Inter-patient heterogeneity in the hepatic ischemia-reperfusion injury transcriptome: Implications for research and diagnostics.

Cellular responses induced by surgical procedure or ischemia-reperfusion injury (IRI) may severely alter transcriptome profiles and complicate molecular diagnostics. To investigate this effect, we characterized such pre-analytical effects in 143 non-malignant liver samples obtained from 30 patients at different time points of ischemia during surgery from two individual cohorts treated either with the Pringle manoeuvre or total vascular exclusion. Transcriptomics profiles were analyzed by Affymetrix microarrays and expression of selected mRNAs was validated by RT-PCR. We found 179 mutually deregulated genes which point to elevated cytokine signaling with NFκB as a dominant pathway in ischemia responses. In contrast to ischemia, reperfusion induced pro-apoptotic and pro-inflammatory cascades involving TNF, NFκB and MAPK pathways. FOS and JUN were down-regulated in steatosis compared to their up-regulation in normal livers. Surprisingly, molecular signatures of underlying primary and secondary cancers were present in non-tumor tissue. The reported inter-patient variability might reflect differences in individual stress responses and impact of underlying disease conditions. Furthermore, we provide a set of 230 pre-analytically highly robust genes identified from histologically normal livers (<2% covariation across both cohorts) that might serve as reference genes and could be particularly suited for future diagnostic applications.

Gallstone as a cause of intestinal obstruction (Bouveret syndrome).

Gallstone ileus is a rare cause of bowel obstruction. Here we report about two cases with clinical findings and therapy options. Both patients were presented with typical ileus-like symptoms, although the surgical treatment differs due to the CT scan and intraoperative findings. There are many methods for treating patients with Bouveret syndrome. Endoscopy should be the first treatment option for young patients with no significant diseases in the medical history, depending on the size of the stone. Surgical approach is the next possible option. Combination of these two methods is associated with higher mortality. In case there is no extraluminal gas or intraperitoneal fluid in CT-scan, there is no need for an acute surgery. Conservative therapy prior to the intervention enables a precise planning of whether the endoscopic approach or open surgery would be beneficial for the patient.

Life threatening rupture of the diaphragm after Covid 19 pneumonia: a case report.

BACKGROUND: The incidence of diaphragmatic rupture is low; however, it may be life threatening. Normally caused by blunt trauma, some cases are reported after pulmonary infections with extensive coughing. Covid 19 causes pulmonary infections and pneumonia and has been associated with weakening of the diaphragm after prolonged ventilation. We present a patient who suffered from diaphragmatic rupture 2 months after recovering from a severe Covid 19 pneumonia. CASE: A 71 years old male patient presented with massive thoraco-abdominal pain and severe dyspnea. At the time of admission, the patient was diagnosed with rupture of the diaphragm and developed cardiogenic shock. Intraoperatively there was a 4 cm diameter large rupture of the diaphragm with enterothorax (transverse colon, stomach, spleen, parts of the jejunum). Avulsion of the mesenteric arteries made a segmental resection of the jejunum together with the spleen necessary. A jejuno-jejunostomy was performed and organs were replaced into the abdomen. The rupture of the diaphragm underwent primary closure with non-resorbable suture material. The patient has shown an uneventful post-operative course, fully recovered and was discharged on day 11 after surgery. CONCLUSION: Covid 19 is a disease that is known to have various effects on different organs. The diaphragm is only paid heed in case of dysfunction. Also in the setting of Covid 19 it is not known as prominent effector organ. Nevertheless its affection by coughing caused by Covid 19 can lead to life threatening complications.

A rare case of internal hernia through the foramen of Winslow.

Internal hernia is a rare cause of intestinal obstruction. The risk of internal herniation is higher in some patients after abdominal surgery or with certain anatomical anomalies. Here, we present a case of an 80-year-old patient with incarcerated internal hernia through the foramen of Winslow due to an anatomical abnormality.

Platelet to Lymphocyte Ratio Correlates With Carcinoma Progression in Pancreatic Intra Epithelial Neoplasia.

BACKGROUND/AIM: Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion to pancreatic adenocarcinoma (PDAC). Yet no criteria to quantify patients at risk for progression to PDAC with PanIN exist. Platelet to lymphocyte ratio is an inflammatory marker that has been associated with overall survival in patients with invasive malignancies including pancreatic cancer. Preoperative sarcopenia has been linked to more aggressive diseases in pancreatic neoplasms. We aimed to assess a relation between PLR and sarcopenia as predictors for tumor progression in patients undergoing pancreatic resection for IPMN. PATIENTS AND METHODS: We retrospectively reviewed 102 patients (46 females, 56 males) who underwent pancreatic resection for PanIn. PLR was calculated and quantified using a cutoff of 110, sarcopenia was quantified using the skeletal muscle index (SMI) on preoperative abdominal imaging. Both were co-evaluated with additional demographic, clinical, pathological, and imaging data for possible correlation with PanIN associated PDAC. RESULTS: PLR was significantly elevated in patients with PanIN - associated PDAC (p=0.006). In the multivariate analysis, invasive carcinomas were significantly more prevalent in patients with PLR above 110 (OR=4.06, 95%CI=3.91-4.12, p=0.04). Patients with elevated PLR had a two-times higher risk to die in the postoperative period (HR=2.26, 95%CI=1.04-2.21, p=0.001). Patients with elevated PLR, preoperative jaundice and sarcopenia were the most likely to have PanIN-associated PDAC (OR=3.48, 95%CI=2.98-8.41, p=0.02). CONCLUSION: PLR is an independent predictive marker for the presence of PanIN associated invasive carcinoma.

Sarcopenia and primary tumor location influence patients outcome after liver resection for colorectal liver metastases.

INTRODUCTION: Right-sided and left-sided colorectal cancer (CRC) is known to differ in their molecular carcinogenic pathways. The prevalence of sarcopenia is known to worsen the outcome after hepatic resection. We sought to investigate the prevalence of sarcopenia and its prognostic application according to the primary CRC tumor site. METHODS: 355 patients (62% male) who underwent liver resection in our center were identified. Clinicopathologic characteristics and long-term outcomes were stratified by sarcopenia and primary tumor location (right-sided vs. left-sided). Tumors in the coecum, right sided and transverse colon were defined as right-sided, tumors in the left colon and rectum were defined as left-sided. Sarcopenia was assessed using the skeletal muscle index (SMI) with a measurement of the skeletal muscle area at the level L3. RESULTS: Patients who underwent right sided colectomy (n = 233, 65%) showed a higher prevalence of sarcopenia (35.2% vs. 23.9%, p = 0.03). These patients also had higher chances for postoperative complications with Clavien Dindo >3 (OR 1.21 CI95% 0.9-1.81, p = 0.05) and higher odds for mortality related to CRC (HR 1.2 CI95% 0.8-1.8, p = 0.03).On multivariable analysis prevalence of sarcopenia remained independently associated with worse overall survival and disease free survival (overall survival: HR 1.47 CI 95% 1.03-2.46, p = 0.03; HR 1.74 CI95% 1.09-3.4, p = 0.05 respectively). CONCLUSION: Sarcopenia is known to have a worse prognosis in patients with CRLM and CRC. Depending on the primary location sarcopenia has a variable effect on the outcome after liver resection.

The Predictive Value of the CRP-to-Albumin Ratio for Patients With Pancreatic Cancer After Curative Resection: A Retrospective Single Center Study.

BACKGROUND/AIM: Prognostic factors like the CRP-to-albumin ratio (CAR) represent potential predictors for survival of pancreatic cancer patients. We aimed to investigate the prognostic strength of the CAR for overall survival of patients with pancreatic cancer undergoing pancreatic resection. PATIENTS AND METHODS: Data from a total of 202 patients with pancreatic adenocarcinoma who had undergone curative pancreatic resection were subjected to a retrospective review. Overall survival was calculated according to the Kaplan-Meier method, and multivariate Cox regression analysis was used for calculating the prognostic strength of CAR. RESULTS: CAR was an independent prognostic factor of overall survival in univariate and multivariate Cox regression analysis. Elevated CAR was associated with a higher median value of Charlson Index, higher Union for International Cancer Control (UICC) classification and increased carcinoembryonic antigen (CEA) levels. CONCLUSION: CAR is a useful prognostic factor for the prediction of overall survival for patients undergoing pancreatic surgery. The impact of CAR in individual risk assessment should be evaluated in further studies.

Marking Disappearing Colorectal Liver Metastases After Complete Response to Neoadjuvant Chemotherapy via CT - A Pilot Study.

BACKGROUND/AIM: The liver is a frequent site for metastases of colorectal cancer. Approximately 15% of patients have hepatic metastases at the time of diagnosis and another 50% develop them over the course of their disease. Only 10-25% of patients are candidates for liver resection. The aim of this study was to assess the benefit of preoperative computed tomography (CT)-guided wire marking of disappearing colorectal liver metastases (CRLMs) (radiological disappearance of metastases) before surgical resection. PATIENTS AND METHODS: Between January 2011 and January 2014, 20 patients with potentially disappearing CRLMs were selected for CT-guided wire marking. Following treatment with neoadjuvant chemotherapy, disappearing CRLMs were marked via CT guidance. Afterwards, the marked sites were resected. RESULTS: Complete histological response to neoadjuvant chemotherapy was only in 10 resected sites (18%), and 46 (82%) resected liver metastases showed metastatic tissue present. Both overall survival and the disease-free rates in patients after using our method were 55%. CONCLUSION: This study demonstrated the usefulness of CT-guided wire marking to mark disappearing CRLMs in order to improve long-term effectiveness of surgical treatment.

Diethylnitrosamine (DENA) recapitulates formation of hepatic angiosarcoma in pigs.

BACKGROUND & AIM: Primary hepatic angiosarcoma is a rare tumor with poor prognosis. The aim of this study was to generate a new angiosarcoma model to improve research on hepatic angiosarcoma. METHODS: Pigs sus scrofa were treated with different regimens of diethylnitrosamine (DENA). Tissues were analyzed by histology and immunohistochemistry. Serum parameters were determined. Angiosarcoma tissue was investigated for chromosomal aberrations by aCGH analysis. RESULTS: Animals of almost all different treatment regimens developed a multitude of variable liver lesions. Different tumor types such as granulation tissue type, cellular-like, hyalinization necrosis-like, angiosarcoma-like, dysplastic nodule-like, hepatocellular-like, glandular structure-like, and leiomyoma-like lesions were observed. Weekly treatment with 15 mg/kg for up to 52 weeks or a single shot of 200 mg/kg DENA led to the development of hepatic angiosarcomas. aCGH analysis of angiosarcoma tissue revealed increased alterations in tumors compared to non-tumorous tissue. Most of the chromosomal alterations were found on chromosomes 6, 7, 12, and 14. CONCLUSION: In this preliminary study treatment of sus scrofa with weekly injections of 15 mg/kg DENA results in a new model for primary hepatic angiosarcoma. This model may help to shed light on the pathomechanisms of primary hepatic angiosarcoma and might therefore open new treatment options.

Operative R0 resection of diffuse large B-cell lymphoma of the pelvis: a case report.

BACKGROUND: Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma with or without involvement of extranodal sites. Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy represents the current standard therapy, achieving a rather dissatisfying outcome in approximately 30-40% of all cases. CASE PRESENTATION: We present the case of a 43-year-old Austrian woman with an incidentally detected large pelvic mass which was diagnosed as diffuse large B-cell lymphoma. Initially, the lymphoma intraoperatively appeared to be an inoperable conglomerate tumor. Soon, intestinal perforation induced by tumor infiltration occurred, which initiated a closure of the small intestine and application of a jejunal probe and a percutaneous endoscopic gastrotomy tube. Treatment utilizing the gold standard rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) was performed, partly resulting in remission according to radiological follow-up. In view of diagnosis and primary treatment development, the predictive outcome appeared unsound. However, within the procedure of the latest surgical intervention, which was intended to at least reconstruct the intestinal passage in order to improve quality of life, a surgical R0 resection of the residual tumor mass was achieved. CONCLUSIONS: The case presented here reports an unanticipated process of diffuse large B-cell lymphoma, underlining the importance of interdisciplinary cooperation and surgical intervention within the realms of state-of-the-art treatment.

Austrian consensus guidelines on imaging requirements prior to hepatic surgery and during follow-up in patients with malignant hepatic lesions.

Rapid advances in imaging technology have improved the detection, characterization and staging of colorectal liver metastases, hepatocellular carcinoma and cholangiocarcinoma. A variety of imaging modalities are available and play a pivotal role in the work-up of patients, particularly as imaging findings determine resectability. Surgery often represents the only measure that can render long-term survival possible. Imaging is also indispensable for the assessment of responses to neoadjuvant treatment and for the detection of recurrence. At a consensus meeting held in June 2017 in Vienna, Austria, Austrian experts in the fields of surgery and radiology discussed imaging requirements prior to and after hepatic surgery for malignant liver lesions. This consensus was refined by online voting on a total of 47 items. Generally, the degree of consensus was high. The recommendations relate to the type of preferred preoperative imaging modalities, technical settings with respect to computed tomography and magnetic resonance imaging, use of contrast agents, reporting, postoperative follow-up, and long-term follow-up. Taking local resources into account, these consensus recommendations can be implemented in daily clinical practice at specialized centers as well as outpatient diagnostic institutes in Austria.

Rarity among benign gastric tumors: Plexiform fibromyxoma - Report of two cases.

Plexiform fibromyxoma is a very rare mesenchymal tumor of the stomach, found almost exclusively in the antrum/pylorus region. The most common presenting symptoms are anemia, hematemesis, nausea and unintentional weight loss, without sex or age predilection. We describe here two cases of plexiform fibromyxoma, involving a 16-year-old female and a 34-year-old male. Both patients underwent complete resection (R0) by distal gastrectomy and retrocolic gastrojejunostomy (according to Billroth 2); for both, the postoperative course was uneventful. Histology showed multiple intramural and subserosal nodules with characteristic plexiform growth, featuring bland spindle cells situated in an abundant myxoid stroma with low mitotic activity. Immunohistochemistry showed α-smooth muscle actin-positive spindle cells, focal positivity for CD10, and negative staining for KIT, DOG1, CD34, S100, ß-catenin, STAT-6 and anaplastic lymphoma kinase. One of the cases showed focal positivity for h-caldesmon and desmin. Upon follow-up, no sign of disease was found. In the differential diagnosis of plexiform fibromyxoma, it is important to exclude the more common gastrointestinal stromal tumors as they have greater potential for aggressive behavior. Other lesions, like neuronal and vascular tumors, inflammatory fibroid polyps, abdominal desmoid-type fibromatosis, solitary fibrous tumors and smooth muscle tumors, must also be excluded.

Metachronous gallbladder metastasis from renal cell carcinoma-a rare clinical manifestation.

Renal cell carcinoma (RCC) represents a rare tumor entity accounting for approximately 3 % of all malignancies in the adult population. Approximately 30 % of all patients suffering from RCC develop metastases after nephrectomy and another 30 % of patients suffer from synchronous metastases at the date of diagnosis. Gallbladder metastases represent an extremely rare clinical condition and up to date there are only 35 published cases of gallbladder metastasis from RCC. Surgical resection should be the treatment of choice in any case based on the reported data in literature. In spite of the small series of cases, survival can be improved even in patients suffering from additional sites of metastases.

Portal vein resection in advanced pancreatic adenocarcinoma: is it worth the risk?

INTRODUCTION: Portal vein resection represents a viable add-on option in standard pancreaticoduodenectomy for locally advanced ductal pancreatic adenocarcinoma, but is often underused as it may set patients at additional risk for perioperative and postoperative morbidity and mortality. We aimed to review our long-term experience to determine the additive value of this intervention for locally advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: Single, university surgical center audit over a 13-year period; cohort comprised 221 consecutive patients undergoing pancreatic resection; in 47 (21 %) including portal vein resection. Predictors for short- and long-term survival were assessed via multivariate logistic and Cox regression. RESULTS: Baseline and perioperative characteristics were similar between the two groups. However, overall skin-to-skin times, intraoperative transfusion requirements as the need for medical inotropic support were higher in patients undergoing additional portal vein resection (p < 0.0001; p = 0.001 and p = 0.03). Postoperative complication rates were 34 vs. 35 % (p = 0.89), 14 patients (5 % vs. 11 %; p = 0.18) died in-hospital. An American Society of Anesthesiologists Score >2 was the only independent predictor for in-hospital mortality (OR 10.66, 95 % CI 1.24-91.30). Follow-up was complete in 99.5 %, one-year survival was 59 % vs. 70 % and five-year overall survival 15 % vs. 12 % with and without portal vein resection, respectively (Log rank: p = 0.25). For long-term outcome, microvascular invasion (HR 2.03, 95 % CI 1.10-3.76) and preoperative weight loss (HR 2.17, 95 % CI 1.31-3.58) were independent predictors. CONCLUSION: Despite locally advanced disease, patients who underwent portal vein resection had no worse perioperative and overall survival than patients with lower staging and standard pancreaticoduodenectomy only. Therefore, the feasibility of portal vein resection should be evaluated in every potential candidate at risk.

The Value of Lymph Node Dissection in the Surgery of Colorectal Cancer Liver Metastases.

BACKGROUND/AIM: Liver resection is the best treatment for metastatic colorectal cancer (CRC). Hepatic lymph node metastases are considered as extrahepatic disease and represent an unfavorable prognostic factor. However, extrahepatic disease, when resectable, provides no contraindication for surgical therapy. The aim of this study was to evaluate the prevalence of hepatic lymph node involvement in our patients' cohort. PATIENTS AND METHODS: Twenty patients submitted to resection for colorectal liver metastases were studied prospectively. Three areas for lymph node dissection were defined and analyzed separately. Lymph nodes were examined by hematoxylin and eosin staining and immunohistochemistry for Pan-Keratin. RESULTS: In average, 5 lymph nodes were harvested per patient. Macroscopic enlargement was not a definite sign for metastatic involvement. No morbidity or mortality was associated with lymphadenectomy. In our patients' collective, no cases of lymph node metastases occurred. CONCLUSION: There is no evidence of a survival benefit after lymph node dissection in patients with CRC liver metastases in the literature. Systematic lymphadenectomy can, however, provide a prognostic tool to better plan further treatment.

Surgical Management of Duodenal Gastrointestinal Stromal Tumors: A Case Report.

Gastrointestinal stromal tumors (GISTs) represent the most common mesenchymal tumor entity of the gastrointestinal tract. In fewer than 5% of cases, primary GISTs are located in the duodenum. Surgery represents the treatment of choice for localized tumor disease and remains challenging in GISTs located at the duodenum. The optimal surgical approach is currently discussed controversially in the literature due to the fact that extended resections in terms of pancreaticoduodenectomy may cause significant postoperative morbidity and mortality compared to limited resection. We report on a rare case of GIST located in the upper part of the duodenum treated by limited surgical resection. Avoidance of postoperative complications may lead to optimal oncological outcome in selected patients.

A Case of Focal Small-cell Neuroendocrine Carcinoma in the Vicinity of the Extrahepatic Bile Duct, Adjacent to an Extensive Biliary Intraepithelial Neoplasm: A Diagnostic Challenge with Major Clinical Implications.

Gastroenteropancreatic neuroendocrine tumors are known for their aggressiveness. Diagnosis of various bile duct pathologies, like biliar intraepithelial neoplasm, mixed adenoneuroendocrine carcinomas or small cell carcinomas, is challenging. This case report focuses on a rare case of a focal primary minute small cell carcinoma in the vicinity of the extrahepatic bile duct, presenting itself next to an extensive biliar intraepithelial neoplasm. This finding led to adjuvant chemotherapy, followed by major surgery. Therapeutic approach was based on CT and MRI scans but most importantly on immunohistochemistry and histological evaluation. Initially CR seemed achievable, but metastases were to be found rapidly. The authors want to underline the fact that major clinical decisions are based on sometimes tiny specimens; as literature shows it is absolutely advisable to use markers to differentiate the dignity of investigated areas. The authors call for keeping collision of tumors in mind and adding KOC staining and using it in a routine manner examining biliary duct lesions.

The role of serum albumin in the prediction of malnutrition in patients at least five yr after heart transplantation.

OBJECTIVES: Malnutrition after heart transplantation (HTX) is related to graft sclerosis. The risk for malnutrition is often underestimated by conventional measurements. We aimed to compare these with objective assessors for malnutrition. METHODS: Recipients at least five yr after HTX were included. Body mass index (BMI), bioimpedance analysis (BIA), serum albumin (SA) and subjective global assessment (SGA) malnutrition, and concomitant diseases were assessed. The BIA was used as gold standard, and a phase difference (PD) <4 was defined as cutoff. RESULTS: Sixty recipients (47 male, 13 female) were analyzed. The prevalence of malnutrition was according to SGA 6.6% (4/60), BMI 8.3% (5/60), SA 31.6% (19/60), and BIA 48.3% (19/60). PD values did not correlate with BMI (r = 0.118; p = 0.079) or SGA (r = 0.289; p = 0.65), but with SA (r = 0.458; p = 0.001). Multivariate analysis yield SA and sCr as independent predictors for an existing malnutrition. ROC analysis showed an area under the receiver operating characteristic curve of 0.606 for SA as compared to 0.515 for the BMI and 0.698 for sCr in the prediction of existing malnutrition as defined by the PD. CONCLUSION: The BMI or the SGA did not show as much power in predicting an existing alimentary deficiency for heart recipients as did SA.

Preparing for prospective clinical trials: a national initiative of an excellence registry for consecutive pancreatic cancer resections.

BACKGROUND: Despite significant improvements in perioperative mortality as well as response rates to multimodality treatment, results after surgical resection of pancreatic adenocarcinoma with respect to long-term outcomes remain disappointing. Patient recruitment for prospective international trials on adjuvant and neoadjuvant regimens is challenging for various reasons. We set out to assess the preconditions and potential to perform perioperative trials for pancreatic cancer within a well-established Austrian nationwide network of surgical and medical oncologists (Austrian Breast & Colorectal Cancer Study Group). METHODS: From 2005 to 2010 five high-volume centers and one medium-volume center completed standardized data entry forms with 33 parameters (history and patient related data, preoperative clinical staging and work-up, surgical details and intraoperative findings, postoperative complications, reinterventions, reoperations, 30-day mortality, histology, and timing of multimodality treatment). Outside of the study group, in Austria pancreatic resections are performed in three "high-volume" centers (>10 pancreatic resections per year), three "medium-volume" centers (5­10 pancreatic resections per year), and the rest in various low-volume centers (<5 pancreatic resections per year) in Austria. Nationwide data for prevalence of and surgical resections for pancreatic adenocarcinoma were contributed by the National Cancer Registry of Statistics of Austria and the Austrian Health Institute. RESULTS: In total, 492 consecutive patients underwent pancreatic resection for ductal adenocarcinoma. All postoperative complications leading to hospital readmission were treated at the primary surgical department and documented in the database. Overall morbidity and pancreatic fistula rate were 45.5 % and 10.1 %, respectively. Within the entire cohort there were 9.8 % radiological reinterventions and 10.4 % reoperations. Length of stay was 16 days in median (0­209); 12 of 492 patients died within 30 days after operation, resulting in a 30-day mortality rate of 2.4 %. Seven of the total 19 deaths (36.8 %) occurred after 30 days, during hospitalization at the surgical department, resulting in a hospital mortality rate of 3.9 % (19/492). With a standardized histopathological protocol, there were 70 % (21/30) R0 resections, 30 % (9/30) R1 resections, and no R2 resections in Vienna and 62.7 % (32/51) R0 resections, 35.3 % (18/51) R1 resections, and 2 % (1/51) R2 resections in Salzburg. Resection margin status with nonstandardized protocols was classified as R0 in 82 % (339/411), R1 in 16 % (16/411), and R2 in 1.2 % (5/411). Perioperative chemotherapy was administered in 81.1 % of patients (8.3 % neoadjuvant; 68.5 % adjuvant; 4.3 % palliative); chemoradiotherapy (1.6 % neoadjuvant; 3 % adjuvant; 0.2 % palliative), in 4.9 % of patients. The six centers that contributed to this registry initiative provided surgical treatment to 40 % of all Austrian patients, resulting in a median annual recruitment of 85 (51­104) patients for the entire ABCSG-group and a median of 11.8 (0­38) surgeries for each individual department. CONCLUSIONS: Surgical quality data of the ABCSG core pancreatic group are in line with international standards. With continuing centralization the essential potential to perform prospective clinical trials for pancreatic adenocarcinoma is given in Austria. Several protocol proposals aiming at surgical and multimodality research questions are currently being discussed