Do Complications After Pancreatoduodenectomy Have an Impact on Long-Term Quality of Life and Functional Outcomes?

Objective: Our aim was to assess whether complications after pancreatoduodenectomy (PD) impact long-term quality of life (QoL) and functional outcomes. Background: There is an increasing number of long-term post-PD survivors, but few studies have evaluated long-term QoL outcomes. Methods: The EORTC QLQ-C30 and QLQ-PAN26 questionnaires were administered to patients who survived >5 years post-PD. Clinical relevance (CR) was scored as small (5-10), moderate (10-20), or large (>20). Patients were stratified based on whether they experienced a complication during the index hospitalization. Results: Of 305 patients >5 years post-PD survivors, with valid contact information, 248 completed the questionnaires, and 231 had complication data available. Twenty-nine percent of patients experienced a complication, of which 17 (7.4%) were grade 1, 27 (11.7%) were grade 2, and 25 (10.8%) were grade 3. Global health status and functional domain scores were similar between both groups. Patients experiencing complications reported lower fatigue (21.4 vs 28.1, P < 0.05, CR small) and diarrhea (15.9 vs 23.1, P < 0.05, CR small) symptom scores when compared to patients without complications. Patients experiencing complications also reported lower pancreatic pain (38.2 vs 43.4, P < 0.05, CR small) and altered bowel habits (30.1 vs 40.7, P < 0.01, CR moderate) symptom scores. There was a lower prevalence of worrying (36.2% vs 60.5%, P < 0.05) and bloating (42.0% vs 56.2%, P < 0.05) among PD survivors with complications. Conclusions: Post-PD complication rates were not associated with long-term global QoL or functionality, and may be associated with less severe pancreas-specific symptoms.

Targeting Patient-Derived Orthotopic Gastric Cancers with a Fluorescent Humanized Anti-CEA Antibody.

BACKGROUND: Gastric cancer poses a major diagnostic and therapeutic challenge as surgical resection provides the only opportunity for a cure. Specific labeling of gastric cancer could distinguish resectable and nonresectable disease and facilitate an R0 resection, which could improve survival. METHODS: Two patient-derived gastric cancer lines, KG8 and KG10, were established from surgical specimens of two patients who underwent gastrectomy for gastric adenocarcinoma. Harvested tumor fragments were implanted into the greater curvature of the stomach to establish patient-derived orthotopic xenograft (PDOX) models. M5A (humanized anti-CEA antibody) or IgG control antibodies were conjugated with the near-infrared dye IRDye800CW. Mice received 50 µg of M5A-IR800 or 50 µg of IgG-IR800 intravenously and were imaged after 72 hr. Fluorescence imaging was performed by using the LI-COR Pearl Imaging System. A tumor-to-background ratio (TBR) was calculated by dividing the mean fluorescence intensity of the tumor versus adjacent stomach tissue. RESULTS: M5A-IR800 administration resulted in bright labeling of both KG8 and K10 tumors. In the KG8 PDOX models, the TBR for M5A-IR800 was 5.85 (SE ± 1.64) compared with IgG-IR800 at 0.70 (SE ± 0.17). The K10 PDOX models had a TBR of 3.71 (SE ± 0.73) for M5A-IR800 compared with 0.66 (SE ± 0.12) for IgG-IR800. CONCLUSIONS: Humanized anti-CEA (M5A) antibodies conjugated to fluorescent dyes provide bright and specific labeling of gastric cancer PDOX models. This tumor-specific fluorescent antibody is a promising potential clinical tool to detect the extent of disease for the determination of resectability as well as to visualize tumor margins during gastric cancer resection.

Factors Affecting Recurrence and Survival for Patients with High-Risk Stage II Melanoma.

BACKGROUND: In the current era of effective adjuvant therapies and de-escalation of surgery, distinguishing which patients with high-risk stage II melanoma are at increased risk of recurrence after excision of the primary lesion is essential to determining appropriate treatment and surveillance plans. METHODS: A single-center retrospective study analyzed patients with stage IIB or IIC melanoma. Demographic and tumor data were collected, and genomic analysis of formalin-fixed, paraffin-embedded tissue samples was performed via an internal next-generation sequencing (NGS) platform (SNaPshot). The end points examined were relapse-free survival (RFS), distant metastasis-free survival (DMFS), overall survival (OS), and melanoma-specific survival (MSS). Uni- and multivariable Cox regressions were performed to calculate the hazard ratios. RESULTS: The study included 92 patients with a median age of 69 years and a male/female ratio of 2:1. A Breslow depth greater than 4 mm, a higher mitotic rate, an advanced T stage, and a KIT mutation had a negative impact on RFS. A primary lesion in the head and neck, a mitotic rate exceeding 10 mitoses per mm2, a CDH1 mutation, or a KIT mutation was significantly associated with a shorter DMFS. Overall survival was significantly lower with older age at diagnosis and a higher mitotic rate. An older age at diagnosis also had a negative impact on MSS. CONCLUSION: Traditional histopathologic factors and specific tumor mutations displayed a significant correlation with disease recurrence and survival for patients with high-risk stage II melanoma. This study supported the use of genomic testing of high-risk stage II melanomas for prognostic prediction and risk stratification.

Humanized Anti-Carcinoembryonic Antigen Antibodies Brightly Target and Label Gastric Cancer in Orthotopic Mouse Models.

INTRODUCTION: Gastric cancer poses a major therapeutic challenge. Improved visualization of tumor margins at the time of gastrectomy with fluorescent tumor-specific antibodies could improve outcomes. The present report demonstrates the potential of targeting gastric cancer with a humanized anti-carcinoembryonic antigen (CEA) antibody in orthotopic mouse models. METHODS: MKN45 cells were injected subcutaneously into nude mice to establish xenograft models. Tumor fragments collected from subcutaneous models were then implanted into the greater curvature of the stomach to establish orthotopic models. For tumor labeling, a humanized anti-CEA antibody (M5A) and IgG as a control, were conjugated with the near-infrared dye IRDye800CW. Time (24-72 h) and dose (50-100 µg) response curves were performed in subcutaneous models. Orthotopic models received 50 µg of M5A-IR800 or 50 µg IgG-IR800 as a control and were imaged after 72 h. Fluorescence imaging was performed on the mice using the LI-COR Pearl Imaging System. RESULTS: In subcutaneous models, tumor to background ratios (TBRs) reached 8.85 at 72 h. Median TBRs of orthotopic model primary tumors were 6.25 (interquartile range [IQR] 6.03-7.12) for M5A-IR800 compared to 0.42 (IQR 0.38-0.54) for control. Abdominal wall metastasis median TBRs were 13.52 (IQR 12.79-13.76) for M5A-IR800 and 3.19 (IQR 2.65-3.73) for the control. Immunohistochemistry confirmed CEA expression within tumors. CONCLUSIONS: Humanized anti-CEA antibodies conjugated to near-infrared dyes provide specific labeling of gastric cancers in mouse models. Orthotopic models demonstrated bright and specific labeling with TBRs greater than ten times that of control. This tumor-specific fluorescent antibody is a promising potential clinical tool for improving visualization of gastric cancer margins at time of surgical resection.

Fluorescence lifetime of injected indocyanine green as a universal marker of solid tumours in patients.

The surgical resection of solid tumours can be enhanced by fluorescence-guided imaging. However, variable tumour uptake and incomplete clearance of fluorescent dyes reduces the accuracy of distinguishing tumour from normal tissue via conventional fluorescence intensity-based imaging. Here we show that, after systemic injection of the near-infrared dye indocyanine green in patients with various types of solid tumour, the fluorescence lifetime (FLT) of tumour tissue is longer than the FLT of non-cancerous tissue. This tumour-specific shift in FLT can be used to distinguish tumours from normal tissue with an accuracy of over 97% across tumour types, and can be visualized at the cellular level using microscopy and in larger specimens through wide-field imaging. Unlike fluorescence intensity, which depends on imaging-system parameters, tissue depth and the amount of dye taken up by tumours, FLT is a photophysical property that is largely independent of these factors. FLT imaging with indocyanine green may improve the accuracy of cancer surgeries.

PEGylated Fluorescent Anti-carcinoembryonic Antigen Antibody Labels Colorectal Cancer Tumors in Orthotopic Mouse Models.

INTRODUCTION: Colorectal cancer (CRC) patients often develop liver metastasis. However, curative resection of liver metastasis is not always possible due to poor visualization of tumor margins. The present study reports the characterization of a humanized anti-carcinoembryonic antigen monoclonal antibody conjugated to a PEGylated near-infrared dye, that targets and brightly labels human CRC tumors in metastatic orthotopic mouse models. METHODS: The hT84.66-M5A (M5A) monoclonal antibody was conjugated with a polyethylene glycol (PEG) chain that incorporated a near infrared (NIR) IR800 dye to establish M5A-IR800 Sidewinder (M5A-IR800-SW). Nude mice with CRC orthotopic primary tumors and liver metastasis both developed from a human CRC cell line, were injected with M5A-IR800-SW and imaged with the Pearl Trilogy Imaging System. RESULTS: M5A-IR800-SW targeted and brightly labeled CRC tumors, both in primary-tumor and liver-metastasis models. M5A-IR800-SW at 75 µg exhibited highly-specific tumor labeling in a primary-tumor orthotopic model with a median tumor-to-background ratio of 9.77 and in a liver-metastasis orthotopic model with a median tumor-to-background ratio of 7.23 at 96 h. The precise labeling of the liver metastasis was due to lack of hepatic accumulation of M5A-IR800-SW in the liver. CONCLUSIONS: M5A-IR800-SW provided bright and targeted NIR images of human CRC in orthotopic primary-tumor and liver-metastasis mouse models. The results of the present study suggest the clinical potential of M5A-IR800-SW for fluorescence-guided surgery including metastasectomies for CRC. The lack of hepatic NIR signal is of critical importance to allow for precise labeling of liver tumors.

Robotic Function-Preserving Resection of Gastric Gastrointestinal Stromal Tumor.

INTRODUCTION: Gastric gastrointestinal stromal tumors (GISTs) located at the gastroesophageal junction (GEJ), lesser curvature, posterior gastric wall, or antrum present challenges for gastric function preservation. The aim of this study was to evaluate safety and effectiveness of robot-assisted resection of gastric GIST in challenging anatomic locations. METHODS: This was a single-center case series of robotic gastric GIST resections in challenging anatomic locations performed from 2019 to 2021. GEJ GISTs are defined as tumors within 5 cm of the GEJ. Location of the tumor and distance from the GEJ were determined from the endoscopy report and/or cross-sectional imaging and operative findings. RESULTS: There were 25 consecutive patients who underwent a robot-assisted partial gastrectomy for a gastric GIST in challenging anatomic locations. Tumors were located at the GEJ (n = 12), lesser curvature (n = 7), posterior gastric wall (n = 4), fundus (n = 3), greater curvature (n = 3), and antrum (n = 2). Median distance of tumor from GEJ was 2.5 cm. Both GEJ and pylorus were successfully preserved in all patients regardless of tumor location. Median operative time was 190 min with a median estimated blood loss of 20 mL and no conversion to open approach. Median hospital stay was 3 d with solid diet intake starting 2 d after surgery. Two (8 %) patients had Grade III or higher postoperative complications. Median tumor size upon resection was 3.9 cm. Negative margins were obtained in 96.3%. There was no evidence of recurrent disease with a median follow-up of 11.3 mo. CONCLUSIONS: We demonstrate the safety and feasibility of using the robotic approach to facilitate function preservation gastrectomy in challenging anatomic locations without compromising oncologic resection.

Colon-cancer liver metastasis is effectively targeted by recombinant methioninase (rMETase) in an orthotopic mouse model.

BACKGROUND: Colorectal cancer liver metastasis (CCLM) is the most frequent cause of death of colorectal cancer. Development of novel new effective therapy is needed for CCLM patients to improve outcome. The aim of the present study was to investigate the efficacy of recombinant methioninase (rMETase) on a CCLM orthotopic mouse model of liver metastasis established using the human colon cancer cell line HT29 expressing red fluorescent protein (RFP). MATERIALS AND METHODS: Orthotopic CCLM nude mouse models were randomized into two groups: control group (n = 6, PBS 200 µl, i.p., daily); rMETase group (n = 6, 100 units/200 µl, i.p., daily). Tumor volume was measured on day 0 and day 15. Body weight was measured twice a week. All mice were sacrificed on day 15. RESULTS: rMETase significantly inhibited the increase of the liver metastasis as determined by RFP fluorescence area and intensity (p = 0.016 and 0.015, respectively). There was no significant difference of body weight between either group on any day. CONCLUSIONS: The present study suggests that rMETase has future potential therapy for CCLM in the clinic.

Multimodality PET and Near-Infrared Fluorescence Intraoperative Imaging of CEA-Positive Colorectal Cancer.

PURPOSE: Molecular imaging is a major diagnostic component for cancer management, enabling detection, staging of disease, targeting therapy, and monitoring the therapeutic response. The coordination of multimodality imaging techniques further enhances tumor localization. The development of a single agent for real-time non-invasive targeted positron emission tomography (PET) imaging and fluorescence guided surgery (FGS) will provide the next generation tool in the surgical management of cancer. PROCEDURES: The humanized anti-CEA M5A-IR800 "sidewinder" (M5A-IR800-SW) antibody-dye conjugate was designed with a NIR 800 nm dye incorporated into a PEGylated linker and conjugated with the metal chelate p-SCN-Bn-deferoxamine (DFO) for zirconium-89 PET imaging (89Zr, half-life 78.4 h). The dual-labeled 89Zr-DFO-M5A-SW-IR800 was evaluated for near infrared (NIR) fluorescence imaging, PET/MRI imaging, terminal tissue biodistribution, and blood clearance in a human colorectal cancer LS174T xenograft mouse model. RESULTS: The 89Zr-DFO-M5A-SW-IR800 NIR fluorescence imaging showed high tumor targeting with normal liver uptake. Serial PET/MRI imaging was performed at 24 h, 48 h, and 72 h and showed tumor localization visible at 24 h that persisted throughout the experiment. However, the PET scans showed higher activity for the liver than the tumor, compared to the NIR fluorescence imaging. This difference is an important finding as it quantifies the expected difference due to the sensitivity and depth of penetration between the 2 modalities. CONCLUSIONS: This study demonstrates the potential of a pegylated anti-CEA M5A-IR800-Sidewinder for NIR fluorescence/PET/MR multimodality imaging for intraoperative fluorescence guided surgery.

ASO Author Reflections: The Evolution of Surgery for Patients with Stage IV Melanoma.

The role of surgery for patients with stage IV melanoma is rapidly evolving. In the past, limited treatment options were available and surgery was offered to carefully selected patients. Currently, in the era of effective immunotherapy, the role of surgery is still being defined. The present study examines outcomes for patients with stage IV melanoma receiving immunotherapy and surgery. Future studies will help to better identify which patients should receive surgery and when it should be performed in the setting of increasingly available therapeutic modalities for patients with stage IV melanoma.

Specific Targeting and Labeling of Colonic Polyps in CPC-APC Mice with Mucin 5AC Fluorescent Antibodies: A Model for Detection of Early Colon Cancer.

Poor visualization of polyps can limit colorectal cancer screening. Fluorescent antibodies to mucin5AC (MUC5AC), a glycoprotein upregulated in adenomas and colorectal cancer, could improve screening colonoscopy polyp detection rate. Adenomatous polyposis coli flox mice with a Cdx2-Cre transgene (CPC-APC) develop colonic polyps that contain both dysplastic and malignant tissue. Mice received MUC5AC-IR800 or IRdye800 as a control IV and were sacrificed after 48 h for near-infrared imaging of their colons. A polyp-to-background ratio (PBR) was calculated for each polyp by dividing the mean fluorescence intensity of the polyp by the mean fluorescence intensity of the background tissue. The mean 25 µg PBR was 1.70 (±0.56); the mean 50 µg PBR was 2.64 (±0.97); the mean 100 µg PBR was 3.32 (±1.33); and the mean 150 µg PBR was 3.38 (±0.87). The mean PBR of the dye-only control was 2.22 (±1.02), significantly less than the 150 µg arm (p-value 0.008). The present study demonstrates the ability of fluorescent anti-MUC5AC antibodies to specifically target and label colonic polyps containing high-grade dysplasia and intramucosal adenocarcinoma in CPC-APC mice. This technology can potentially improve the detection rate and decrease the miss rate of advanced colonic neoplasia and early cancer at colonoscopy.

Surgical Utilization and Outcomes for Patients with Stage IV Melanoma in the Modern Immunotherapy Era.

BACKGROUND: The benefit of surgery for patients with stage IV melanoma in the modern era of effective immunotherapy is unclear. This study aimed to evaluate trends and outcomes after surgical resection of stage IV melanoma in the modern immunotherapy era. METHODS: Patients with stage IV melanoma who received surgery, immunotherapy, or both from 2012 to 2017 were identified from the National Cancer Database (NCDB). Demographics, facility-level characteristics, and use of immunotherapy were compared between patients who received surgery and those who did not. Multivariate Poisson regression modeling, Kaplan-Meier survival analysis, and Cox regression analysis were performed. RESULTS: The study identified 9800 patients with stage IV melanoma, and 2160 of these patients (22 %) underwent surgery. The patients who received surgery were more likely to be younger (P < 0.001), to have private insurance (P < 0.001), to have a higher median income (P = 0.008), and to receive treatment at academic/research programs (P < 0.001), whereas they were less likely to receive immunotherapy (33.7 % vs 36.6 %; P = 0.013). The patients who received immunotherapy had a lower likelihood of undergoing surgery (relative risk [RR], 0.82; 95 % confidence interval [CI[, 0.75-0.88; P < 0.001). The patients who received both surgery and immunotherapy had a better overall survival rate (hazard ratio [HR], 0.41; 95 % CI, 0.36-0.46; P < 0.01) than the patients who received neither immunotherapy nor surgery. CONCLUSIONS: The use of immunotherapy was associated with a lower use of surgery for patients with stage IV melanoma. The patients with stage IV disease who received both surgery and immunotherapy had the highest overall survival rates.

The Mucin Family of Proteins: Candidates as Potential Biomarkers for Colon Cancer.

Mucins (MUC1-MUC24) are a family of glycoproteins involved in cell signaling and barrier protection. They have been implicated in the progression of numerous malignancies including gastric, pancreatic, ovarian, breast, and lung cancer. Mucins have also been extensively studied with respect to colorectal cancer. They have been found to have diverse expression profiles amongst the normal colon, benign hyperplastic polyps, pre-malignant polyps, and colon cancers. Those expressed in the normal colon include MUC2, MUC3, MUC4, MUC11, MUC12, MUC13, MUC15 (at low levels), and MUC21. Whereas MUC5, MUC6, MUC16, and MUC20 are absent from the normal colon and are expressed in colorectal cancers. MUC1, MUC2, MUC4, MUC5AC, and MUC6 are currently the most widely covered in the literature regarding their role in the progression from normal colonic tissue to cancer.

Four-Day Robotic Whipple: Early Discharge after Robotic Pancreatoduodenectomy.

BACKGROUND: The authors aimed to assess the safety of an enhanced recovery after surgery (ERAS) and early discharge pathway in a robotic pancreatoduodenectomy (PD) program and compared outcomes with an open PD control cohort to identify the synergistic effects of robotic surgery and an ERAS pathway on lengths of stay (LOS). STUDY DESIGN: Consecutive patients undergoing open or robotic PD from a single surgeon between March 2020 and July 2022 were identified. Logistic regression models were used for adjusted analyses of postoperative outcomes. RESULTS: There were 134 consecutive PD patients, of which 40 (30%) were performed robotically. Pancreatic adenocarcinoma was the most common indication in both open (56%) and robotic (55%, p = 0.51) groups, with a similar proportion of them being borderline resectable or locally advanced tumors (78% vs 82% in robotic group, p = 0.82). The LOS was significantly shorter in the robotic PD group (median, 5 [IQR 4 to 7] days) when compared with the open PD group (median, 6 [IQR 5 to 8] days, p < 0.001). LOS of 4 days or fewer were observed in 40% of the robotic PD group compared with only 3% of patients in the open PD group (p < 0.001). There was no difference in the overall readmission rate (10% vs 12% in the robotic PD group, p = 0.61). On multivariable logistic regression, robotic PD was independently associated with higher odds of LOS of 4 days or fewer (odds ratio 22.4, p = 0.001) when compared with open PD. CONCLUSIONS: An ERAS and early discharge pathway could be safely implemented in a robotic PD program. Patients undergoing robotic PD have significantly shorter length of stay without increased complication or readmission rate compared with open PD, with 40% of patients undergoing robotic PD achieving a LOS of 4 days or fewer.

Proof of Principle of Combining Fluorescence-Guided Surgery with Photoimmunotherapy to Improve the Outcome of Pancreatic Cancer Therapy in an Orthotopic Mouse Model.

BACKGROUND: Pancreatic cancer is a recalcitrant disease in which R0 resection is often not achieved owing to difficulty in visualization of the tumor margins and proximity of adjacent vessels. To improve outcomes, we have developed fluorescence-guided surgery (FGS) and photoimmunotherapy (PIT) using a fluorescent tumor-specific antibody. METHODS: Nude mice received surgical orthotopic implantation (SOI) of the human pancreatic cancer cell line BxPC-3 expressing green fluorescent protein. An anti-carcinoembryonic antigen-related cell adhesion molecule (CEACAM) monoclonal antibody (6G5j) was conjugated to the 700-nm fluorescent dye IR700DyeDX (6G5j-IR700DX). Three weeks after SOI, 16 mice received 50 µg 6G5j-IR700DX via the tail vein 24 h before surgery and were randomized to two groups: FGS-only (n = 8) and FGS + PIT (n = 8). All tumors were imaged with the Pearl Trilogy imaging system and resected under the guidance of the FLARE imaging system. The FGS + PIT group received PIT of the post-surgical bed at an intensity of 150 mW/cm2 for 30 min. Mice were sacrificed 4 weeks after initial surgery, and tumors were imaged with a Dino-Lite digital microscope, excised, and weighed. RESULTS: The 6G5j-IR700DX dye illuminated the orthotopic pancreatic tumors for FGS and PIT. The metastatic recurrence rate was 100.0% for FGS-only and 25.0% for FGS + PIT (p = 0.007). The average total recurrent tumor weight was 2370.3 ± 1907.8 mg for FGS-only and 705.5 ± 1200.0 mg for FGS + PIT (p = 0.039). CONCLUSIONS: FGS and adjuvant PIT can be combined by using a single antibody-fluorophore conjugate to significantly reduce the frequency of pancreatic cancer recurrence.

Proof of concept of improved fluorescence-guided surgery of colon cancer liver metastasis using color-coded imaging of a tumor-labeling fluorescent antibody and indocyanine green restricted to the adjacent liver segment.

BACKGROUND: Indocyanine green has been used for fluorescence-guided surgery of liver metastasis and labeling of liver segments. However, indocyanine green is nonspecific, and indocyanine green labeling does not always clearly outline tumor margins. In addition, it is difficult to distinguish between a tumor and its adjacent liver segment colored with indocyanine green alone. In the present study, we performed fluorescence-guided surgery in an orthotopic colon-cancer liver metastasis mouse model by labeling the metastatic liver tumor with an anti-carcinoembryonic antigen fluorescent antibody and with indocyanine green restricted to the adjacent liver segment. METHODS: A liver metastasis model was established with human LS174T colon cancer tumor fragments. To label the tumor, mice received SGM-101, an anti-carcinoembryonic antigen antibody conjugated to a near-infrared fluorophore (700 nm), currently in clinical trials, 3 days before surgery. Indocyanine green (800 nm) was injected after ligation of the tumor-bearing Glissonean pedicle with fluorescence labeling restricted to the liver segment adjacent to the tumor. Bright-light surgery and fluorescence-guided surgery were performed to resect the liver metastasis. To assess recurrence, mice underwent necropsy 3 weeks after surgery and the tumor was weighed. RESULTS: Fluorescence-guided anatomic left lateral lobectomy and fluorescence-guided partial liver resection were both performed with color-coded double labeled imaging. Tumor weight 3 weeks after surgery was significantly lower with fluorescence-guided surgery compared to bright-light surgery (38 ± 57 mg vs 836 ± 668 mg, P = .011) for partial liver resection. CONCLUSION: The present study provides a proof-of-concept that color-coded and double labeling of the tumor and adjacent liver segment has the potential to improve liver metastasectomy.