Protective measures for patients with advanced cancer during the Sars-CoV-2 pandemic: Quo vadis?

Cancer patients represent a vulnerable cohort during the Sars-CoV-2 pandemic. Oncological societies have generated a plethora of recommendations, but precise instructions about routine oncological procedures remain scarce. Here, we report on local COVID-19 protection measures established in an interdisciplinary approach at a tertiary care center during the first wave of the pandemia in Germany. Following these measures, no additional morbidity or mortality during oncological procedures was observed, and no nosocomial infections were registered. However, Validation of our measures is outstanding and regional SARS-CoV-2 prevalence was low. However, specific oncological measures might be important to ensure optimal oncological results, especially for advanced cancer stages during this and future pandemia. In the future, communication about these measures might be crucial to a cancer patient´s assigned network to reduce the danger of excess mortality within the second wave of the COVID-19 pandemic.

Complex role of miR-130a-3p and miR-148a-3p balance on drug resistance and tumor biology in esophageal squamous cell carcinoma.

miRNAs play a crucial role in cancer development and progression. However, results on the impact of miRNAs on drug sensitivity and tumor biology vary, and most studies to date focussed on either increasing or decreasing miRNA expression levels. Therefore, the current study investigated the role of different expression levels of miR-130a-3p and miR-148a-3p on drug resistance and tumor biology in four esophageal squamous cell carcinoma cell lines. Interestingly, up- and downregulation of both miRNAs significantly increased sensitivity towards chemotherapy. MiRNA modulation also reduced adherence and migration potential, and increased apoptosis rates. Target analyses showed that up- and downregulation of both miRNAs activated the apoptotic p53-pathway via increased expression of either BAX (miR-148a-3p) or Caspase 9 (miR-130a-3p). miR-148a-3p downregulation seemed to mediate its effects primarily via regulation of Bim rather than Bcl-2 levels, whereas we found the opposite scenario following miR-148a-3p upregulation. A similar effect was observed for miR-130a-3p regulating Bcl-2 and XIAP. Our data provide the first evidence that miRNA modulation in both directions may lead to similar effects on chemotherapy response and tumor biology in esophageal squamous cell carcinoma. Most interestingly, up- and downregulation seem to mediate their effects via modulating the balance of several validated or predicted targets.

Role of miRNAs in cell signaling of cancer associated fibroblasts.

The tumor microenvironment (TME) of cancer cells is regarded as a strong determinant for cancer development and acquisition of metastatic potential of cancer cells. Because of its influence on tumorigenesis, the TME increasingly gained attention in research within the last years. Activated fibroblasts, so-called cancer-associated fibroblasts (CAFs), which are the most prominent cell type in the stromal compartment, are responsible for the synthesis, deposition and remodeling of the extracellular matrix in tumor stroma thus creating a favorable microenvironment for cancer cells. Besides, they secrete paracrine factors, such as growth factors, chemokines and exosomes impacting on proliferation, invasion and cell signaling of cancer cells. Molecular mechanisms responsible for activation of fibroblasts and regulation of metastatic microenvironment are complex and not yet fully elucidated. However, mounting evidence suggests that miRNAs play a powerful role in the communication between cancer cells and TME. Via regulation of various signaling pathways, release of cytokines/growth factors or exosomes, miRNAs are able to regulate tumor promoting effects of CAFs. In this review, we describe baseline differences in miRNAs signatures between CAFs and normal fibroblasts and highlight the influence of miRNAs on cell signaling within CAFs.

MiR-23a/-24-induced gene silencing results in mesothelial cell integration of pancreatic cancer.

BACKGROUND: Invasion of the surrounding tissue is part of the metastatic cascade. Here, we examined the invasion of pancreatic ductal adenocarcinoma (PDAC) cells into the mesothelial barrier and identified the related microRNA (miRNA) expression profiles. METHODS: The interactions between PDAC cells and mesothelial monolayers were characterised and quantified using a specific time-lapse videomicroscopy assay. Pancreatic ductal adenocarcinoma cells were further evaluated using the adhesion assay, and miRNA, mRNA and protein expressions were determined using microarray, q-RT-PCR and western blots, respectively. These data were correlated with in vivo dissemination scores. RESULTS: Two groups of PDAC cell lines were distinguished by their integration capacity into the mesothelial monolayer using mean elongation factors (MEFs). Adhesion assays showed a concordant relation between adhesive properties and integration capacity. The distant metastases scores were reverse correlated with MEFs. Microarray analysis of these groups revealed that miR-23a and/or miR-24 target for FZD5, HNF1B and/or TMEM92, respectively, and that they are significantly deregulated. CONCLUSIONS: MiR-23a and/or miR-24 overexpression leads to gene silencing of FZD5, TMEM92 and/or HNF1B. Their downregulation induces deregulated expression and degradation of E-cadherin and ß-catenin causing destabilisation of the cadherin/catenin complex, and altered the expression of Wnt-related genes. We propose a molecular (epi)genetic mechanism by which increased EMT-like cell shape transformation and integration into mesothelial monolayers of PDAC cells can be observed.

[Current legal framework conditions for running and utilization of biobanks: Part 3: ownership and rights of use]. / Gegenwärtige rechtliche Rahmenbedingungen für den Betrieb und die Nutzung von Biobanken: Teil 3: Eigentum und Nutzungsrechte.

The organizing institution of a biobank can be of public or private law in nature and the form can be freely selected. Biomaterials must be legally valued as objects whereby inalienable personality rights are still valid even if ownership is transferred. The treating physician does not automatically acquire a comprehensive right of ownership or utilization for the materials taken during the treatment. The biobank acquires tangible property and user rights on the samples by a legal agreement between the donor and the biobank. Reutilization clauses in submission contracts should not be used due to the danger of a formularization development and surprise clauses. During the processing of biomaterials within the biobank substantially new characteristics can appear which have an effect on ownership and commercialization rights. The donor does not have a utilization right in the sense of a patent or copyright. If there are changes in the legal form and the use by third parties, the declaration of consent by the donor remains fully effective. There are special risks for the donor if the biobank transfers these biomaterials. This must be clarified before finalizing the agreement on sample transference and utilization in the sense of an informed decision.

[Patients' Rights Act - Relevance for surgical disciplines]. / Das Patientenrechtegesetz.

The new Patients' Rights Act does not reflect rights of patients as professional obligations of physicians for the first time. It adopted common longtime jurisdiction, but in some respects it is going beyond. This law clearly extends the documentation requirements of physicians, especially concerning the extent of documentation. In surgical fields the requirements for enlightening physicians were more strongly worded than in previous jurisdiction. In medical facilities it is now mandatory to establish an internal quality management system.

Immunohistochemical analysis on potential new molecular targets for esophageal cancer.

Despite multimodal therapeutic options, esophageal cancer is still among the most deadly malignancies. In the past decade, targeted therapy has shown great potential in other cancers, but data on esophageal carcinoma are still rare. Five potential new molecular targets in esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) were investigated for their expression characteristics: vascular endothelial growth factor receptor (VEGFR)-3, human epidermal growth factor receptor-2, stem cell growth factor receptor, tissue inhibitors of metalloproteinase (TIMP)-4 and TIMP-3. One hundred seventy-one EAC and ESCC tissue samples obtained from patients undergoing esophagectomy from 2000 to 2008 were included. Clinical data were evaluated retrospectively. Immunohistochemical staining was performed using tumor tissue with and without neoadjuvant treatment and healthy tissue. For samples without neoadjuvant treatment, expression of all targets was higher in tumor tissue than in healthy tissue except for VEGFR-3 (>98% expression in both tissues). For TIMP-4, TIMP-3 and stem cell growth factor receptor, trends to higher expression in tumor tissue were also found in EAC and ESCC that had received neoadjuvant treatment. Using Matched-pair analysis, we compared target expression in tumor tissue with and without neoadjuvant treatment. Only TIMP-3 had significantly lower expression in neoadjuvant treated tumor tissue (EAC: P = 0.059, ESCC: P = 0.006). TIMP-4, TIMP-3 and VEGFR-3 appear to qualify for targeted therapy in esophageal cancer because of their high expression in neoplastic tissue. TIMP-3 appears to be downregulated in neoadjuvantly treated esophageal cancer, and VEGFR-3 shows high expression in healthy mucosa leading to severe side effects by molecular targeting. Thus, TIMP-4 seems the most promising target.

[Current legal framework conditions for running and utilization of biobanks. Part 2: data protection and informed consent]. / Gegenwärtige rechtliche Rahmenbedingungen für den Betrieb und die Nutzung von Biobanken. Teil 2: Datenschutz und informierte Einwilligung.

Informed consent of donors of biomaterials represents an essential pillar of legal conformity of business organizations even for biobanks. For the assessment of self-determination of donors and freedom of research for users of biobanks there is a general consensus on the necessity for a social and individual agreement for the participation of donors in research projects. However, demands are often made for which the legal implementation is at least contentious and can be considered as excessive and biased. In part 2 of this review series the current legal foundation of data protection and informed consent is summarized on the basis of normative and ethical principles. With respect to appropriation of data and biosamples it can be deduced that by conformation to corresponding framework conditions the informed consent of donors in particular can be constructed independent of the project.

In vivo quantification of metastatic tumor cell adhesion in the pulmonary microvasculature.

In vivo and ex vivo fluorescence video microscopy used to be a well-established method in life science with a variety of applications, such as in inflammation or cancer research. In this book chapter, we describe a model of in vivo fluorescence microscopy of the rat's lung with the exclusive advantage of qualitative and quantitative in vivo analysis of cell adhesion within the complex microenvironment of the ventilated and perfused lung. Observation can include real-time, time-lapse, or fast-motion analysis. In our laboratory, we have used the model for qualitative and quantitative real-time analyses of metastatic colon cancer cell adhesion within the rat's pulmonary microcirculation. Using some modifications in another series, we have also applied the model to analyze thrombocyte and leucocyte adhesion within the pulmonary capillaries in experimental sepsis. For interventional studies, injected cells or animals may be pretreated with various reagents or drugs for further analysis of adhesion molecules involved in tumor cell-endothelial cell interactions.

[Current legal framework conditions for running and utilization of biobanks : part 1: legal principles]. / Gegenwärtige rechtliche Rahmenbedingungen für den Betrieb und die Nutzung von Biobanken : Teil 1: Rechtsgrundlagen.

Research biomaterial banks (biobanks) are institutions which collect and prepare samples of human bodily substances (e.g. cells, tissues, body fluids and isolates from them), store personal, health and problem-related data of donors, collate samples and data and make them available in a suitable form for research purposes. The valid legal norms for the utilization and running of biobanks are complex and sometimes necessitate an assessment by the legal guardian.

[Medicolegal aspects of tumor boards]. / Medizinrechtliche Aspekte von Tumorboards.

The presentation of tumor patients to tumor boards has widely developed into a medical standard. The necessary compliance to the medical standard can lead to obligatory presentation if the complexity of a case dictates that this cannot be comprehensively covered by a single treating physician. The organization of a tumor board must be so that the structure and specialist competence guarantees an adequate consultative function of the represented specialties. Tumor board members are not automatically promoted to become part of the treating team just by participation and therefore do not have a guarantor position but do have the obligation of care of a consulting physician. Tumor board decisions have a recommendation character, are not binding in the legal sense and do not relieve the treating physician from the obligation to critically scrutinize the recommendations before implementation. On the other hand the treating physician must be able to justify not following the recommendations on the basis of the medical obligation to care. The tumor board must fulfil the same requirements for documentation as any other consultative activity.

Laser secondary neutral mass spectrometry for copper detection in micro-scale biopsies.

Disease progression and clinical diagnostics of a number of hereditable metabolic diseases are determined by organ involvement in disturbed deposition of certain molecules. Current clinical imaging is unable to visualize this maldistribution with sufficient specificity and sensitivity, such as in Wilson's disease. The quest for understanding cellular Cu distribution in these patients requires element- and molecule-specific images with nanometer-scale spatial resolution. We have used a new cryo-mass spectrometric instrument with an integrated cryosectioning chamber for preparation and analysis of frozen hydrated samples of Wilson's disease tissue. With laser post-ionization secondary neutral mass spectrometry (laser-SNMS), we were able to image Cu and other intrinsic elements and molecules in less than 1 mg of frozen hydrated liver tissue from a murine model of Wilson's disease. A 40-50 times higher Cu concentration was measured in the disease tissue as compared to the control mouse. Furthermore, major histomorphological changes were observed using this advanced nano-science tool. The results showed that the combination of in-vacuum cryosectioning and cryo-laser-SNMS technologies is particularly well suited for identifying specific cell structures and imaging trace element concentrations with subcellular resolution and upper-parts-per-billion sensitivity in biological samples. This technology can provide a novel diagnostic tool for clinical applications in various diseases involving trace elements.

Expression of tight and adherens junction proteins in ulcerative colitis associated colorectal carcinoma: upregulation of claudin-1, claudin-3, claudin-4, and beta-catenin.

BACKGROUND: Tight junction (TJ) proteins play a critical role in cellular adhesion, glandular differentiation, and cellular proliferation. The function of these proteins is compromised in a number of intestinal diseases, including ulcerative colitis that has an increased incidence for colorectal carcinoma (CAC). The aim of this study was to determine the expression of TJ proteins, claudin-1-4, occludin, ZO-1, and the adherens junction (AJ) protein beta-catenin in CAC. METHODS: Sixteen colectomy specimens with CAC, adjoining intraepithelial neoplasia, and normal mucosa were studied by immunofluorescence. A semiquantitative evaluation of all investigated proteins was performed by scoring the staining intensity, and the TJ and AJ protein expression in neoplastic cells was compared to normal and intraepithelial neoplastic colonic mucosa. RESULTS: Using an intensity scoring system, mucosa of crypts and surfaces of CAC exhibited significantly elevated expression levels of claudin-1, claudin-3, claudin-4, and beta-catenin compared to intraepithelial neoplasia and normal mucosa (p<0.05). These data were confirmed by a comparative score. The expression of claudin-2, occludin, and ZO-1 showed no differences between the groups. CONCLUSION: TJ proteins claudin-1, claudin-3, claudin-4, and the AJ protein beta-catenin are overexpressed in CAC. This suggests that these proteins may become potential markers and targets in CAC.

[Are leukocytes and CRP early indicators for anastomotic leakage after esophageal resection?]. / Sind Leukozyten und C-reaktives Protein geeignete Parameter als Frühindikatoren der Anastomoseninsuffizienz nach Osophagusresektion?1.

BACKGROUND: Anastomotic leaks represent the most common severe postoperative complications after esophagectomy. In this study standard inflammatory laboratory parameters [leukocytes, C-reactive protein (CRP)] were evaluated as indicators for anastomotic leakage after esophagectomy. PATIENTS AND METHODS: Between 1 / 1997 and 12 / 2006 a total of 558 patients with esophageal cancer underwent an Ivor-Lewis esophagectomy. Among these patients, all those (n = 50, 8.9 %) suffering from an anastomotic leak were matched to 50 patients without anastomotic leakage. Leukocytes, CRP level and clinical parameters (body temperature, cardiac / respiratory problems, wound secretion) were retrospectively analysed at short-term intervals in both groups. RESULTS: Patients with anastomotic leaks showed significant continuously increased CRP levels and leukocyte counts from the second or, respectively, 5 (th) postoperative day onwards compared to patients without anastomotic leaks. Using a stepwise regression, an 80 % sensitivity for leakage detection has been calculated by a cut-off value for CRP set at 13.5 mg / dL from day 2 onwards or, respectively, for leukocytes at 10.5 Gpt / L from day 8 onwards. Concomitantly, patients with anastomotic leaks suffered significantly more from respiratory problems and abdominal pain. CONCLUSION: CRP appears to be a reliable and predictable indicator for anastomotic leakage after esophagectomy and should, therefore, be routinely used as a screening marker to provide a reason for extended diagnosis.

Viral reactivation is not related to septic complications after major surgical resections.

Anastomotic leakage and septic complications are the most important determinants of postoperative outcome after major surgical resections. Malignant diseases and surgical trauma can influence immune responses and the ability to react against infectious factors, such as bacteria and viruses. Comparable immune suppression can cause viral reactivation in transplantation and trauma patients. In this prospective study, patients who underwent major surgical resections for oesophageal or pancreatic cancer were investigated for the potential involvement of viral reactivation in the development of septic complications. 86 patients (40 oesophageal resections, 27 pancreatic resections, 19 surgical explorations) were included. Viral antigens, viral DNA, antibodies against viral structures (IgG, IgM, IgA) and, in part, viral cultivation were performed for CMV, EBV, HSV1, HSV2, HZV6 and VZV in serum, urine, sputum and swabs from buccal mucosa preoperatively and at postoperative days 1, 3 and 5. Test results were compared with the postoperative outcome (30-day morbidity, in-hospital mortality) and clinical scores (SOFA, TISS). For statistical analyses Student's t-tests and Chi2-tests were used. The overall complication rate was 19.8% (30-day morbidity) with an in-hospital mortality of 1.2% (1/86 patients). Postoperatively, anti-CMV-IgG titres were significantly reduced (p<0.05) and remained suppressed in patients with septic complications. Anti-CMV-gB-IgG were also reduced, but showed considerable interindividual differences. Anti-CMV-IgA and -IgM did not show significant alterations in the postoperative course. In addition, direct viral detection methods did not support viral reactivation in patients in any of the investigated groups. The reduction of anti-CMV antibodies is likely caused by an immune suppression, specifically by reduced B-cell counts after major surgical interventions. Viral reactivation, however, did not occur in the early postoperative period as a specific risk for septic complications.

Randomized clinical trial of the influence of intraperitoneal local anaesthesia on pain after laparoscopic surgery.

BACKGROUND: There is controversy about the effectiveness of intraperitoneal local anaesthesia (LA) in laparoscopic surgery. The aim of the present randomized clinical trial was to compare the analgesic effect of pre-emptive (preoperative) versus postoperative intraperitoneal LA in two different types of laparoscopic surgery. METHODS: Between July 2004 and January 2005, 133 consecutive patients scheduled to undergo laparoscopic fundoplication or hernia repair were randomly assigned to one of three treatments: placebo solution (50 ml 0.9 per cent saline) or LA (50 ml 0.5 per cent lidocaine) administered immediately after creation of the pneumoperitoneum, or LA (50 ml 0.5 per cent lidocaine) at the end of the operation. Analgesic requirements were analysed, and pain was assessed using a visual analogue scale (VAS) from 0 to 100 at 6, 12, 24 and 48 h after surgery. RESULTS: The duration of pneumoperitoneum (median 66 versus 46 min respectively; P < 0.001) and overall pain intensity (median VAS score 46.7 versus 6.5; P < 0.001) were higher for laparoscopic fundoplication than for hernia repair. Preoperative application of LA reduced abdominal pain (median 28.6 versus 74.9; P < 0.005), shoulder pain (median 24.3 versus 43.8; P = 0.004) and analgesic consumption (mean(s.d.) 11.1(5.0) versus 18.5(5.4) mg piritramide per 48 h; P = 0.002) after fundoplication, but had no analgesic effects after hernia repair. CONCLUSION: Pre-emptive application of LA reduced postoperative pain and analgesic requirements after laparoscopic fundoplication.

Expression of MAGE-A cancer/testis antigens in esophageal squamous cell carcinomas.

BACKGROUND: Although the diagnosis and therapy of esophageal cancer have improved over the past decade, the prognosis remains dismal. Since MAGE-A cancer/testis antigens (CTA) are potential targets for immunotherapy, this study was aimed at evaluating their expression in these patients and its prognostic value. MATERIALS AND METHODS: Using 57B monoclonal antibody, MAGE-A CTA expression was analyzed in paraffin-embedded tumor specimens of 98 patients with esophageal squamous cell carcinoma or adenocarcinomas who had undergone surgical resection. For all patients, a postoperative follow-up of at least 4 years was available. The expression was quantified using a scoring system considering intensity and homogeneity of the immunostaining. The prognostic relevance of MAGE-A expression was analyzed in univariate analyses as well as Cox proportional hazard regression analysis. RESULTS: 57B positivity could be detected in 38 tumors (38.8%). Positive staining was observed in five out of 32 adenocarcinomas (15.2%) and in 33 out of 66 (50%) squamous cell carcinomas. MAGE-A expression did not correlate with the TNM classification, grading or age of the patients. Both univariate (p=0.88) and multivariate analyses (p = 0.82) revealed that MAGE-A expression lacked prognostic significance in esophageal carcinomas. CONCLUSION: MAGE-A was expressed in half of the squamous cell carcinomas of the esophagus, but rarely in adenocarcinomas. Although its immunodetection was insufficient for prognostic evaluation, the high expression rate suggests MAGE-A as a potential target for immunotherapy in the first group with the ability for pretherapeutic testing.

Role of tumor cell adhesion and migration in organ-specific metastasis formation.

To form clinically evident metastases--the main cause of death in cancer patients--, tumor cells (TC) must complete a highly complex series of steps called the metastatic cascade, including local invasiveness, intravasation, circulation, adhesion and extravasation, survival, proliferation and angiogenesis. Since failure of any one of these steps results in metastatic failure, understanding the metastatic cascade may guide us to new therapeutic concepts. Here we review the role of specific TC adhesion and migration processes for organ-selective metastasis formation. TC adhesion in the microvasculature of host organs is a specific and highly regulated process mainly mediated by selectins for TC/endothelial cell binding and by integrins for TC/extracellular matrix interactions. Defined expression of the adhesion molecules and their corresponding ligands in the host organs and on the TC governs organ-selective non-random TC arrest. TC motility and subsequent chemotactically guided extravasation of adherent cells is the second rate-limiting step in organ-specific metastasis formation. Only if cells have completed adhesion and extravasation the growth of micrometastases and finally clinically evident metastases can occur.

[A multidisciplinary mModule for oncological documentation within a hospital information system]. / Ein interdisziplinäres Modul zur onkologischen Dokumentation in einem Klinikinformationssystem.

The follow-up documentation of oncological patients in Germany is inadequate in many cases: it is usually limited to a minimal dataset mandated by the epidemiological tumor registers; it is carried out in a paper-based fashion and rarely in a multi-disciplinary context. Parallel documentation efforts can result in redundant or erroneous data and excess work. The introduction of hospital information systems (HIS) allows the implementation of digital oncological documentation systems integrated in surrounding clinical workflows that can provide access to existing data sources as well as data entry and presentation across departmental boundaries. This concept enables the integration of tumor documentation, quality assurance and process optimization within HIS. Feasibility requirements include a high flexibility and adaptability of the underlying HIS to reach a seamless integration of oncological documentation forms within routine clinical workflows. This paper presents the conceptual design and implementation of a modular oncological documentation system at the Muenster University Hospital that is capable of integrating the documentation requirements of multiple departments within the hospital.

Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms.

Previously we and others found that a majority of chronic fatigue syndrome (CFS) patients showed evidence of systemic mycoplasmal infections, and their blood tested positive using a polymerase chain reaction assay for at least one of the four following Mycoplasma species: M. fermentans, M. hominis, M. pneumoniae or M. penetrans. Consistent with previous results, patients in the current study (n=200) showed a high prevalence (overall 52%) of mycoplasmal infections. Using forensic polymerase chain reaction we also examined whether these same patients showed evidence of infections with Chlamydia pneumoniae (overall 7.5% positive) and/or active human herpes virus-6 (HHV-6, overall 30.5% positive). Since the presence of one or more infections may predispose patients to other infections, we examined the prevalence of C. pneumoniae and HHV-6 active infections in mycoplasma-positive and -negative patients. Unexpectedly, we found that the incidence of C. pneumoniae or HHV-6 was similar in Mycoplasma-positive and -negative patients, and the converse was also found in active HHV-6-positive and -negative patients. Control subjects (n=100) had low rates of mycoplasmal (6%), active HHV-6 (9%) or chlamydial (1%) infections, and there were no co-infections in control subjects. Differences in bacterial and/or viral infections in CFS patients compared to control subjects were significant. Severity and incidence of patients' signs and symptoms were compared within the above groups. Although there was a tendency for patients with multiple infections to have more severe signs and symptoms (p<0.01), the only significant differences found were in the incidence and severity of certain signs and symptoms in patients with multiple co-infections of any type compared to the other groups (p<0.01). There was no correlation between the type of co-infection and severity of signs and symptoms. The results indicate that a large subset of CFS patients show evidence of bacterial and/or viral infection(s), and these infections may contribute to the severity of signs and symptoms found in these patients.