Hyperthermic Intraperitoneal Chemotherapy in the Treatment Armamentarium of Epithelial Ovarian Cancer: Time to End the Dichotomy

<b><i>Background:</i></b> Advanced epithelial ovarian cancer (EOC) is an incurable disease with over 75% of the patients developing recurrence in the peritoneum. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising treatment option for both first-line therapy and treatment of recurrence. In this article, we review the rationale and current evidence for performing HIPEC and the role of HIPEC in the light of targeted systemic therapies. <b><i>Summary:</i></b> There are few randomized trials and several retrospective studies on the role of HIPEC in the management of EOC. A 12-month-overall survival (OS) benefit of the addition of HIPEC to interval cytoreductive surgery (CRS) was demonstrated in 1 randomized trial following which HIPEC has been included as a treatment option for this indication in several national/international guidelines. One retrospective propensity score-matched analysis showed a 16-month OS benefit of adding HIPEC to primary CRS. One randomized trial showed no benefit of the addition of carboplatin HIPEC to secondary CRS over secondary CRS alone. For patients undergoing primary CRS and secondary CRS for recurrence, the results of ongoing randomized trials are needed to define the role of HIPEC in these situations. All clinical trials have shown that the morbidity of HIPEC performed after CRS is acceptable. Along with the emergence of HIPEC as a promising surgical therapy, targeted therapies like bevacizumab and poly adenosine diphosphate-ribose polymerase inhibitors have been developed that have shown a survival benefit in selected patients. In principle, HIPEC and targeted therapies work in different ways and it is plausible to assume that their benefit could be additive, and their combination should be evaluated in clinical trials. The impact of prognostic factors like the disease extent, pathological response to systemic chemotherapy (SC), the histological subtype and molecular profile on the benefit of HIPEC, and targeted therapies has not been evaluated in clinical trials. <b><i>Key Messages:</i></b> HIPEC is an important therapeutic strategy in the treatment of EOC. While its role in patients undergoing interval CRS has been established, the results of ongoing randomized trials are needed to define its benefit at other time points. The morbidity of HIPEC in addition to CRS is acceptable. More research is needed to define subgroups that benefit most from HIPEC based on the extent of disease, response to SC, histology, and molecular profile. The combination of HIPEC and maintenance therapies should be evaluated in well-designed randomized clinical trials that evaluate not just the survival benefit and morbidity but also the cost-effectiveness of each therapy.

Cell Type of Pancreatic Ductal Adenocarcinoma Origin: Implications for Prognosis and Clinical Outcomes

<b><i>Background:</i></b> Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that has no effective early detection method or treatment to date. <b><i>Summary:</i></b> The normal cell type that initiates PDAC, or its cellular origin, is still unknown. To investigate the contribution of distinct normal epithelial cell types to PDAC tumorigenesis, genetically engineered mouse models were used to show that both acinar and ductal cells are capable of giving rise to PDAC. These studies indicated that genetic mutations and pancreatic injury interact differently with each cellular origin to affect their predilection and process for forming PDAC. In this review, we summarize recent findings using various genetically engineered mouse models in the identification and characterization of the PDAC cell of origin. We also discuss potential implications for cellular origin on tumor development, PDAC transcriptional subtype, and disease prognosis of patients. <b><i>Key Message:</i></b> Although it is clear that both ductal and acinar cells have the potential to form PDAC, whether cellular origin can indeed influence patient prognosis and whether knowledge of cellular origin will aid in the diagnosis or treatment of patients in the future will need further study.

Emerging Role of Exosomal-Derived Long Noncoding RNAs in Human PDAC

<b><i>Background:</i></b> The incidence and mortality of pancreatic ductal adenocarcinoma (PDAC) are increasing recently. Most patients with PDAC are diagnosed at advanced stage because of the high invasiveness of cancer cells and the lack of typical early symptoms. Therefore, early diagnosis of PDAC is very important to improve the prognosis. Exosomes play crucial role in intercellular communication and deliver the contents to recipient cells to regulate their biological behaviors. Recent evidence suggests emerging role of exosomes in the carcinogenesis of a variety of cancers including PDAC. Long noncoding RNAs (LncRNAs) have been reported to be involved in the development of PDAC. It has been proved that LncRNAs have the potential to be biomarkers and therapeutic targets for PDAC. Moreover, increasing number of studies focus on the role of exosomal LncRNAs in PDAC. <b><i>Summary:</i></b> In this review, we summarize the current status on our understanding of the role of exosomal-derived LncRNAs in the progression and metastasis of PDAC. <b><i>Key Messages:</i></b> We focus on challenges in the potential of exosomal-derived LncRNAs as novel diagnostic and prognostic markers and therapeutic targets of PDAC. In addition, we provide an overview about the demonstrated important role of exosomal LncRNAs in the progression of PDAC.

Epigenetic Therapeutic Strategies to Target Molecular and Cellular Heterogeneity in Pancreatic Cancer

<b><i>Background:</i></b> Pancreatic ductal adenocarcinoma (PDAC) remains a major challenge in cancer medicine and is characterized by a 5-year survival rate of &#x3c;10%. Compelling evidence suggests that the devastating disease outcome of PDAC patients is linked to a high degree of intra- and interindividual tumor heterogeneity, which is predominantly installed at the level of gene transcription. The cellular and molecular complexities of the disease explain the poor efficacy of “one-size-fits-all” therapeutic approaches in PDAC treatment and strongly argue for pursuing tailored therapeutic strategies to tackle PDAC. In a highly dynamic manner, a network of transcription factors and epigenetic regulatory proteins temporally and spatially control the diverse transcriptomic states determining PDAC heterogeneity. Given the reversibility of epigenetic processes, pharmacological intervention with key epigenetic drivers of PDAC heterogeneity appeals as a promising concept to shift the transcriptomic phenotype of PDAC toward a less aggressive and more chemosensible state. <b><i>Summary:</i></b> In this review, we discuss the chances and pitfalls of epigenetic treatment strategies in overcoming and shifting molecular and cellular PDAC heterogeneities in order to combat PDAC. To this end, we utilized the keywords “pancreatic cancer,” “heterogeneity,” and “epigenetics” to search for relevant articles on the database PubMed and selected interventional studies enrolling PDAC patients as displayed in clinicaltrails.gov to generate a synopsis of clinical trials involving epigenetic targeting. <b><i>Key Messages:</i></b> Targeting epigenetic regulators in PDAC represents a promising concept to reprogram molecular and cellular tumor heterogeneities in the pancreas and hence to modulate the PDAC phenotype in favor of a less aggressive and more therapy susceptible disease course. However, we just start to understand the complex interactions of epigenetic regulators in controlling PDAC plasticity, and a clinical breakthrough utilizing epigenetic targeting in PDAC patients has not been achieved yet. Nevertheless, increasing translational efforts which consider the pleiotropic effects of targeting epigenetic regulation in different cellular compartments of the tumor and that focus on the utility and sequence of combinatory treatment approaches might pave the way toward novel epigenetic treatment strategies in PDAC therapy.

Advanced Robotic Surgery: Liver, Pancreas, and Esophagus – The State of the Art?

<b><i>Background:</i></b> The trend in performing robotic-assisted operations in visceral surgery has been increasing in the last decade, also reaching the challenging field of hepatic, pancreatic, and esophageal surgery. Nevertheless, solid data about advantages and disadvantages of the robotic approach are still missing. The aim of this review is to analyze the benefit and impact of robotic surgery in the field of hepatic, pancreatic, and esophageal surgery, focusing on the comparison with the conventional laparoscopic or open approach. <b><i>Summary:</i></b> The well-known advantages of laparoscopic surgery in comparison to the open approach are also valid for robotic surgery, with the addition of a 3D-view camera, wristed instrumentation, and an ergonomic console. On the other hand, the use of a robotic system leads to longer operating time and higher costs. Randomized controlled trials comparing the robotic approach with the laparoscopic one are still missing. <b><i>Key Message:</i></b> Recent meta-analyses show promising results of the usage of robotic systems in advanced surgical procedures, like hepatic, pancreatic, and esophageal resections. Further randomized studies are needed to validate the postulated benefit.

Digital Technology in Visceral Medicine: An Overview in Outpatient Care in Germany

<b><i>Background:</i></b> Digital technology has become an integral part of healthcare and will revolutionize the practice of medicine. Although previously the administrative tasks were captured by digital technologies, now the communication channels with the patients are also being focused. For example, taking medical histories is now made possible by this new technology, information and explanatory forms can be sent digitally, and even face-to-face consultations are increasingly made possible by video consultations. Especially in the COVID pandemic, this form of contactless encounter has become a valuable enrichment of medical care. But also telemedical tasks such as teleconsultation or artificial intelligence in the context of adenoma detection are techniques that are conquering outpatient and inpatient visceral medical care. <b><i>Summary:</i></b> This article gives an overview of digital communication and possible uses of digital technologies in medical practices in Germany. <b><i>Key Message:</i></b> Medicine is renewing itself through digital techniques. The pace of change is rapid and unstoppable. Today’s medical progress is no longer conceivable without these techniques.

Resection of Recurrent Pancreatic Cancer: Who Can Benefit?

<b><i>Background:</i></b> Recurrence after resection of pancreatic cancer occurs in up to 80% of patients in the first 2 years after complete resection. While most patients are not eligible for surgical treatment due to disseminated disease, a certain group of patients can be evaluated for re-resection of local recurrence. This review summarizes the current literature on surgical treatment of recurrent pancreatic cancer and potential prognostic factors. <b><i>Summary:</i></b> Re-resection of recurrent pancreatic cancer provides a significant survival benefit to selected patients with acceptable procedure-related mortality. Median overall survival after re-resection of recurrent pancreatic cancer is up to 28 months. The most relevant clinical parameters associated with a prognostic benefit are young patient age (&#x3c;65 years), time to initial resection (&#x3e;10 months), and preoperative chemotherapy before re-resection. Molecular markers are currently under investigation and might help to improve patient selection in the future. <b><i>Key Message:</i></b> Re-resection of recurrent pancreatic cancer is safe and feasible in experienced hands. Selected patients benefit from surgical treatment, but future studies are needed to identify reliable prognostic markers predicting survival.

Machine Perfusion in Liver Transplantation: A Systematic Review and Meta-Analysis

<b><i>Background:</i></b> Liver transplantation (LTx) is the only treatment option for patients with end-stage liver disease. Novel organ preservation techniques such as hypothermic machine perfusion (HMP) or normothermic machine perfusion (NMP) are under investigation in order to improve organ quality from extended criteria donors and donors after circulatory death. The aim of this study was to systematically review the literature reporting LTx outcomes using NMP or HMP compared to static cold storage (SCS). <b><i>Methods:</i></b> The following data were retrieved: graft primary nonfunction rate, early allograft dysfunction (EAD) rate, biliary complication rate, and 12-month graft and patient survival. A total of 15 studies were included (6 NMP and 9 HMP studies), and meta-analysis was performed only for HMP studies because NMP had considerable differences. <b><i>Results:</i></b> The systematic review showed the potential of NMP to reduce graft injury and lower the liver graft discard rate. The performed quantitative analyses showed that the use of HMP reduces the rate of EAD (odds ratio [OR] 0.51; 95% confidence interval [CI] 0.34–0.76; <i>p</i> = 0.001; <i>I</i>² = 0%) and non-anastomotic biliary strictures (OR 0.34; 95% CI 0.17–0.67; <i>p</i> = 0.002; <i>I</i>² = 0%) compared to SCS. <b><i>Conclusion:</i></b> Our systematic review and meta-analysis revealed that the use of HMP reduces the rate of EAD and non-anastomotic biliary strictures compared to SCS.

Marked Increase of Gamma-Glutamyltransferase as an Indicator of Drug-Induced Liver Injury in Patients without Conventional Diagnostic Criteria of Acute Liver Injury

<b><i>Introduction:</i></b> Clinically significant drug-induced liver injury (DILI) is defined by elevations of alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN), alkaline phosphatase (ALP) ≥2 × ULN, or ALT ≥3 × ULN and total bilirubin TBIL &#x3e;2 × ULN. However, DILI might also occur in patients who do not reach those thresholds and still may benefit from discontinuation of medication. <b><i>Methods:</i></b> Fifteen patients recruited for our prospective study on potentially hepatotoxic drugs were included. DILI diagnosis was based on RUCAM (Roussel Uclaf Causality Assessment Method) score and expert opinion and was supported by an in vitro test using monocyte-derived hepatocyte-like (MH) cells. <b><i>Results:</i></b> Median RUCAM score was 6 (range 4–8), indicating that DILI was possible or probable in all cases. The predominant types of liver injury were mixed (60%) and cholestatic (40%). While no elevation above 2 × ULN of ALP and TBIL was observed, gamma-glutamyltransferase (GGT) above 2 × ULN was identified in 8 of the patients. Six of the 15 patients did not achieve full remission and showed persistent elevation of GGT, which was significantly associated with peak GGT elevation above 2 × ULN (<i>p</i> = 0.005). <b><i>Conclusion:</i></b> Here we present a case series of patients with liver enzyme elevation below the conventional thresholds who developed DILI with a predominant GGT elevation leading to drug withdrawal and/or chronic elevation of liver parameters, in particular of GGT. Thus, we propose that DILI should be considered in particular in cases with marked increase of GGT even if conventional DILI threshold levels are not reached, resulting in discontinuation of the causative drug and/or close monitoring of the patients.