Stauffer, John

Objectives Optimal use of surgery first (SF) vs neoadjuvant therapy (NAT) for localized pancreatic ductal adenocarcinoma (PDAC) is still unclear. There is concern that NAT may result in worsened post-operative outcomes. Our study objectives were to show the impact of NAT on post-operative morbidity and mortality. Methods All patients undergoing resection for PDAC between 1/1/2010 and 12/31/2020 were reviewed and those who underwent pancreaticoduodenectomy (PD) were included. Demographics, perioperative details, and pathology details were gathered. Data pertaining to 90-day complications were obtained and graded according to international consensus guidelines. Those undergoing SF were compared to those who had NAT. Categorical variables were compared by Fisher’s exact test and continuous variables by Student’s t-test. Results Two hundred and forty-one subjects who underwent PD for PDAC were included in this review. There was no significant difference in the rate of major morbidity between subjects who received NAT vs SF (19.4 vs 20.3%, P = 1.0). Similarly, there were no significant differences in the rates of mortality (3.1 vs 4.2%, P = .742), post-operative pancreatic fistula (8.2 vs 10.5%, P = .658), or post-pancreatectomy hemorrhage (7.1 vs 7.7%, P = 1.0), respectively. Conclusion Post-operative outcomes are not worsened by the use of the NAT approach prior to PD for PDAC. Further investigation is needed to reveal which patient subgroups may benefit from the use of NAT, especially regarding survival.

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.

Objectives Pancreatic acinar cell carcinoma (ACC) is a rare pancreatic cancer. The advancement of treatment is hampered because of the limited knowledge of its molecular mechanism. Methods Whole-exome sequencing was performed on DNA extracted from 11 pure ACC surgical samples. Potential germline variants were removed on the basis of polymorphic databases, alternative allele frequency, coverage depth, and Catalogue of Somatic Mutations in Cancer (COSMIC) annotations after variant calling procedure. Mutation profiles and signatures were assessed through the Mutational Patterns package. Results A median of 34 somatic mutations were detected (range, 19–60). Three novel recurrent small deletions were identified. Common pancreatic ductal adenocarcinoma mutations or neuroendocrine tumor mutants were not found. FAT atypical cadherin 4, mucin 5B, titin, and zinc finger homeobox 3 were consistently mutated across 4 independent ACC studies. A high contribution of COSMIC mutational signature 1 was seen in ACC, indicating deamination of 5-methylcytosine. The majority of the patients had COSMIC signatures 6, 15, or 20, relating to defective DNA mismatch repair. Six patients showed COSMIC mutational signature 10 because of the altered activity of DNA polymerase epsilon. Conclusions Distinct mutational signatures pathways were found in ACC and targeting them may improve clinical outcome.

Background Surgical resection is the curative treatment for all subtypes of cholangiocarcinoma (CCA), including intrahepatic, hilar/peri-hilar, and distal. This study evaluates patients with CCA who underwent surgery and determines factors that impact their survival. Methods A retrospective cohort study was performed for patients who underwent surgical resection for CCA at our institution from 1995 to 2016. Demographics, operative variables between CCA tumors, and postoperative complications were analyzed. Predictors of overall and recurrence-free survival were determined via statistical analysis. Results A total of 170 patients with a mean age of 61 years old underwent surgical resection of intrahepatic (n = 64, 37.6%), hilar/peri-hilar (n = 75, 44.1%), and distal (n = 31, 18.2%) CCA. Operations performed included liver resections (n = 83, 48.8%), liver transplants (n = 56, 32.9%), and pancreaticoduodenectomies (n = 31, 18.2%). The overall survival rate at 1, 5, and 10 years was 81.1%, 32.4%, and 17.2%, respectively. Low pathological stage and negative resection margins were associated with lower recurrence and higher survival rates. Tumor location and the type of operation performed were not predictive of recurrence or OS in this cohort. Discussion This study shows that definitive surgical resection with negative margins can result in long-term survival even at 10 years. Small tumor size and low pathological stage are predictive of higher survival rates post-surgery, emphasizing the importance of early diagnosis and appropriate surgical treatment in achieving positive outcomes.

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.