HDAC-Linked “Proliferative” miRNA Expression Pattern in Pancreatic Neuroendocrine Tumors

Epigenetic factors are essentially involved in carcinogenesis, tumor promotion, and chemoresistance. Two epigenetic key players are miRNAs and histone deacetylases (HDACs). As previously shown by own theoretical databank analysis, the crosstalk between miRNAs and HDACs is relevant in different human chronic diseases and cancerogenic pathways. We aimed to investigate a potential connection between the expression of a well-defined subset of “proliferation-associated” miRNAs and the expression of HDACs as well as clinical parameters in pancreatic neuroendocrine tumors (pNETs). Materials and Methods: Expression levels of miRNA132-3p, miRNA145-5p, miRNA183-5p, miRNA34a-5p, and miRNA449a in 57 pNETs resected between 1997 and 2015 were measured and linked to the immunohistochemical expression pattern of members of the four HDAC classes on human tissue microarrays. All pNET cases were clinically and pathologically characterized according to published guidelines. Correlation analysis revealed a significant association between expression of specific miRNAs and two members of the HDAC family (HDAC3 and HDAC4). Additionally, a linkage between miRNA expression and clinico-pathological parameters like grading, TNM-staging, and hormone activity was found. Moreover, overall and disease-free survival is statistically correlated with the expression of the investigated miRNAs. Overall, we demonstrated that specific miRNAs could be linked to HDAC expression in pNETs. Especially miRNA449a (associated with HDAC3/4) seems to play an important role in pNET proliferation and could be a potential prognostic factor for poor survival. These first data could help, to improve our knowledge of the complex interactions of the epigenetic drivers in pNETs for further therapeutic approaches

Progressive Oncological Surgery Is Associated with Increased Curative Resection Rates and Improved Survival in Metastatic Colorectal Cancer

Background: Secondary resection rates in first-line chemotherapy trials for metastatic colorectal cancer (mCRC) remain below 15%, representing a clear contrast to reports by specialised surgical centres, where progressive liver, peritoneal-surface, and pulmonary surgery increased access to curative-intent treatment. We present a long-term evaluation of oncosurgical management in a single-centre, analysing the aggregate effect of gradual implementation of surgical subspecialties and systemic treatments on mCRC patients’ resection rates and prognosis. Methods: Patients with newly diagnosed mCRC from 2003 to 2014 were retrospectively categorised into palliative treatment (PAT) and curative intent surgery (CIS) and three time periods were analysed for treatment changes and factors associated with survival. Results: Four hundred-twenty patients were treated (PAT:250/CIS:170). Over time periods, the number of presenting patients remained consistent, whereas curative resection rates increased from 29% to 55%, facilitated by an increment of patients undergoing hepatectomy (21 to 35%), pulmonary surgery (6 to 17%), and peritonectomy/intraoperative chemotherapy (0 to 8%). Also, recently, significantly more multi-line systemic treatments were applied. The median survival markedly improved from 21.9 months (2003⁻2006; 95% confidence interval (CI) 17.3⁻26.5) to 36.5 months (2011⁻2014; 95% CI 26.6⁻46.4; p = 0.018). PAT was a significant factor of poor survival and diagnosis of mCRC in the latest time period was independently associated with a distinctly lower risk for palliative treatment (odds ratio 0.15). Conclusions: In modern eras of medical oncology, achieving appropriate resection rates through utilization of state-of-the-art oncological surgery by dedicated experts represents a cornerstone for long-term survival in mCRC

Pharmacological Inhibition of Class IIA HDACs by LMK-235 in Pancreatic Neuroendocrine Tumor Cells

Histone deacetylases (HDACs) play a key role in epigenetic mechanisms in health and disease and their dysfunction is implied in several cancer entities. Analysis of expression patterns in pancreatic neuroendocrine tumors (pNETs) indicated HDAC5 to be a potential target for future therapies. As a first step towards a possible treatment, the aim of this study was to evaluate the in vitro cellular and molecular effects of HDAC5 inhibition in pNET cells. Two pNET cell lines, BON-1 and QGP-1, were incubated with different concentrations of the selective class IIA HDAC inhibitor, LMK-235. Effects on cell viability were determined using the resazurin-assay, the caspase-assay, and Annexin-V staining. Western Blot and immunofluorescence microscopy were performed to assess the effects on HDAC5 functionality. LMK-235 lowered overall cell viability by inducing apoptosis in a dose- and time-dependent manner. Furthermore, acetylation of histone-H3 increased with higher LMK-235 concentrations, indicating functional inhibition of HDAC4/5. Immunocytochemical analysis showed that proliferative activity (phosphohistone H3 and Ki-67) decreased at highest concentrations of LMK-235 while chromogranin and somatostatin receptor 2 (SSTR2) expression increased in a dose-dependent manner. HDAC5 expression was found to be largely unaffected by LMK-235. These findings indicate LMK-235 to be a potential therapeutic approach for the development of an effective and selective pNET treatment

How We Treat Localized Rectal Cancer—An Institutional Paradigm for Total Neoadjuvant Therapy

Total neoadjuvant therapy (TNT)—the neoadjuvant employment of radiotherapy (RT) or chemoradiation (CRT) as well as chemotherapy (CHT) before surgery—may lead to increased pathological complete response (pCR) rates as well as a reduction in the risk of distant metastases in locally advanced rectal cancer. Furthermore, increased response rates may allow organ-sparing strategies in a growing number of patients with low rectal cancer and upfront immunotherapy has shown very promising early results in patients with microsatellite instability (MSI)-high/mismatch-repair-deficient (dMMR) tumors. Despite the lack of a generally accepted treatment standard, we strongly believe that existing data is sufficient to adopt the concept of TNT and immunotherapy in clinical practice. The treatment algorithm presented in the following is based on our interpretation of the current data and should serve as a practical guide for treating physicians—without any claim to general validity

Short- and Long-Term Outcome of Laparoscopic- versus Robotic-Assisted Right Colectomy: A Systematic Review and Meta-Analysis

Background: There is a rapidly growing literature available on right hemicolectomy comparing the short- and long-term outcomes of robotic right colectomy (RRC) to that of laparoscopic right colectomy (LRC). The aim of this meta-analysis is to revise current comparative literature systematically. Methods: A systematic review of comparative studies published between 2000 to 2021 in PubMed, Scopus and Embase was performed. The primary endpoint was postoperative morbidity, mortality and long-term oncological results. Secondary endpoints consist of blood loss, conversion rates, complications, time to first flatus, hospital stay and incisional hernia rate. Results: 25 of 322 studies were considered for data extraction. A total of 16,099 individual patients who underwent RRC (n = 1842) or LRC (n = 14,257) between 2002 and 2020 were identified. Operative time was significantly shorter in the LRC group (LRC 165.31 min ± 43.08 vs. RRC 207.38 min ± 189.13, MD: −42.01 (95% CI: −51.06−32.96), p 0.001). Blood loss was significantly lower in the RRC group (LRC 63.57 ± 35.21 vs. RRC 53.62 ± 34.02, MD: 10.03 (95% CI: 1.61–18.45), p = 0.02) as well as conversion rate (LRC 1155/11,629 vs. RRC 94/1534, OR: 1.65 (1.28–2.13), p p = 0.003). Oncological long-term results did not differ between both groups. Conclusion: The advantages of robotic colorectal procedures were clearly demonstrated. RRC can be regarded as safe and feasible. Most of the included studies were retrospective with a limited level of evidence. Further randomized trials would be suitable

Is Robotic Assisted Colorectal Cancer Surgery Equivalent Compared to Laparoscopic Procedures during the Introduction of a Robotic Program? A Propensity-Score Matched Analysis

Background: Robotic surgery represents a novel approach for the treatment of colorectal cancers and has been established as an important and effective method over the last years. The aim of this work was to evaluate the effect of a robotic program on oncological findings compared to conventional laparoscopic surgery within the first three years after the introduction. Methods: All colorectal cancer patients from two centers that either received robotic-assisted or conventional laparoscopic surgery were included in a comparative study. A propensity-score-matched analysis was used to reduce confounding differences. Results: A laparoscopic resection (LR Group) was performed in 82 cases, and 93 patients were treated robotic-assisted surgery (RR Group). Patients’ characteristics did not differ between groups. In right-sided resections, an intracorporeal anastomosis was significantly more often performed in the RR Group (LR Group: 5 (26.31%) vs. RR Group: 10 (76.92%), p = 0.008). Operative time was shown to be significantly shorter in the LR Group (LR Group: 200 min (150–243) vs. 204 min (174–278), p = 0.045). Conversions to open surgery did occur more often in the LR Group (LR Group: 16 (19.51%) vs. RR Group: 5 (5.38%), p = 0.004). Postoperative morbidity, the number of harvested lymph nodes, quality of resection and postoperative tumor stage did not differ between groups. Conclusion: In this study, we could clearly demonstrate robotic-assisted colorectal cancer surgery as effective, feasible and safe regarding postoperative morbidity and oncological findings compared to conventional laparoscopy during the introduction of a robotic system

Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis Model

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) was considered a promising treatment for patients with peritoneal metastasis from colorectal cancer. However, the recently published randomized controlled PRODIGE 7 trial failed to demonstrate survival benefits through the addition of short-term oxaliplatin-based HIPEC. Constituting a complex multifactorial treatment, we investigated HIPEC in a preclinical model concerning the elimination of minimal tumor residues, thereby aiming to better understand the size of effects and respective clinical trial results. Patient samples of peritoneal perfusates obtained during HIPEC treatments and oxaliplatin-containing solutions at clinically relevant dosages, conforming with established HIPEC protocols, were assessed regarding their ability to eliminate modelled ~100 µm thickness cancer cell layers. Impedance-based real-time cell analysis and classical end-point assays were used. Flow cytometry was employed to determine the effect of different HIPEC drug solvents on tumor cell properties. Effectiveness of peritoneal perfusate patient samples and defined oxaliplatin-containing solutions proved limited but reproducible. HIPEC simulations for 30 min reduced the normalized cell index below 50% with peritoneal perfusates from merely 3 out of 9 patients within 72 h, indicating full-thickness cytotoxic effects. Instead, prolonging HIPEC to 1 h enhanced these effects and comprised 7 patients’ samples, while continuous drug exposure invariably resulted in complete cell death. Further, frequently used drug diluents caused approximately 25% cell size reduction within 30 min. Prolonging oxaliplatin exposure improved effectiveness of HIPEC to eliminate micrometastases in our preclinical model. Accordingly, insufficient penetration depth, short exposure time, and the physicochemical impact of drug solvents may constitute critical factors

Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis Model

SIMPLE SUMMARY: Absence of survival benefits when adding hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin to cytoreductive surgery in peritoneal metastasis from colorectal cancer has recently been shown in the randomized controlled PRODIGE 7 trial. We therefore aimed to investigate the effects of this treatment modality in a preclinical micrometastasis model. Cancer cells were incubated with either patient samples obtained during HIPEC procedures or with defined oxaliplatin-containing solutions prepared according to clinically established HIPEC protocols. Our results demonstrate a limited effectiveness of short-term HIPEC in simulations with oxaliplatin to eliminate micrometastases, although we used platinum-sensitive cell lines for our model. Since these results are in line with findings from current research, our studies might offer further convincing evidence and potential explanations for HIPEC futility observed in clinical application. ABSTRACT: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) was considered a promising treatment for patients with peritoneal metastasis from colorectal cancer. However, the recently published randomized controlled PRODIGE 7 trial failed to demonstrate survival benefits through the addition of short-term oxaliplatin-based HIPEC. Constituting a complex multifactorial treatment, we investigated HIPEC in a preclinical model concerning the elimination of minimal tumor residues, thereby aiming to better understand the size of effects and respective clinical trial results. Patient samples of peritoneal perfusates obtained during HIPEC treatments and oxaliplatin-containing solutions at clinically relevant dosages, conforming with established HIPEC protocols, were assessed regarding their ability to eliminate modelled ~100 µm thickness cancer cell layers. Impedance-based real-time cell analysis and classical end-point assays were used. Flow cytometry was employed to determine the effect of different HIPEC drug solvents on tumor cell properties. Effectiveness of peritoneal perfusate patient samples and defined oxaliplatin-containing solutions proved limited but reproducible. HIPEC simulations for 30 min reduced the normalized cell index below 50% with peritoneal perfusates from merely 3 out of 9 patients within 72 h, indicating full-thickness cytotoxic effects. Instead, prolonging HIPEC to 1 h enhanced these effects and comprised 7 patients’ samples, while continuous drug exposure invariably resulted in complete cell death. Further, frequently used drug diluents caused approximately 25% cell size reduction within 30 min. Prolonging oxaliplatin exposure improved effectiveness of HIPEC to eliminate micrometastases in our preclinical model. Accordingly, insufficient penetration depth, short exposure time, and the physicochemical impact of drug solvents may constitute critical factors