Inguinal Lymph Node Metastasis of a Primary Serous Papillary Carcinoma of the Peritoneum One Year after CRS and HIPEC

Background: Primary peritoneal serous papillary carcinoma is a rare malignant epithelial tumor which was first described in 1959. Peritoneal serous papillary carcinoma arises from the peritoneal epithelium and originates from a single or multicentric focus of the peritoneum involving the peritoneum of the abdomen and pelvis. The involvement of retroperitoneal lymph nodes occurs in 64% of the patients diagnosed with this malignancy. So far, there is no report about inguinal lymph node metastasis in this disease. Case Report: We present a rare case of a 63-year-old female patient who developed singular inguinal lymph node metastasis 1 year after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy due to peritoneal serous papillary carcinoma. The lymph node metastasis was found by computed tomography (CT) scan and was resected and histologically confirmed. The postoperative course was uneventful, and the patient was discharged on postoperative day 1. The last CT scan 24 months after initial cytoreduction and 12 months after lymph node resection showed no further tumor recurrence. Conclusion: This case report should raise the awareness of potentially unexpected presentation of extraperitoneal metastasis and highlights the importance of patient follow-up including clinical examination and CT scans of thorax/abdomen/pelvis following a systematic schedule

Robot-assisted pancreatic surgery—optimized operating procedures: set-up, port placement, surgical steps

Even in most complex surgical settings, recent advances in minimal-invasive technologies have made the application of robotic-assisted devices more viable. Due to ever increasing experience and expertise, many large international centers now offer robotic-assisted pancreatic surgery as a preferred alternative. In general however, pancreatic operations are still associated with high morbidity and mortality, while robotic-assisted techniques still require significant learning curves. As a prospective post-marketing trial, we have established optimized operating procedures at our clinic. This manuscript intends to publicize our standardized methodology, including pre-operative preparation, surgical set-up as well as the surgeons' step-by-step actions when using pancreatic-assisted robotic surgery. This manuscript is based on our institutional experience as a high-volume pancreas operating center. We introduce novel concepts that should standardize, facilitate and economize the surgical steps in all types of robotic-assisted pancreatic surgery. The "One Fits All" principle enables single port placement irrespective of the pancreatic procedure, while the "Reversed 6-to-6 Approach" offers an optimized manual for pancreatic surgeons using the robotic console. Novel and standardized surgical concepts could guide new centers to establish a robust, efficient and safe robotic-assisted pancreatic surgery program

Perineural Invasion in Pancreatic Ductal Adenocarcinoma (PDAC): A Saboteur of Curative Intended Therapies?

(1) Background: Perineural invasion (PNI) is a common characteristic of pancreatic ductal adenocarcinoma (PDAC) and is present in most resection margins. We hypothesized that curative pancreatic tumor resection with long-term survival could only be achieved in PNI-negative patients. (2) Material and Methods: A retrospective investigation of PDAC patients who underwent curative-intended surgery during the period 2008 to 2019 was performed at our institution. (3) Results: We identified 571 of 660 (86.5%) resected patients with well-annotated reports and complete datasets. Of those, 531 patients (93%) exhibited tumors with perineural invasion (Pn1), while 40 (7%) were negative for PNI (Pn0). The majority of patients in the Pn1 group presented advanced tumor stage and positive lymph node infiltration. Patients in the Pn0 group showed an improved disease-free and long-term survival compared to the Pn1 group (p < 0.001). Subgroup analysis of all R0-resected patients indicated improved long-term survival and disease-free survival of R0 Pn0 patients when compared to R0 Pn1 patients (p < 0.001). (4) Conclusion: Our study confirmed that Pn0 improves the long-term survival of PDAC-resected cancer patients. Furthermore, PNI significantly challenges the long-term survival of formally curative (R0) resected patients. We provide new insights into the dynamics of PNI in pancreatic cancer patients which are needed to define subgroups of patients for risk stratification and multimodal treatment strategies

possible consequences for clinical application

Peritonealkarzinose galt lange Zeit als palliative Situation. Die Entwicklung eines lokalen Behandlungskonzepts, zytoreduktive Chirurgie in Kombination mit hyperthermer intraperitonealer Chemotherapie (HIPEC), ermöglicht heutzutage eine kurative Therapie. Die häufig verwendeten Chemotherapeutika Mitomycin C (MMC) und Cisplatin (CDDP) führen über ihre alkylierende Wirkung zu Doppelstrangbrüchen. Die DNA-Defekte induzieren Reparaturmechanismen, an denen das COP9 Signalosom (CSN) beteiligt ist. Das CSN ist ein Proteinkomplex, bestehend aus 8 Untereinheiten. Es ist ein Regulator des Ubiquitin-Proteasom- Systems (UPS) und kontrolliert die Stabilität von Proteinen, die an der DNA- Reparatur beteiligt sind. Außerdem ist es bei der Zellzykluskontrolle involviert und bestimmt die Aktivität von Tumorsuppressorproteinen wie p53. Die koordinierte Expression des CSN wird durch miRNAs der let-7-Familie reguliert. miRNA let-7a-1 bindet an die mRNA der CSN-Untereinheiten und agiert als negativer Regulator der CSN-Expression. Um die Rolle des CSN bei der HIPEC zu entschlüsseln, wurden HT29-Kolontumorzellen entsprechend den Bedingungen der HIPEC für 1 h und 4 h mit unterschiedlichen Konzentrationen MMC und CDDP, erwärmt in Medium auf 42°C, behandelt. Mittels Western Blot wurde das CSN und die mit dem CSN-interagierenden Proteine analysiert, wobei sich ein Anstieg der CSN-Untereinheiten unter MMC-Inkubation als Hinweis auf DNA-Reparatur zeigte. Dieser Prozess konnte durch Transfektion der HT29-Zellen mit miRNA Mimics der let-7-Familie verhindert werden und eine verstärkte Expression des Zellzyklusregulators p27 und des Tumorsuppressorproteins p53 wurde beobachtet. Außerdem wurde die Apoptoserate nach HIPEC mittels Caspase-3-Elisa quantifiziert, wobei sich nach 4 h MMC-Inkubation ein signifikanter Anstieg der aktivierten Caspase-3 zeigte. Nach 1 h MMC-Behandlung wurde nur unter sehr hoher MMC-Konzentration ein Anstieg der aktivierten Caspase-3 nachgewiesen. Um die Apoptoserate zu steigern, wurde Curcumin, ein Hemmstoff CSN-assoziierter Kinasen mit anti-proliferativen und anti-karzinogenen Eigenschaften getestet. Durch die Kombination von Curcumin mit MMC konnte eine signifikante Verbesserung der Apoptoserate erzielt werden. Zusammenfassend lässt sich sagen, dass das CSN eine restriktive Rolle bei der HIPEC spielt, da es die Tumorzellen bei der DNA-Reparatur unterstützt und die Apoptose verzögert. Um die CSN-Aktivität zu blockieren und die Effizienz der HIPEC zu verbessern, kommen zwei Mechanismen in Betracht: Erstens die Anwendung von Curcumin bei der HIPEC. Curcumin blockiert CSN-assoziierte Kinasen und steigert den MMC- Effekt. Mit dem Einsatz von Curcumin könnte die MMC-Konzentration reduziert werden, mit der Konsequenz geringerer toxischer Nebenwirkungen für Patienten. Zweitens wäre die Zugabe von miRNA-let-7a-1 Mimic zur Chemoperfusionslösung denkbar. miRNA let-7a-1 Mimics verhindern die CNS-Expression und begünstigen pro-apoptotische Bedingungen. Weitere Studien sind notwendig, um die hier gewonnenen Erkenntnisse unter klinischen Bedingungen anzuwenden.Peritonealcarcinomatosis has long been considered as a palliative situation. Local treatment strategies have been developed combining cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) offering a curative therapy. The frequently used chemotherapeutic agent Mitomycin C (MMC) and Cisplatin (CDDP) generating double-strand breaks with their alkylating properties. The DNA damage induces repair mechanisms including the COP9 signalosome (CSN). The CSN is a protein complex composed of 8 subunits (CSN1-CSN8). It is a regulator of the ubiquitin proteasome system (UPS) and controls protein stability of DNA damage repair effectors. Furthermore it is involved in cell cycle regulation and determines the activity of tumor suppressor proteins such as p53. The coordinated expression of CSN subunits is modulated by miRNAs of the let-7 family. miRNA let-7a-1 binds to the mRNA of CSN subunits and acts as a negative regulator of their expression. To investigate the role of the CSN during HIPEC, colon cancer HT29 cells were incubated under HIPEC-conditions for 1 h or 4 h with different concentrations of MMC and CDDP in medium heated to 42oC. By Western blotting the CSN and its interacting proteins were analysed. Increased CSN subunit expression has been detected, possibly as an indication for DNA-damage repair. Transfection of the HT29-cells with miRNA let-7a-1 mimic prevents this process and an overexpression of cellcycle regulator p27 and of tumor suppressor protein p53 has been monitored. Moreover apoptosis after HIPEC has been detected with Caspase-3-ELISA. Significant increase of activated Caspase-3 was measured after 4 h MMC-incubation. After 1 h MMC-treatment increase of activated Caspase-3 has been detected only under high MMC-concentration. To improve apoptosis Curcumin, an inhibitor of CSN-assoiated kinases with anti- proliferative and anti-carcinogenic qualities has been tested. The combination of Curcumin with MMC achieved a significant improvement of apoptosis. In summary the CSN plays a restrictive role during HIPEC because it supports the tumor cells during DNA-repair and delayed apoptosis. For blocking CSN- activities and improving the efficiency of HIPEC two mechanisms are possible: First, the application of Curcumin during HIPEC. Curcumin blocks CSN- assiociated kinases and enhances the MMC-effect. With Curcumin the MMC- concentration could be reduced with the consequence of less toxic side effects for the patients. Secondly, addition of miRNA mimic to the chemoperfusion media would be a plausible strategy. miRNA let-7a-1 mimic impairs the CSN- expression and promotes pro-apoptotic conditions. Further studies are necessary to apply these findings under clinical conditions

Oncolytic Immunotherapy: Conceptual Evolution, Current Strategies, and Future Perspectives

The concept of oncolytic virus (OV)-mediated cancer therapy has been shifted from an operational virotherapy paradigm to an immunotherapy. OVs often induce immunogenic cell death (ICD) of cancer cells, and they may interact directly with immune cells as well to prime antitumor immunity. We and others have developed a number of strategies to further stimulate antitumor immunity and to productively modulate the tumor microenvironment (TME) for potent and sustained antitumor immune cell activity. First, OVs have been engineered or combined with other ICD inducers to promote more effective T cell cross-priming, and in many cases, the breaking of functional immune tolerance. Second, OVs may be armed to express Th1-stimulatory cytokines/chemokines or costimulators to recruit and sustain the potent antitumor immunity into the TME to focus their therapeutic activity within the sites of disease. Third, combinations of OV with immunomodulatory drugs or antibodies that recondition the TME have proven to be highly promising in early studies. Fourth, combinations of OVs with other immunotherapeutic regimens (such as prime-boost cancer vaccines, CAR T cells; armed with bispecific T-cell engagers) have also yielded promising preliminary findings. Finally, OVs have been combined with immune checkpoint blockade, with robust antitumor efficacy being observed in pilot evaluations. Despite some expected hurdles for the rapid translation of OV-based state-of-the-art protocols, we believe that a cohort of these novel approaches will join the repertoire of standard cancer treatment options in the near future

Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics

Abstract Cancer vaccines and oncolytic immunotherapy are promising treatment strategies with potential to provide greater clinical benefit to patients with advanced-stage cancer. In particular, recombinant vaccinia viruses (VV) hold great promise as interventional agents. In this article, we first summarize the current understanding of virus biology and viral genes involved in host-virus interactions to further improve the utility of these agents in therapeutic applications. We then discuss recent findings from basic and clinical studies using VV as cancer vaccines and oncolytic immunotherapies. Despite encouraging results gleaned from translational studies in animal models, clinical trials implementing VV vectors alone as cancer vaccines have yielded largely disappointing results. However, the combination of VV vaccines with alternate forms of standard therapies has resulted in superior clinical efficacy. For instance, combination regimens using TG4010 (MVA-MUC1-IL2) with first-line chemotherapy in advanced-stage non-small cell lung cancer or combining PANVAC with docetaxel in the setting of metastatic breast cancer have clearly provided enhanced clinical benefits to patients. Another novel cancer vaccine approach is to stimulate anti-tumor immunity via STING activation in Batf3-dependent dendritic cells (DC) through the use of replication-attenuated VV vectors. Oncolytic VVs have now been engineered for improved safety and superior therapeutic efficacy by arming them with immune-stimulatory genes or pro-apoptotic molecules to facilitate tumor immunogenic cell death, leading to enhanced DC-mediated cross-priming of T cells recognizing tumor antigens, including neoantigens. Encouraging translational and early phase clinical results with Pexa-Vec have matured into an ongoing global phase III trial for patients with hepatocellular carcinoma. Combinatorial approaches, most notably those using immune checkpoint blockade, have produced exciting pre-clinical results and warrant the development of innovative clinical studies. Finally, we discuss major hurdles that remain in the field and offer some perspectives regarding the development of next generation VV vectors for use as cancer therapeutics