Moaven, Omeed

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival rate of 13.3%. First-line treatment relies on two chemotherapy regimens, FOLFIRINOX (FOLFNX) or gemcitabine plus nab-paclitaxel (GEMPAC). However, direct clinical comparisons between these regimens have yielded inconsistent results across survival and toxicity endpoints, and the molecular basis of heterogeneous treatment responses remains poorly defined. To investigate regimen-specific tumor-cell-intrinsic mechanisms, we performed quantitative proteomic profiling of a primary PDAC-derived MIA PaCa-2 cell line following treatment with FOLFNX or GEMPAC. Differentially expressed proteins were analyzed using Gene Ontology, KEGG, and Ingenuity Pathway Analysis to define pathway-level alterations, and findings were contextualized using TCGA transcriptomic data. Proteomic analyses revealed that FOLFNX and GEMPAC engage in distinct cytotoxic programs. FOLFNX predominantly suppressed ribosome biogenesis and mitochondrial translation, consistent with sustained metabolic and biosynthetic stress, whereas GEMPAC preferentially disrupted mitotic cytokinesis and phosphatidylinositol phosphate biosynthesis, consistent with mitotic failure. Integration with TCGA data showed that FOLFNX-altered proteins aligned with favorable prognostic expression signatures, whereas GEMPAC-associated proteins were enriched among adverse profiles, reflecting engagement of distinct tumor-intrinsic programs. Together, these findings provide mechanistic insight into differential chemotherapy responses and establish a foundation for proteomics-based biomarkers to guide personalized chemotherapy selection in PDAC.

AbstractBackgroundThis study investigates the impact of margin status after colorectal liver metastasis (CLM) resection on outcomes of patients after neoadjuvant treatment versus those who underwent upfront resection.MethodsAn international collaborative database of CLM patients who underwent surgical resection was used. Proportional hazard regression models were created for single and multivariable models to assess the relationship between independent measures and median overall survival (mOS).ResultsR1 was associated with worse OS in the neoadjuvant group (mOS: 51.8 m for R0 vs. 26.0 m for R1; HR: 2.18). In the patients who underwent upfront surgery, R1 was not associated with OS. (mOS: 46.7 m for R0 vs. 42.6 m for R1). When patients with R1 in each group were stratified by adjuvant treatment, there was no significant difference in the neoadjuvant group, while in the upfront surgery group with R1, adjuvant treatment was associated with significant improvement in OS (mOS: 42.6 m for adjuvant vs. 25.0 m for no adjuvant treatment; HR: 0.21).ConclusionR1 is associated with worse outcomes in the patients who receive neoadjuvant treatment with no significant improvement with the addition of adjuvant therapy, likely representing an aggressive tumor biology. R1 did not impact OS in patients with upfront surgery who received postoperative chemotherapy.

AbstractBackgroundThermal ablation has recently become a key therapy for the treatment of colorectal liver metastasis (CLM). However, the role of ablation in combination with resection has not yet been firmly established. We hypothesize that in patients with CLM, those who undergo liver resection with ablation (RA) have similar outcomes compared with those who undergo liver resection only.MethodsWe reviewed a multicenter international database of 906 surgical procedures for CLM from 5 high volume hepatobiliary surgical units. Patients undergoing RA (n = 63) were matched based on the number of lesions and tumor size using a 1:1 balanced propensity score analysis with those having resection only (n = 63). Our primary outcomes were overall survival (OS) and disease‐free survival (DFS).ResultsThe mean age of our cohort was 58 ± 11 years, with 43% females. With a median follow‐up of 70.8 months, patients in the resection and RA group had a median OS of 45.1 and 54.8 months (p = 0.71), respectively. The median DFS was 22.7 and 14.2 months (p = 0.045), respectively. Using a multivariate Cox proportional hazards regression model, the treatment approach was not associated with OS (p = 0.94) or DFS (p = 0.059). A higher number of lesions is independently associated with worse DFS (hazard ratio: 1.12, p < 0.01). When there was disease recurrence, the region of recurrence was similar between the RA versus resection only groups (p = 0.27), but there was a shorter time to recurrence in the RA group (p = 0.002).ConclusionFor CLM, the treatment approach was not significantly associated with OS or DFS, while tumor biology likely played an important role. Prospective research on the quality and effectiveness of thermal ablation combined with hepatic resection is warranted.

BACKGROUND: Surgical intervention remains the cornerstone of a multidisciplinary approach in the treatment of colorectal liver metastases (CLM). Nevertheless, patient outcomes vary greatly. While predictive tools can assist decision-making and patient counseling, decades of efforts have yet to result in generating a universally adopted tool in clinical practice. STUDY DESIGN: An international collaborative database of CLM patients who underwent surgical therapy between 2000 and 2018 was used to select 1,004 operations for this study. Two different machine learning methods were applied to construct 2 predictive models for recurrence and death, using 128 clinicopathologic variables: gradient-boosted trees (GBTs) and logistic regression with bootstrapping (LRB) in a leave-one-out cross-validation. RESULTS: Median survival after resection was 47.2 months, and disease-free survival was 19.0 months, with a median follow-up of 32.0 months in the cohort. Both models had good predictive power, with GBT demonstrating a superior performance in predicting overall survival (area under the receiver operating curve [AUC] 0.773, 95% CI 0.743 to 0.801 vs LRB: AUC 0.648, 95% CI 0.614 to 0.682) and recurrence (AUC 0.635, 95% CI 0.599 to 0.669 vs LRB: AUC 0.570, 95% CI 0.535 to 0.601). Similarly, better performances were observed predicting 3- and 5-year survival, as well as 3- and 5-year recurrence, with GBT methods generating higher AUCs. CONCLUSIONS: Machine learning provides powerful tools to create predictive models of survival and recurrence after surgery for CLM. The effectiveness of both machine learning models varies, but on most occasions, GBT outperforms LRB. Prospective validation of these models lays the groundwork to adopt them in clinical practice.

AbstractBackgroundResection of colorectal liver metastasis (CLM) is beneficial when feasible. However, the benefit of second hepatectomy for hepatic recurrence in CLM remains unclear.MethodsThe Colorectal Liver Operative Metastasis International Collaborative retrospectively examined 1004 CLM cases from 2000 to 2018 from a total of 953 patients. Hepatic recurrence after initial hepatectomy was identified in 218 patients. Kaplan–Meier analysis was performed for overall survival (OS) and recurrence‐free survival (RFS). Propensity score matching (PSM) was performed to offset selection bias. Cox proportional‐hazards regression was performed to identify risk factors associated with OS.ResultsA total of 51 patients underwent second hepatectomy. Unadjusted median OS was 60.1 months in repeat‐hepatectomy versus 38.3 months in the single‐hepatectomy group (p = 0.015). In the PSM population, median OS remained significantly better in the repeat‐hepatectomy group (60.1 vs. 33.1 months; p = 0.0023); median RFS was 12.4 months for the repeat‐hepatectomy group, versus 9.8 months in the single‐hepatectomy group (p = 0.0050). Repeat hepatectomy was associated with lower risk of death (hazard ratio: 0.283; p = 0.000012). Obesity, tobacco use, and high intraoperative blood loss were associated with significant risk of death (p < 0.05).ConclusionIn CLM with hepatic recurrence, second hepatectomy was beneficial for OS. With PSM, the OS benefit of performing a second hepatectomy remained significant.

AbstractBackgroundChemotherapy has been increasingly combined with surgery as multimodality treatment for resectable colorectal‐liver metastases (CLM). There is paucity of clinical data addressing optimal timing of chemotherapy relative to surgery. We examined outcomes of patients undergoing hepatectomy for resectable CLM.MethodsSeven hundred and eighteen patients treated with hepatectomy for CLM were analyzed from five hepatobiliary institutions between 2000 and 2018. Overall survival (OS) was measured from time of hepatectomy for patients receiving: surgery alone, neoadjuvant, adjuvant, and neoadjuvant‐plus‐adjuvant (perioperative) chemotherapy. Kaplan–Meier analysis was performed to detect differences in OS between treatment groups. Single‐ and multi‐variable analysis with Cox proportional hazards were run for OS between groups.ResultsOne hundred and thirty‐seven patients (19.08%) received surgery, 104 (14.48%) received neoadjuvant‐only, 214 (29.81%) received adjuvant‐only, and 263 (36.63%) received perioperative chemotherapy; with median OS of 48.20, 46.83, 56.27, and 49.93 months, respectively. No differences in median OS were seen between groups on Kaplan–Meier analysis. No significant difference in Charlson‐Deyo comorbidity status was seen between groups (p = 0.853), while significant difference was seen in maximum tumor size (p = 0.0023). On multivariate analysis, adjuvant (p = 0.010) and perioperative (p = 0.020) chemotherapy were independently associated with OS compared to surgery alone.DiscussionDespite group differences, chemotherapy after surgery was independently associated with improved OS in CLM.

AbstractIntroductionHyperthermic intraperitoneal chemotherapy (HIPEC) during cytoreductive surgery (CRS) is typically reserved for a complete or optimal cytoreduction. There is the potential for therapeutic effect of HIPEC with an incomplete cytoreduction, particularly for near optimal cytoreductions.MethodsRetrospective review of incomplete cytoreductions (R2b, R2c) for appendiceal and colorectal primaries. Primary endpoints were overall survival (OS) and progression‐free survival (PFS). Subgroup analysis for primary etiology and specific cytoreductive score.ResultsA total of 121 cases of incomplete CRS, 74 CRS alone, and 47 CRS‐HIPEC. For the entire study group there was a survival benefit with HIPEC. OS and PFS were 2.3 versus 1.4 (p = 0.001) and 1.6 versus 0.7 (p < 0.0001) respectively for cases with and without HIPEC. Subgroup analysis of appendiceal neoplasms, 43 CRS‐HIPEC and 50 CRS alone, found HIPEC benefit persisted; OS and PFS were 2.4 versus 1.5 (p = 0.016) and 1.7 versus 0.8 (p < 0.0001), respectively for cases with and without HIPEC. Benefit most pronounced in low‐grade cases with doubling of the OS and PFS (p = 0.004). With colorectal primary cases, 10 CRS‐HIPEC and 18 CRS alone, no difference in OS and PFS. When stratifying out by cytoreduction scores, R2b and R2c, HIPEC only provided a benefit for R2b cases; OS and PFS for R2b cases were 2.28 versus 1.01 (p = 0.011) and 1.67 versus 0.75 (p = 0.001), respectively for cases with and without HIPEC.ConclusionHIPEC has utility for incomplete cytoreductions with appendiceal neoplasms, greatest effect with low‐grade appendiceal neoplasms. HIPEC is only beneficial for near optimal cytoreductions (R2b).

Despite advancements in cancer therapy that have occurred over the past several decades, successful treatment of advanced malignancies remains elusive. Substantial resources and significant efforts have been directed toward the development of novel therapeutic modalities to improve patient outcomes. Oncolytic viruses (OVs) are emerging tools with unique characteristics that have attracted great interest in developing effective anticancer treatment. The original attraction was directed toward selective replication and cell-specific toxicity, two unique features that are either inherent to the virus or could be conferred by genetic engineering. However, recent advancements in the knowledge and understanding of OVs are shifting the therapeutic paradigm toward a greater focus on their immunomodulatory role. Nonetheless, there are still significant obstacles that remain to be overcome to enhance the efficiency of OVs as effective therapeutic modalities and potentially establish them as part of standard treatment regimens. In this review, we discuss advances in the design of OVs, strategies to enhance their therapeutic efficacy, functional translation into the clinical settings, and various obstacles that are still encountered in the efforts to establish them as effective anticancer treatments.

Selective oncotropism and cytolytic activity against tumors have made certain viruses subject to investigation as novel treatment modalities. However, monotherapy with oncolytic viruses (OVs) has shown limited success and modest clinical benefit. The capacity to genetically engineer OVs makes them a desirable platform to design complementary treatment modalities to overcome the existing treatment options' shortcomings. In recent years, our knowledge of interactions of the tumors with the immune system has expanded profoundly. There is a growing body of literature supporting immunomodulatory roles for OVs. The concept of bioengineering these platforms to induce the desired immune response and complement the current immunotherapeutic modalities to make immune-resistant tumors responsive to immunotherapy is under investigation in preclinical and early clinical trials. This review provides an overview of attempts to optimize oncolytic virotherapy as essential components of the multimodality anticancer therapeutic approach and discusses the challenges in translation to clinical practice.

The genetic and molecular underpinnings of metastatic colorectal cancer have been studied for decades, and the applicability of these findings in clinical decision making continues to evolve. Advancements in translating molecular studies have provided a basis for tailoring chemotherapeutic regimens in metastatic colorectal cancer (mCRC) treatment, which have informed multiple practice guidelines. Various genetic and molecular pathways have been identified as clinically significant in the pathogenesis of metastatic colorectal cancer. These include rat sarcoma (RAS), epithelial growth factor receptor (EGFR), vascular endothelial growth factor VEGF, microsatellite instability, mismatch repair, and v-raf murine sarcoma viral oncogene homolog b1 (BRAF) with established clinical implications. RAS mutations and deficiencies in the mismatch repair pathway guide decisions regarding the administration of anti-EGFR-based therapies and immunotherapy, respectively. Furthermore, there are several emerging pathways and therapeutic modalities that have not entered mainstream use in mCRC treatment and are ripe for further investigation. The well-established data in the arena of targeted therapies provide evidence-based support for the use or avoidance of various therapeutic regimens in mCRC treatment, while the emerging pathways and platforms offer a glimpse into the future of transforming a precision approach into a personalized treatment.