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BackgroundWhile parenchymal hepatic metastases were previously considered a contraindication to cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC), liver resection (LR) is increasingly performed with CRS/HIPEC.MethodsPatients from the US HIPEC Collaborative (2000-2017) with invasive appendiceal or colorectal adenocarcinoma undergoing primary, curative intent CRS/HIPEC with CC0-1 resection were included. LR was defined as a formal parenchymal resection. Primary endpoints were postoperative complications and overall survival (OS).ResultsA total of 658 patients were included. About 83 (15%) underwent LR of colorectal (58%) or invasive appendiceal (42%) metastases. LR patients had more complications (81% vs. 60%; p = .001), greater number of complications (2.3 vs. 1.5; p

BackgroundPostoperative complications (POCs) are associated with worse oncologic outcomes in various cancer histologies. The impact of POCs on the survival of patients with appendiceal or colorectal cancer after cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is unknown.MethodsThe US HIPEC Collaborative (2000-2017) was reviewed for patients who underwent CCR0/1 CRS/HIPEC for appendiceal/colorectal cancer. The analysis was stratified by noninvasive appendiceal neoplasm versus invasive appendiceal/colorectal adenocarcinoma. The POCs were grouped into infectious, cardiopulmonary, thromboembolic, and intestinal dysmotility. The primary outcomes were overall survival (OS) and recurrence-free survival (RFS).ResultsOf the 1304 patients, 33% had noninvasive appendiceal neoplasm (n = 426), and 67% had invasive appendiceal/colorectal adenocarcinoma (n = 878). In the noninvasive appendiceal cohort, POCs were identified in 55% of the patients (n = 233). The 3-year OS and RFS did not differ between the patients who experienced a complication and those who did not (OS, 94% vs 94%, p = 0.26; RFS, 68% vs 60%, p = 0.15). In the invasive appendiceal/colorectal adenocarcinoma cohort, however, POCs (63%; n = 555) were associated with decreased 3-year OS (59% vs 74%; p

BackgroundCytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis can be performed in two ways: Open or closed abdominal technique.AimTo evaluate the impact of HIPEC method on post-operative and long-term survival outcomes.MethodsPatients undergoing CRS with HIPEC from 2000-2017 were identified in the United States HIPEC collaborative database. Post-operative, recurrence, and overall survival outcomes were compared between those who received open vs closed HIPEC.ResultsOf the 1812 patients undergoing curative-intent CRS and HIPEC, 372 (21%) patients underwent open HIPEC and 1440 (79%) underwent closed HIPEC. There was no difference in re-operation or severe complications between the two groups. Closed HIPEC had higher rates of 90-d readmission while open HIPEC had a higher rate of 90-d mortalities. On multi-variable analysis, closed HIPEC technique was not a significant predictor for overall survival (hazards ratio: 0.75, 95% confidence interval: 0.51-1.10, P = 0.14) or recurrence-free survival (hazards ratio: 1.39, 95% confidence interval: 1.00-1.93, P = 0.05) in the entire cohort. These findings remained consistent in the appendiceal and the colorectal subgroups.ConclusionIn this multi-institutional analysis, the HIPEC method was not independently associated with relevant post-operative or long-term outcomes. HIPEC technique may be left to the discretion of the operating surgeon.

Cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with improved survival for patients with colorectal peritoneal metastases (CR-PM). However, the role of neoadjuvant chemotherapy (NAC) prior to CRS-HIPEC is poorly understood. A retrospective review of adult patients with CR-PM who underwent CRS+/-HIPEC from 2000-2017 was performed. Among 298 patients who underwent CRS+/-HIPEC, 196 (65.8%) received NAC while 102 (34.2%) underwent surgery first (SF). Patients who received NAC had lower peritoneal cancer index score (12.1 + 7.9 vs. 14.3 + 8.5, p = 0.034). There was no significant difference in grade III/IV complications (22.4% vs. 16.7%, p = 0.650), readmission (32.3% vs. 23.5%, p = 0.114), or 30-day mortality (1.5% vs. 2.9%, p = 0.411) between groups. NAC patients experienced longer overall survival (OS) (median 32.7 vs. 22.0 months, p = 0.044) but similar recurrence-free survival (RFS) (median 13.8 vs. 13.0 months, p = 0.456). After controlling for confounding factors, NAC was not independently associated with improved OS (OR 0.80) or RFS (OR 1.04). Among patients who underwent CRS+/-HIPEC for CR-PM, the use of NAC was associated with improved OS that did not persist on multivariable analysis. However, NAC prior to CRS+/-HIPEC was a safe and feasible strategy for CR-PM, which may aid in the appropriate selection of patients for aggressive cytoreductive surgery.

Background: KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC) represents a distinct entity with unique biology. The therapeutic impact of matched targeted therapy in these patients in a real-world setting, to date, is less established. Objectives: The aim of our study was to review our institutional database to identify the prevalence of actionable genomic alterations in patients with KRAS -WT tumors and to evaluate the therapeutic impact of matched targeted therapy in these patients. Design: We reviewed electronic medical records of patients with KRAS-WT PDAC and advanced disease (n = 14) who underwent clinical-grade tissue ± liquid next-generation sequencing (315–648 genes for tissue) between years 2015 and 2021. Methods: Demographic and disease characteristics were summarized using descriptive parameters. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Results: Of 236 PDAC patients, 14 had advanced/metastatic disease with KRAS-WT tumors. Median age at diagnosis was 66 years. There was a high frequency of potentially actionable genomic alterations, including three (21%) with BRAF alterations, two (14%) with fusions [ RET-PCM1 and FGFR2-POC1B (N = 1 each)]; and one with a druggable EGFR (EGFR E746_A755delISERD) variant; two other patients had an STK11 and a MUTYH alteration. Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR -altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Duration of time on chemotherapy-free matched targeted therapy for these patients was 17+, 11, and 18+ months, respectively. Conclusion: Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted. [ABSTRACT FROM AUTHOR]

Purpose/Objectives: Most patients with pancreatic adenocarcinoma (PDAC) will present with distant metastatic disease at diagnosis. We sought to identify clinical characteristics associated with prolonged overall survival (OS) in patients presenting with metastatic PDAC. Materials/Methods: Patients presenting with metastatic PDAC that received treatment at our institution with FOLFIRINOX or gemcitabine-based chemotherapies between August 1, 2011 and September 1, 2017 were included in the study. Metastatic disease burden was comprehensively characterized radiologically via individual diagnostic imaging segmentation. Landmark analysis was performed at 18months, and survival curves were estimated using the Kaplan– Meier method and compared between groups via the log-rank test. ECOG and Charlson Comorbidity Index (CCI) were calculated for all patients. Results: 121 patients were included with a median age of 62 years (37–86), 40% were female, 25% had ECOG 0 at presentation. Of the 121 patients included, 33% (n=41) were alive at 12months and 25% (n=31) were alive at 18months. Landmark analysis demonstrated a significant difference between patients surviving <18months and ≥18months regarding the presence of lung only metastases (36% vs. 16%, p=0.04), number of organs with metastases (≥2 vs. 1, p=0.04), and disease volume (mean of 19.1 cc vs. 1.4 cc, p=0.04). At Year 1, predictors for improved OS included ECOG status at diagnosis (ECOG 0 vs. ECOG 1, p=0.04), metastatic disease volume at diagnosis (≤0.1 cc vs. >60 cc, p=0.004), metastasis only in the liver (p=0.04), and normalization of CA 19-9 (p<0.001). At Year 2, the only predictor of improved OS was normalization of the CA 19-9 (p=0.03). In those patients that normalized their CA 19-9, median overall survival was 16months. Conclusions: In this exploratory analysis normalization of CA-19-9 or volumetric metastatic disease burden less than 0.2 cc demonstrated a remarkable OS, similar to that of patients with non-metastatic disease. These metrics are useful for counseling patients and identifying cohorts that may be optimal for trials exploring metastatic and/or local tumor-directed interventions. [ABSTRACT FROM AUTHOR]

Background: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) imaging is not routine in patients with localized pancreatic cancer (PC). We evaluated the prognostic value of PET/CT in patients who received neoadjuvant therapy. Methods: Patients with localized PC underwent pretreatment PET/CT with or without posttreatment (preop) PET/CT. Maximum standardized uptake values (SUV) were classified as high or low based on a cut point of 7.5 at diagnosis (SUVdx) and 3.5 after neoadjuvant therapy (preoperative; SUVpreop). Preop carbohydrate antigen 19-9 (CA19-9) was classified as normal (≤ 35 U/mL) or elevated. Results: Pretreatment PET/CT imaging was performed on 201 consecutive patients; SUVdx was high in 98 (49%) and low in 103 (51%). Preop PET/CT was available in 104 (52%) of the 201 patients; SUVpreop was high in 60 (58%) and low in 44 (42%). Following neoadjuvant therapy, preop CA19-9 was normal in 90 (45%) patients and elevated in 111 (55%). Median overall survival (OS) of all patients was 27 months; 33 months for the 103 patients with a low SUVdx and 22 months for the 98 patients with a high SUVdx (p = 0.03). Median OS for patients with low SUVdx/normal preop CA19-9, high SUVdx/normal preop CA19-9, low SUVdx/elevated preop CA19-9, and high SUVdx/elevated preop CA19-9 were 66, 34, 23, and 17 months, respectively (p < 0.0001). OS was 44 months for the 148 (74%) patients who completed all intended neoadjuvant therapy and surgery and 13 months for the 53 (26%) who did not undergo surgery (p < 0.001). Conclusion: Pretreatment PET/CT avidity and preop CA19-9 are clinically significant prognostic markers in patients with PC. [ABSTRACT FROM AUTHOR]

Context Elucidating the genomic landscape of sporadic parathyroid carcinoma (PC) has been limited by low tumor incidence. Objective Identify driver mutations of sporadic PC and potential actionable pathways. Methods Patients undergoing surgical resection for sporadic PC between 1980 and 2016 at MD Anderson Cancer Center were identified. Patients with sporadic PC according to World Health Organization diagnostic criteria and with available formalin-fixed, paraffin-embedded (FFPE) PC tumor tissue were included and their clinical data analyzed to assess extent of disease. Patients with parathyroid tumors of uncertain malignancy or atypical parathyroid neoplasms were excluded. Thirty-one patients meeting diagnostic criteria had available tissue for analysis. FFPE PC tumors were subjected to DNA extraction and next-generation whole-exome sequencing. All variant calls are single-algorithm only. Twenty-nine samples passed quality assurance after DNA extraction. Main Outcome Measures Somatic or private germline mutations present in sporadic PC and identification of pathways involved in tumorigenesis. Results We identified 35 genes with considerable mutational load; only eight genes were previously identified in other PC cohorts. These genes mediate critical processes, including chromosome organization, DNA repair, and cell cycle regulations. Gene mutations involved in MAPK signaling and immune response are also heavily implicated. These findings are limited by inherent molecular artifacts in FFPE tissue analysis and the absence of matched germline DNA. Additionally, variant calls are only single algorithm and may include false-positive/negative calls. Conclusion We identified 33 candidate driver genes of sporadic PC, in addition to previously known driver genes CDC73 and MEN1. [ABSTRACT FROM AUTHOR]

Background: 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) imaging is not routine in patients with localized pancreatic cancer (PC). We evaluated the prognostic value of PET/CT in patients who received neoadjuvant therapy. Methods: Patients with localized PC underwent pretreatment PET/CT with or without posttreatment (preop) PET/CT. Maximum standardized uptake values (SUV) were classified as high or low based on a cut point of 7.5 at diagnosis (SUV dx ) and 3.5 after neoadjuvant therapy (preoperative; SUV preop ). Preop carbohydrate antigen 19-9 (CA19-9) was classified as normal ( ≤ 35 U/mL) or elevated. Results: Pretreatment PET/CT imaging was performed on 201 consecutive patients; SUV dx was high in 98 (49%) and low in 103 (51%). Preop PET/CT was available in 104 (52%) of the 201 patients; SUV preop was high in 60 (58%) and low in 44 (42%). Following neoadjuvant therapy, preop CA19-9 was normal in 90 (45%) patients and elevated in 111 (55%). Median overall survival (OS) of all patients was 27 months; 33 months for the 103 patients with a low SUV dx and 22 months for the 98 patients with a high SUV dx ( p = 0.03). Median OS for patients with low SUV dx /normal preop CA19-9, high SUV dx /normal preop CA19-9, low SUV dx /elevated preop CA19-9, and high SUV dx /elevated preop CA19-9 were 66, 34, 23, and 17 months, respectively ( p < 0.0001). OS was 44 months for the 148 (74%) patients who completed all intended neoadjuvant therapy and surgery and 13 months for the 53 (26%) who did not undergo surgery ( p < 0.001). Conclusion: Pretreatment PET/CT avidity and preop CA19-9 are clinically significant prognostic markers in patients with PC., (Copyright © 2020 Barnes, Aldakkak, Clarke, Christians, Bucklan, Holt, Tolat, Ritch, George, Hall, Erickson, Evans and Tsai.)

Arginine methylation of the epidermal growth factor receptor (meEGFR) increases the binding affinity of EGFR ligands and is reported to have a role in predicting response to anti-EGFR agents. This study investigated the predictive impact of meEGFR in metastatic colorectal cancer (mCRC) patients treated with anti-EGFR agents. Two patient cohorts were evaluated. Cohort 1 consisted of mCRC patients with documented disease progression following anti-EGFR treatment. Circulating tumor cells (CTCs) were isolated and distinguished based on CD45 - and Epcam + . Cohort 2 consisted of formalin fixed paraffin-embedded (FFPE) blocks from a prospective cohort. meEGFR in both cohorts was identified by positive staining for me-R198/200 EGFR signal. CTCs were identified in 30 out of 47 cases in cohort 1. Of those 30, meEGFR-CTCs were identified in 19 cases. Mean total meEGFR-CTCs counts was 2.3 (range 0-30) cells per 7.5 ml. There was no association between meEGFR-CTCs and clinic-pathological-molecular features. In RAS wt / BRAF wt patients with high levels of meEGFR-CTCs ratio (≥ 0.23) had significantly inferior PFS with anti-EGFR treatment (HR = 3.4, 95% CI 1.5-7.9, P = 0.004). By contrast, high levels of meEGFR in the untreated tumor tissues had no correlation with anti-EGFR treatment duration in cohort 2. Therefore, meEGFR-CTCs may have the potential to serve as a "liquid biopsy" biomarker to predict anti-EGFR treatment efficacy., Competing Interests: None.

Despite new and more effective cytotoxic chemotherapy, limitations to conventional agents have been reached in a subset of patients with advanced colorectal cancer (CRC). The identification of novel prognostic and predictive biomarkers to guide individualized treatment plans is critical to overcoming therapeutic resistance. Mutation of the BRAF proto-oncogene is linked to a variety of cancers and is increasingly being used as a prognostic tool and therapeutic target. This paper is a comprehensive review of the literature that summarizes the clinical, pathologic, and molecular features of BRAF mutated CRC that support the hypothesis that BRAF mutant cancers represent a distinct subset of CRC with its own clinical implications with regard to prognosis, treatments and emerging therapeutic strategies.

Aim: To investigate the mechanisms of liver growth and atrophy after portal vein ligation (PVL) and its effects on tumor growth., Methods: Mice were subjected to PVL, partial hepatectomy, or sham surgery. The morphological alterations, activation of transcription factors, and expression of cytokines and growth factors involved in liver regeneration were evaluated. In a separate set of experiments, murine colorectal carcinoma cells were injected via the portal vein and the effect of each operation on liver tumor growth was studied., Results: Liver regeneration after PVL and partial hepatectomy were very similar. In ligated lobes, various cytokines, transcription factors and regulatory factors were significantly upregulated compared to non-ligated lobes after PVL. Atrophy in ligated lobes was a result of early necrosis followed by later apoptosis. Tumor growth was significantly accelerated in ligated compared to non-ligated lobes., Conclusion: Tumor growth was accelerated in ligated liver lobes and appeared to be a result of increased growth factor expression.