A propensity-matched study of full laparoscopic versus hand-assisted minimal-invasive liver surgery.

BACKGROUND AND AIM: The implications of multi-incision (MILS) and hand-assisted (HALS) laparoscopic techniques for minimally invasive liver surgery with regard to perioperative outcomes are not well defined. The purpose of this study was to compare MILS and HALS using propensity score matching. METHODS: 309 patients underwent laparoscopic liver resections (LLR) between January 2013 and June 2018. Perioperative outcomes were analyzed after a 1:1 propensity score match. Subgroup analyses of matched groups, i.e., radical lymphadenectomy (LAD) as well as resections of posterosuperior segments (VII and/or VIII), were performed. RESULTS: MILS was used in 187 (65.2%) and HALS in 100 (34.8%) cases, with a significant decrease of HALS resections over time (p = 0.001). There were no significant differences with regard to age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) Score, previous abdominal surgery and cirrhosis between both groups. Patients scheduled for HALS were characterized by a significantly higher rate of malignant tumors (p < 0.001) and major resections (p < 0.001). After propensity score matching (PMS), 70 cases remained in each group and all preoperative variables as well as resection extend were well balanced. A significantly higher rate of radical LAD (p = 0.039) and posterosuperior resections was found in the HALS group (p = 0.021). No significant differences between the matched groups were observed regarding operation time, conversion rate, frequency of major complications, length of intensive care unit (ICU) stay, overall hospital stay and R1 rate. CONCLUSION: Our analysis suggests MILS and HALS to be equivalent regarding postoperative outcomes. HALS might be particularly helpful to accomplish complex surgical procedures during earlier stages of the learning curve.

Incidence of incisional hernia after laparoscopic liver resection.

BACKGROUND: Minimally invasive techniques have been broadly introduced to liver surgery during the last couple of years. In this study, we aimed to report the incidence and potential risk factors for incisional hernia (IH) as well as health-related quality of life (HRQoL) after laparoscopic liver resections (LLR). METHODS: All patients undergoing LLR between January 2014 and June 2017 were contacted for an outpatient hernia examination. In all eligible patients, photo documentation of the scar was performed and IH was evaluated by clinical examination and by ultrasound. Patients also completed a questionnaire to evaluate IH-specific symptoms and HRQoL. Obtained results were retrospectively analyzed with regard to patients' characteristics, perioperative outcomes and applied minimally invasive techniques, such as multi-incision laparoscopic liver surgery or hand-assisted/single-incision laparoscopic surgery (HALS/SILS). RESULTS: Of 184 patients undergoing surgery, 161 (87.5%) met the inclusion criteria and 49 patients (26.6%) participated in this study. After a median time of 26 months (range 19-50 months) after surgery, we observed an overall incidence of IH of 12%. Five of 6 patients were overweight or obese (BMI ≥ 25) and 5 of 6 hernias were located at the umbilical site. Univariate analysis suggested the performance status at time of operation (ASA score ≥ 3; HR 5.616, 95% CI 1.012-31.157, p = 0.048) and the approach (HALS/SILS, HR 6.571, 95% CI 1.097-39.379, p = 0.039) as potential risk factors for IH. A higher frequency of hernia-related physical restrictions (HRR; p = 0.058) and a decreased physical functioning (p = 0.17) were noted in patients with IH; however, both being short of statistical significance. CONCLUSION: Advantages of laparoscopic surgery with regard to low rates of IH can be translated to minimally invasive liver surgery. Even though there are low rates of IH, patients with poor performance status at the time of operation should be monitored closely. While patients' characteristics are hard to influence, it might be worth focusing on surgical factors such as the approach and the closure of the umbilical site to further minimize the rate of IH.

[Large multicystic space-occupying liver lesion in a 19-year-old woman]. / Große multizystische Leberraumforderung bei einer 19-jährigen Frau.

A 19-year-old woman presented with liver capsule pain and a liver lesion on sonography, which contained microvesicular cystic, necrotic and solid fibrotic formations typical for alveolar echinococcosis (AE). The diagnosis was confirmed by serology and histopathology. This parasitic infection which is endemic in Germany is feared because of its malignant growth. The increasing expansion of E. multilocularis in Europe will lead to a higher incidence of AE with an occurrence of cases outside classical endemic regions.

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus.

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon-γ cytokine production and promote interleukin-10 production in old CD4+ T cells. In addition, TAC administration decreased interleukin-2 secretion in old CD4+ T cells more effectively while inhibiting the proliferation of CD4+ T cells in old mice. Both TAC-treated murine and human CD4+ T cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8+ T cells did not alter allograft survival outcome in old TAC-treated mice, suggesting that TAC age-specific effects were mainly CD4+ T cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4+ T cell mediated. The suppression of calcineurin levels and Ca2+ influx in both old murine and human T cells emphasizes the clinical relevance of age-specific effects when using TAC.

Risk Stratification of Ruptured Abdominal Aortic Aneurysms in Patients Treated by Open Surgical Repair.

OBJECTIVE: The present study tested scoring models for ruptured abdominal aortic aneurysms (rAAAs) in patients treated by open surgical repair (OSR). Scores were tested in a European population to validate their applicability for predicting outcome. METHODS: Between 2002 and 2013, 92 patients with rAAAs underwent OSR and medical records were reviewed retrospectively. The Edinburgh Rupture Aneurysm Score (ERAS), Vascular Study Group of New England (VSGNE) rAAA risk score, Hardman Index, and Glasgow Aneurysm Score (GAS) were calculated and analyzed according to in hospital mortality. The discriminatory power and calibration of all models were assessed by applying the receiver operating characteristic and the Hosmer-Lemeshow test χ(2). RESULTS: An ERAS ≤ 1 (n = 55), 2 (n = 15) and 3 (n = 16) was associated with a mortality of 27%, 47%, and 69%, respectively. The calibration was the best of all tested scores (χ(2) = 0.44; p = .81) and the area under the curve (AUC) was 0.71 (95% CI 0.6-0.82; p = .001). A VSGNE rAAA risk score = 0 (n = 19), 1 (n = 15), 2 (n = 19), 3 (n = 25), and ≥ 4 (n = 9) was associated with a mortality of 11%, 20%, 32%, 72%, and 56%, and an AUC of 0.76 (95% CI 0.66-0.87; p = .001). The calibration was reduced (χ(2) = 6.9; p = .08). The GAS and Hardman Index increased stepwise with increasing in hospital mortality, but were inferior to ERAS and the VSGNE rAAA risk score. The Hardman Index showed the smallest AUC (0.68; 95% CI 0.56-0.80; p = .011) and demonstrated a lack of fit (χ(2) = 8.2; p = .04). The GAS showed good discrimination (AUC = 0.75; 95% CI 0.64-0.85; p < .001) and calibration (χ(2) = 0.85; p = .66); however, the parametric scale of GAS limits its use to classifying patients according to their risk. CONCLUSION: The present study revealed remarkable differences in survival between subgroups (10-70%) and underscores the need for risk stratification. The ERAS was favorable with striking ease of use and high accuracy in predicting outcome.

Pulmonary metastasectomy for metastasized hepatocellular carcinoma after liver resection and liver transplantation: a single center experience.

BACKGROUND: The role of surgery in the treatment of metastasized hepatocellular carcinoma (HCC) remains uncertain. We here report our single centre experience with pulmonary metastasectomy (PM) for metachronous HCC metastases to the lung following curative liver resection (LR) and liver transplantation (LT), respectively. METHODS: Of 270 patients with HCC being treated by LR or LT at the University Hospital of Leipzig between January 1996 and July 2014, PM was performed in the follow up of 10 patients because of metachronous pulmonary HCC metastases. We retrospectively analyzed demographic and clinicopathological factors as well as the outcome after primary and secondary tumor treatment in these patients. RESULTS: Following LR/LT and metastasectomy, respectively, mean overall survival was 4.58 ± 0.84 years and 2.4 ±â€Š0.69 years. Postoperative morbidity after primary and secondary tumor treatment was 30 % and 20 %, respectively. Perioperative 30-day mortality was 0 %. Univariate analysis suggest tumor grading (p < 0.05), and a disease free-intervall > 1 year (p = 0.02) as significant prognostic parameters for survival in our collective. CONCLUSION: PM can be performed safely with a reasonable morbidity even in immunosuppressed patients after LT. Further studies are needed to evaluate whether PM can increase long-term survival in selected patients with resectable metastases and represents an alternative or additive treatment modality to the protein kinase inhibitor sorafenib.

[The Impact of Tumor Cell Proliferation on Occult Micrometastases, Tumor Recurrence and Patient Outcome Following Resection for Liver Malignancies]. / Stellenwert des Proliferationsreizes auf die okkulte Mikrometastasierung sowie Rezidivhäufigkeit und Prognose nach Resektion von Lebermalignomen.

Liver resection is currently considered to be essential part of the curative treatment of primary and secondary liver malignancies. However, long-term survival in these patients is limited by the high incidence of tumor recurrence. Recent clinical and experimental studies have indicated that cellular and molecular mechanisms associated with liver regeneration after partial hepatectomy may have a proliferative effect on occult micrometastases and circulating tumor cells and are thus responsible for recurrent disease. Growth factors and cytokines involved in liver regeneration have also been shown to influence tumour growth and metastasis. However, the underlying mechanisms explaining the interactions between regenerating liver tissue and tumour cell proliferation remain unclear. The development of modern agents specifically targeting these processes may improve disease-free and overall survival rates after oncological hepatectomy.

Invasive cardiac aspergillosis after orthotopic liver transplantation.

Invasive aspergillus infection occurs in 5 - 42 % of liver-transplanted recipients and is a dangerous complication, associated with high mortality if untreated. However, the early diagnosis of invasive aspergillosis can be elusive, as clinical signs are unspecific and the pathogenic agent is difficult to demonstrate. We here report about a 58-year-old man with acute liver failure caused by newly diagnosed chronic hepatitis B infection who underwent liver transplantation. The postoperative course was uneventful, and the patient was discharged after 30 days. After 105 days the patient was readmitted because of fever, recurrent chest and abdominal pain. Computed tomography revealed a cardiac lesion; other diagnostic steps including bone-marrow and endomycordial biopsy, virological and microbiological investigations gave no clear findings. To exclude a malignant process, thoracotomy with mass and simultaneous lower left lobe resection were performed. Histopathological findings revealed an invasive perimyocardial aspergillosis. Immediate intravenous therapy with voriconazole and caspofungin was initiated and monitoring of the mass was performed with transesophageal echocardiography and Cardio-MRI. Due to slightly increase of the lesion, medication was switched to posaconazole and caspofungin. Under this dual fungal treatment the lesion regressed and the patient could be discharged after two months in good clinical condition. Frequent Cardio-MRI scan after discharge showed further mass-regression. Therefore antifungal treatment was switched to oral posaconazole mono-therapy. After one year, complete reduction of the mass was achieved and antifungal therapy was discontinued. Recent diagnostic imaging follow-up showed no pathological finding.

[Sex differences in hepatobiliary and transplantation surgery]. / Geschlechtsunterschiede in der hepatobiliären und Transplantationschirurgie.

Gender-specific differences in hepatobiliary and transplantation surgery are decisive for the diagnosis, treatment and long-term outcomes. Men exhibit a higher risk of late recurrences and cancer-specific death after liver cancer resection. The emphasis on screening recommendations and ensuring equal access to treatment options are vital to minimize disparities. In kidney and liver transplantations, women are less frequently listed and endure longer waiting times, while men dominate the waiting list. Gender-specific disparities in drug compatibility necessitate differentiated dosing. Further studies are needed to ensure equity in transplantation treatment. Individualized treatment considering these differences can enhance treatment outcomes and the quality of life of patients.

[Stem cell-induced liver regeneration]. / Stammzell-induzierte Leberregeneration.

BACKGROUND: The liver has an excellent regenerative capacity after resection. However, below a critical level of future liver remnant volume (FLRV), partial hepatectomy is accompanied by a significant increase of postoperative liver failure. There is accumulating evidence for the contribution of bone marrow stem cells (BMSC) to participate in liver regeneration. Here we report our experience with portal vein embolisation (PVE) and CD133+ BMSC administration to the liver, compared with PVE alone, to augment hepatic regeneration in patients with critically low FLRV or impaired liver function. PATIENTS AND METHODS: Eleven patients underwent PVE of liver segments I and IV-VIII to stimulate hepatic regeneration prior to extended right hepatectomy. In these 11 patients with a FLRV below 25% and/or limited quality of hepatic parenchyma, PVE alone did not promise adequate proliferation. These patients underwent additional BMSC administration to segments II and III. Two radiologists blinded to patients' identity and each other's results measured liver and tumour volumes with helical computed tomography. Absolute, relative and daily FLRV gains were compared with a group of patients that underwent PVE alone. RESULTS: The increase of the mean absolute FLRV after PVE with BMSC application from 239.3 mL±103.5 (standard deviation) to 417.1 mL±150.4 was significantly higher than that from 286.3 mL±77.1 to 395.9 mL±94.1 after PVE alone (p<0.05). Also the relative gain of FLRV in this group (77.3%±38.2%) was significantly higher than that after PVE alone (39.1%±20.4%) (P=0.039). In addition, the daily hepatic growth rate after PVE and BMSC application (9.5±4.3 mL/d) was significantly superior to that after PVE alone (4.1±1.9 mL/d) (p=0.03). Time to surgery was 27 days±11 in this group and 45 days±21 after PVE alone (p=0.02). Short- and long-term survival were not negatively influenced by the shorter waiting period. CONCLUSION: In patients with malignant liver lesions, the combination of PVE with CD133+ BMSC administration substantially increased hepatic regeneration compared with PVE alone. This procedure bears the potential to allow the safe resection of patients with a curative intention that would otherwise carry the risk post-operative liver failure.

Perioperative outcome and long-term survival for intrahepatic cholangiocarcinoma after portal vein embolization and subsequent resection: A propensity-matched study.

INTRODUCTION: In view of the high therapeutic value of surgical resection for intrahepatic cholangiocarcinomas (ICC), our study addresses the question of clinical management and outcome in case of borderline resectability requiring hypertrophy induction of the future liver remnant prior to resection. METHODS: Clinical data was collected of all primary ICC cases receiving major liver resection with or without prior portal vein embolization (PVE) from a single high-volume center. PVE was performed via a percutaneous transhepatic access. Propensity score matching was performed. Perioperative morbidity was assessed as well as long-term survival with a minimum follow-up of 36 months. RESULTS: No significant difference in perioperative morbidity was seen between the PVE and the control group. For the PVE group, median OS was 28 months vs. 37 months for the control group (p = 0.418), median DFS 18 and 14 months (p = 0.703). Disease progression during hypertrophy was observed in 38% of cases. Here, OS and DFS was reduced to 18 months (p = 0.479) and 6 months (p = 0.013), respectively. In case of positive N-status or multifocal tumor (MF+) OS was also reduced (18 vs. 26 months, p = 0.033; MF+: 9 vs. 36months p = 0.013). CONCLUSION: Our results suggest that the surgical therapy in case of borderline resectability offers acceptable results with non-inferior OS rates compared to cases without preoperative hypertrophy induction and comparable oncological features. In the presence of additional risk factors (multifocal tumor, lymph node metastasis, PD during hypertrophy) the OS is notably reduced.

[Digital documentation of complications in visceral surgery: possibilities and evaluation of an instrument for quality management]. / Digitale Komplikationserfassung in der Viszeralchirurgie: Möglichkeiten und Evaluation eines Instrumentes für das Qualitätsmanagement.

Against the background of the growing economization of clinical medicine, in the last decades the topics of risk and complication management have also become more important in surgical disciplines. The standardization and reproducible documentation of outcome and complication data play a key role for valid quality control. In this article a digital system implemented at the surgical clinic of the Charité University Medicine in Berlin is analyzed with respect to its practicability for perioperative and postoperative monitoring of complications within the framework of quality assurance.

[Impact of the COVID-19 pandemic on hepato-pancreato-biliary surgery and organ transplantation]. / Auswirkung der COVID-19-Pandemie auf die hepatopankreatobiliäre Chirurgie und die Organtransplantation.

BACKGROUND AND OBJECTIVE: Due to the coronavirus disease 2019 (COVID-19) pandemic extensive reorganization and limitation of resources within the healthcare system became inevitable. This review highlights the direct and indirect impact of the COVID-19 pandemic on the fields of hepato-pancreato-biliary (HPB) surgery and organ transplantation incorporating the current literature and expert opinions published by national and international societies. Trends in surgical numbers were analyzed via the Eurotransplant Statistics Report Library and an in-center evaluation of HPB surgical procedures. RESULTS: For the fields of HPB surgery and organ transplantation a drastic decrease of procedures performed during the first wave of the pandemic was broadly reported. Interestingly, a compensatory increase of procedures was mostly not observed during the following months resulting in a slight overall decrease for 2020 compared to 2019. Whether this trend was due to increased mortality because of postponed surgeries and altered treatment regimens cannot be ruled out at this time. A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is definitely associated with a complicated course, especially in the perioperative course and after transplantation. DISCUSSION: Due to the increased risk profile of the named patient groups, there is an increased risk for a severe COVID-19 course. This must be considered when weighing up the treatment alternatives, protection recommendations and prioritization for vaccinations.

Platelet activation and increased tissue factor expression on monocytes in reperfusion injury following orthotopic liver transplantation.

Platelets have been implicated in the pathogenesis of liver damage after orthotopic liver transplantation (OLT). Early graft dysfunction is frequently caused by reperfusion injury subsequent to cold ischemia (IRI). Therefore, we investigated activation of the pivotal haemostatic cells, platelets and monocytes, from patients with elevated markers of IRI and from patients with uneventful course (control-group), respectively during the first week after OLT. Flow cytometry analysis of citrate anticoagulated blood samples revealed that platelets from IRI patients became significantly activated within 48 h after OLT in vivo, with increased surface presentation of P-selectin, CD40L, thrombospondin-1 and tissue-factor. Platelet activation in IRI patients on post-transplant day 2 was accompanied by significantly enhanced tissue-factor expression on peripheral blood monocytes, significant elevated levels of C-reactive protein and hepatocellular damage. Towards post-transplant day 4, levels of platelet-derived microparticles rose significantly in IRI patients if contrasted to control patients. Thus, activated cellular haemostasis is involved in the early inflammatory response of hepatocellular damage subsequent to reperfusion of the transplanted liver. Targeting distinct activation patterns of platelets and monocytes in an early phase of hepatic grafting may counteract the extent of IRI via inhibition of micro-thrombus formation and inflammation without exacerbating the existing bleeding risk.

[Surgical treatment of malignant biliary tract diseases]. / Chirurgische Therapie maligner Gallengangserkrankungen.

BACKGROUND: Cancer of the intrahepatic and extrahepatic biliary tracts is characterized by a low incidence and a very heterogeneous appearance. OBJECTIVE: Summary and evaluation of current surgical strategies in the treatment of malignant biliary tract diseases. MATERIAL AND METHODS: An analysis of English language publications as well as European and American guidelines and recommendations for the surgical treatment of malignant diseases of the biliary tract was carried out. The results and recommendations were summarized and evaluated on the basis of experiences in this center. RESULTS: Surgery is considered to be the only curative treatment option; however, prospective randomized studies and existing guidelines are based on limited evidence. Surgical strategies and the extent of resection differ between carcinomas of the intrahepatic and extrahepatic bile ducts depending on localization, size and number of lesions as well as their proximity to surrounding structures. CONCLUSION: Sufficient experience in the treatment of these rare tumors is of special importance for the implementation of individualized overall concepts and for the sufficient performance of the mostly complex resections.

[Frontiers in liver transplantation in indication and techniques]. / Grenzbereiche der Lebertransplantation in Indikation und Technik.

BACKGROUND: The frontiers in liver transplantation are intrinsically expansions of indications, e.g. hepatocellular carcinoma and (perihilar) cholangiocarcinoma, recipients with more severe concomitant diagnoses or "soft" contraindications and technically demanding reconstruction procedures of vascular structures (for portal vein thrombosis or aorto-hepatic conduits). In addition, an extension of the donor pool with suboptimal donor organs (old donors and steatotic livers) is of interest. METHODS: This article presents the current situation based on personal experiences in daily practice and an appropriate literature review. RESULTS: A significant reduction of 1­year patient survival has been reported in Germany. The percentage of so-called marginal donor organs is inversely proportional to the very low donation rate and parallel to the waiting list mortality. Simultaneously, the proportion of inpatients with multiple organ failure is rising. CONCLUSION: Results-oriented and controlled liver transplantation currently prohibits making inroads into the previously intrinsic frontiers. As long as the current circumstances do not change, a shift in the intrinsic frontiers of that which is surgically feasible will not be possible. The current situation forces the transplant surgeon to apply a more restrictive indications and organ acceptance policy. With this approach we can try to regain the previously excellent short- and long-term results of a 1­year survival of 90% and a 20-year survival of 50%.

Modern therapy of rectal carcinoma.

Throughout the past decade the treatment of rectal carcinoma has improved remarkably. Today, individualized multimodality treatment allows local and distant tumor freedom with preservation of anorectal and genitourinary function in a majority of patients. Radiotherapy is elementary in reducing the risk of local recurrence whereas chemotherapy including promising novel agents prevents or eliminates distant metastases. However, surgery revolutionized by TME (total mesorectal excision) remains the only curative treatment for rectal carcinoma. In this study the authors review the developments as well as the current status of modern treatment for rectal carcinoma.

[Treatment of hepatocellular carcinoma in the cirrhotic and non-cirrhotic liver]. / Therapie des hepatozellulären Karzinoms in der zirrhotischen und nicht-zirrhotischen Leber.

BACKGROUND AND OBJECTIVES: The treatment of hepatocellular carcinoma (HCC) includes surgical, interventional and systemic approaches. This review highlights the importance of surgical treatment approaches in the multimodal treatment of HCC, based on the currently available literature, corresponding German guidelines as well as current developments in organ donation in Germany. RESULTS: Curative treatment options for HCC include liver transplantation, partial liver resection, and local ablative procedures depending on the lesion size. In the case of an early HCC in a cirrhotic liver fulfilling the Milan criteria, liver transplantation is the treatment of choice. In view of the organ shortage in Germany and improved results after partial liver resection, surgery can alternatively be performed in patients with a sufficient liver function. In selected patients with multinodular HCC, regional lymph node metastases or macrovascular invasion, the possibility of liver resection must be decided on an individual basis; however, the latter two criteria are contraindications for transplantation. Local ablative procedures can be considered as an alternative to resection in selected patients with early solitary HCC. Surgery of HCC in the non-cirrhotic liver with a curative intent is guided by the general principles of oncological liver surgery. DISCUSSION: Curative treatment options for HCC include liver transplantation, partial liver resection and local ablative procedures. Current developments in the area of organ donation and technical advances in minimally invasive liver surgery should be included in decision-making in tumor boards.

Interdisciplinary treatment of primary hepatic angiosarcoma: emergency tumor embolization followed by elective surgery.

Among primary hepatic malignancies, sarcomas represent a minority of 2 %. Of those, primary hepatic angiosarcoma is the most common one. In the past its incidence has been related to the exposure of certain chemicals like thorotrast, vinyl-chloride or arsenic. - Patients suffering from this aggressive, highly vascular tumor have a poor prognosis in general. Without treatment most of them die after rapid tumor progression with multifocal dissemination. In case of tumor perforation, fatal abdominal hemorrhage has been observed. - We herein report the successful interdisciplinary treatment of an 81 year-old woman with a perforated primary hepatic angiosarcoma of the left hepatic lobe. Initially, tumor bleeding was stopped by emergency interventional coil embolization. After stabilization of the patient, we performed an elective tumor resection. The patient could eventually be discharged in a good clinical condition. - So far, no standard therapy has established for patients with primary hepatic angiosarcoma. Surgery seems to be the treatment of choice. In addition, preoperative interventional embolization of the tumor supplying vessels reduces the risk of pre- and intraoperative bleeding. The value of adjuvant chemotherapy is not yet clarified. - The outcome of most patients with primary hepatic angiosarcoma remains poor and there is a need for clinical studies.