Programmatic support must be obtained from the hospital, cancer center, and department administration. Day-to-day pump access for chemotherapy and maintenance saline fills must be performed by appropriately trained infusion nurses to avoid complications. Nuclear and diagnostic radiology experience is key to identifying extrahepatic perfusion and hepatic artery infusion pump-specific complications. Additionally, skilled interventional radiologists and gastroenterologists are necessary to identify and treat rare complications rapidly. Finally, given the current rapid expansion of hepatic artery infusion pump programs, new programs must identify engaged mentors to help guide patient selection, navigate the nuanced issues that may arise, and provide advice in the case of complications. Although hepatic artery infusion pump dissemination outside of several major tertiary centers previously had stalled, establishing a successful and active hepatic artery infusion pump is feasible with appropriate training, mentorship, and thoughtful assembly of a dedicated multidisciplinary team.

Robot-assisted laparoscopic removal of an extraperitoneal pelvic solitary fibrous tumor.

•Pelvic SFTs are rare, typically benign soft tissue neoplasms that pose a diagnostic challenge for gynecologists.•Retroperitoneal pelvic SFTs can mimic gynecologic malignancies and should be considered in diagnosis of a solitary pelvic mass.•Pathologic diagnosis is typically confirmed by immunohistochemistry staining positively for CD34 and STAT6.•Complete surgical excision is recommended for these tumors and can be completed with a minimally invasive approach.•Close long-term follow-up is necessary due to possible recurrence or metastasis, especially for high-risk pathologic features.

A Multicenter Phase 1 Trial Evaluating Nanoliposomal Irinotecan for Heated Intraperitoneal Chemotherapy Combined with Cytoreductive Surgery for Patients with Peritoneal Surface Disease.

BACKGROUND: Nanoliposomal irinotecan (nal-IRI) is a promising novel hyperthermic intraperitoneal chemotherapy (HIPEC) agent given its enhanced efficacy against gastrointestinal tumors, safety profile, thermo-synergy, and heat stability. This report describes the first in-human phase 1 clinical trial of nal-IRI during cytoreductive surgery (CRS) and HIPEC. METHODS: Patients with peritoneal surface disease (PSD) from appendiceal and colorectal neoplasms were enrolled in a 3 + 3 dose-escalation trial using nal-IRI (70-280 mg/m2) during HIPEC for 30 min at 41 ± 1 °C. The primary outcome was safety. The secondary outcomes were pharmacokinetics (PK) and disease-free survival. Adverse events (AEs) categorized as grade 2 or higher were recorded. The serious AEs (SAEs) were mortality, grade ≥ 3 AEs, and dose-limiting toxicity (DLT). Irinotecan and active metabolite SN38 were measured in plasma and peritoneal washings. RESULTS: The study enrolled 18 patients, who received nal-IRI during HIPEC at 70 mg/m2 (n = 3), 140 mg/m2 (n = 6), 210 mg/m2 (n = 3), and 280 mg/m2 (n = 6). No DLT or mortality occurred. The overall morbidity for CRS/HIPEC was 39% (n = 7). Although one patient experienced neutropenia, no AE (n = 131) or SAE (n = 3) was definitively attributable to nal-IRI. At 280 mg/m2, plasma irinotecan and SN38 measurements showed maximum concentrations of 0.4 ± 0.6 µg/mL and 3.0 ± 2.4 ng/mL, a median time to maximum concentration of 24.5 and 26 h, and areas under the curve of 22.6 h*µg/mL and 168 h*ng/mL, respectively. At the 6-month follow-up visit, 83% (n = 15) of the patients remained disease-free. CONCLUSIONS: In this phase 1 HIPEC trial (NCT04088786), nal-IRI was observed to be safe, and PK profiling showed low systemic absorption overall. These data support future studies testing the efficacy of nal-IRI in CRS/HIPEC.

The Development of Investigator-Initiated Clinical Trials in Surgical Oncology.

Investigator-initiated trials (IITs) are designed by principal investigators who identify important, unaddressed clinical gaps and opportunities to answer these questions through clinical trials. Surgical oncologists are poised to lead IITs due to their multidisciplinary clinical practice and substantial research background. The process of developing, organizing, and implementing IITs is multifaceted and involves important steps including (but not limited to) navigating regulatory requirements, obtaining funding, and meeting enrollment targets. Here, the authors explore the steps, methodology, and barriers of IIT development by surgical oncologists and highlight the importance of IITs in oncology.

New Cancer-Related Symptoms Predict Recurrence in CA19-9 Non-Expressers After Resection of Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: CA19-9 elevation has been reported to predict recurrence after resection of pancreatic ductal adenocarcinoma (PDAC), although only two-thirds of patients are expressers. Preoperatively, cancer-related symptoms predict outcome; however, it is unknown whether symptoms predict recurrence during surveillance, particularly for CA19-9 non-expressers. METHODS: Patients undergoing resection of PDAC at our institution from 2012 to 21 (n = 165) were retrospectively reviewed for CA19-9 and symptoms, which were correlated with recurrence-free survival (RFS). Multivariate analysis was performed using Cox regression. RESULTS: During postoperative surveillance, CA19-9 elevation and development of symptoms (abdominal pain, weight loss, or jaundice) were associated with worse RFS (P < .05). Multivariate analysis showed that both symptoms and CA19-9 were independently predictive of RFS (HR 1.8 [1.1-2.9; P = .025] and 2.5 [1.0-6.0; P = .048]). Among CA19-9 non-expressers (n = 51), development of symptoms was associated with detection of recurrence (P = .012). CONCLUSIONS: Among CA19-9 non-expressers, development of symptoms predicted recurrence, providing a useful tool for recurrence detection in these patients.

Interaction of immune checkpoint PD-1 and chemokine receptor 4 (CXCR4) promotes a malignant phenotype in pancreatic cancer cells.

Despite recent therapeutic advances, pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with limited therapeutic options. Immune checkpoint inhibitors (ICIs) have demonstrated promising results in many cancers, but thus far have yielded little clinical benefit in PDAC. Based on recent combined targeting of programmed cell death protein-1 (PD-1) and C-X-C chemokine receptor 4 (CXCR4) in patient-derived xenografts (PDXs) and a pilot clinical trial, we sought to elucidate potential interactions between PD-1 and CXCR4. We observed concomitant expression and direct interaction of PD-1 and CXCR4 in PDAC cells. This interaction was disrupted upon CXCR4 antagonism with AMD3100 and led to increased cell surface expression of PD-1. Importantly, CXCR4-mediated PDAC cell migration was also blocked by PD-1 inhibition. Our work provides a possible mechanism by which prior studies have demonstrated that combined CXCR4 and PD-1 inhibition leads to decreased tumor growth. This is the first report investigating PD-1 and CXCR4 interactions in PDAC cells and our results can serve as the basis for further investigation of combined therapeutic targeting of CXCR4 and PD-1.

Endogenous Pancreatic Cancer Cell PD-1 Activates MET and Induces Epithelial-Mesenchymal Transition to Promote Cancer Progression.

We recently demonstrated that immune checkpoint PD-1 was endogenously expressed in pancreatic ductal adenocarcinoma (PDAC) cells. Our data indicated that PD-1 proteins are not exclusive to immune cells and have unrecognized signal transduction cascades intrinsic to cancer cells. Building on this paradigm shift, we sought to further characterize PD-1 expression in PDAC. We utilized a phospho-explorer array to identify pathways upregulated by PD-1 signaling. We discovered PD-1-mediated activation of the proto-oncogene MET in PDAC cells, which was dependent on hepatocyte growth factor (MET ligand) and not secondary to direct protein interaction. We then discovered that the PD-1/MET axis in PDAC cells regulated growth, migration, and invasion. Importantly, the PD-1/MET axis induced epithelial-to-mesenchymal transition (EMT), a well-established early oncogenic process in PDAC. We observed that combined targeting of PDAC cell PD-1 and MET resulted in substantial direct tumor cell cytotoxicity and growth inhibition in PDAC cell lines, patient-derived organoids, and patient-derived xenografts independent of cytotoxic immune responses. This is the first report of PDAC-endogenous PD-1 expression regulating MET signaling, which builds upon our growing body of work showing the oncogenic phenotype of PD-1 expression in PDAC cells is distinct from its immunogenic role. These results highlight a paradigm shift that the tumor-specific PD-1 axis is a novel target to effectively kill PDAC cells by antagonizing previously unrecognized PD-1-dependent oncogenic pathways.

Current Trends in Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Peritoneal Disease from Appendiceal and Colorectal Malignancies.

Peritoneal carcinomatosis (PC) is a poor prognostic factor for all malignancies. This extent of metastatic disease progression remains difficult to treat with systemic therapies due to poor peritoneal vascularization resulting in limited drug delivery and penetration into tissues. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are surgical interventions that directly target peritoneal tumors and have improved outcomes for PC resulting from appendiceal and colorectal cancer (CRC). Despite these radical therapies, long-term survival remains infrequent, and recurrence is common. The reasons for these outcomes are multifactorial and signal the need for the continued development of novel therapeutics, techniques, and approaches to improve outcomes for these patients. Here, we review landmark historical studies that serve as the foundation for current recommendations, recent discoveries, clinical trials, active research, and areas of future interest in CRS/HIPEC to treat PC originating from appendiceal and colorectal malignancies.

Targetable IDH1 mutation identified in a rare case of pancreatic serous cystadenocarcinoma but not a series of serous cystadenomas.

Serous cystadenocarcinoma (SCAC) of the pancreas is rare, with only 35 cases reported in the literature. We present a case of SCAC, comparing the clinical presentation, management and molecular features of this case to a series of serous cystadenoma (SCA), which may be a precursor. Compared with SCAs (n = 5), SCAC was larger (11.5 vs median 3.6 cm). The case of SCAC invaded the spleen and exhibited distant metastasis, a requirement for diagnosis since pathologic features are otherwise indistinguishable from SCA. VHL mutations have been reported in about half of SCA in the literature. Accordingly, we identified either somatic or germline VHL mutations in 3 of 5 SCAs (60%), yet no pathogenic mutation was identified in the SCAC. A somatic mutation in IDH1 was found in SCAC only. This has been associated with multiple malignancies, is targetable with the drug ivosidenib and should be studied as a progression factor in SCAC.

Development of a Single-Cell Technique to Increase Yield and Use of Gastrointestinal Cancer Organoids for Personalized Medicine Application.

BACKGROUND: Organoids are excellent 3-dimensional in vitro models of gastrointestinal cancers. However, patient-derived organoids (PDOs) remain inconsistent and unreliable for rapid actionable drug sensitivity testing due to size variation and limited material. STUDY DESIGN: On day10/passage 2 after standard creation of organoids, half of PDOs were dissociated into single-cells with TrypLE Express Enzyme/DNase I and mechanical dissociation; and half of PDOs were expanded by the standard technique. Hematoxylin and eosin and immunohistochemistry with CK7 and CK20 were performed for characterization. Drug sensitivity testing was completed for single-cells and paired standard PDOs to assess reproducibility. RESULTS: After 2 to 3 days, >50% of single-cells reformed uniform miniature PDOs (∼50 µm). We developed 10 PDO single-cell lines (n = 4, gastric cancer, [GC]; and n = 6, pancreatic ductal adenocarcinoma, [PDAC]), which formed epithelialized cystic structures and by IHC, exhibited CK7(high)/CK20(low) expression patterns mirroring parent tissues. Compared with paired standard PDOs, single-cells (n = 2, PDAC; = 2, GC) showed similar architecture, albeit smaller and more uniform. Importantly, single cells demonstrated similar sensitivity to cytotoxic drugs to matched PDOs. CONCLUSIONS: PDO single-cells are accurate for rapid clinical drug testing in gastrointestinal cancers. Using early passage PDO single-cells facilitates high-volume drug testing, decreasing time from tumor sampling to actionable clinical decisions, and provides a personalized medicine platform to optimally select drugs for gastrointestinal cancer patients.

Concurrent hysterectomy and bilateral salpingo-oophorectomy during cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for non-gynecologic cancers.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is a key component of treatment in non-gynecologic peritoneal surface malignancies. As many as 10-15% of patients with a gastrointestinal primary malignancy will present with carcinomatosis. Maximal cytoreductive surgery directly affects the prognosis of patients. The routine inclusion of hysterectomy with bilateral salpingo-oophorectomy during these procedures optimizes cytoreduction despite negative pre-operative imaging and findings at the time of surgery. In this case series, we review twenty non-gynecologic cancer patients who underwent cytoreductive surgery with concurrent hysterectomy and bilateral salpingo-oophorectomy and HIPEC at our institution.

An Organotypic Microcosm for the Pancreatic Tumor Microenvironment.

Pancreatic duct adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related deaths in the next few years. Unfortunately, the development of novel therapies for PDAC has been challenged by a uniquely complex tumor microenvironment. The development of in vitro cancer organoids in recent years has demonstrated potential to increase therapies for patients with PDAC. Organoids have been established from PDAC murine and human tissues and they are representative of the primary tumor. Further, organoids have been shown beneficial in studies of molecular mechanisms and drug sensitivity testing. This review will cover the use of organoids to study PDAC development, invasiveness, and therapeutic resistance in the context of the tumor microenvironment, which is characterized by a dense desmoplastic reaction, hindered immune activity, and pro-tumor metabolic signaling. We describe investigations utilizing organoids to characterize the tumor microenvironment and also describe their limitations. Overall, organoids have great potential to serve as a versatile model of drug response and may be used to increase available therapies and improve survival for patients with PDAC.

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer.

Hyperthermic intraperitoneal chemotherapy (HIPEC) in conjunction with cytoreductive surgery (CRS) holds promise as an adjunctive treatment strategy in malignancies affecting the peritoneal surface, effectively targeting remaining microscopic residual tumor. HIPEC increases concentrations of chemotherapy directly within the peritoneal cavity compared with the intravenous route and reduces the systemic side effects associated with prolonged adjuvant intraperitoneal exposure. Furthermore, hyperthermia increases tissue penetration and is synergistic with the therapeutic chemotherapy agents used. In ovarian cancer, evidence is building for its use in both primary and recurrent scenarios. In this review, we examine the history of HIPEC, the techniques used, and the available data guiding its use in primary and recurrent ovarian cancer.

Pilot Study Comparing Systemic and Tissue Pharmacokinetics of Irinotecan and Metabolites after Hepatic Drug-Eluting Chemoembolization.

Differences in drug metabolism associated with UGT1A1 polymorphism could result in individualized local response to hepatic chemoembolization with irinotecan-eluting beads (DEBIRI) or predictable toxicities. Five patients with inoperable hepatic metastases from colorectal or anal malignancies treated with DEBIRI were assessed for UGT1A1 mutations. No difference in area under the curve (AUC) for SN38 in normal liver and tumor tissue samples was noted with variant or wild-type UBT1A1 (P = .16 and P = .05, respectively). Plasma SN-38 AUC was significantly lower in wild-type compared to variant patients (P < .0001). UGT1A1 genotype may not be predictive of hematologic toxicity after DEBIRI.