Treatment Outcomes in Patients with Recurrent Adrenocortical Carcinoma.

BACKGROUND: While numerous studies have explored treatment outcomes for the overall ACC patient cohort, data on the subpopulation of patients with recurrent disease are limited. Therefore, the aim of this study was to assess treatment outcomes in patients with recurrent ACC. METHODS: In this retrospective study, we included 18 patients median age 49 years (42-62); 67% female) diagnosed with recurrent ENSAT stage I-III ACC who underwent either R0 (n = 16) or Rx (n = 2) surgical resection of the tumor. RESULTS: The median time from the initial surgery to ACC recurrence was 29 months (IQR 18-50). Seven patients (39%) manifested local recurrence, while 11 patients (61%) developed distant metastases. The median follow-up duration after tumor recurrence was 32 months (IQR 25-53). Regarding the treatment of ACC recurrence, 10 patients underwent a second surgery either as an alone procedure (n = 4), or in combination with mitotane (n = 4), mitotane and chemotherapy (n = 1), or mitotane combined with radiotherapy (n = 1). The remaining patients received treatment involving chemotherapy±mitotane (n = 4) and locoregional therapy ±chemotherapy (n = 3). One patient chose not to proceed with further management and follow-up. The median PFS was 17 (95% CI 8-26) months while the median OS was not reached. In the multivariate model, increased mortality was associated with advanced age (p = 0.04) and a shorter interval to ACC recurrence (p = 0.03). CONCLUSION: A significant proportion of patients with ACC recurrence experience disease progression or second recurrence, despite all treatment efforts. Nevertheless, by integrating diverse treatment modalities, many patients have the potential to attain long-term survival.

Intravesical Gemcitabine and Docetaxel Therapy for BCG-Naïve Patients: A Promising Approach to Non-Muscle Invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) therapy for patients with non-muscle invasive bladder cancer (NMIBC) faces limitations in efficacy and significant side effects, aggravated by a recent global shortage. In this prospective clinical study, we report the outcomes of sequential intravesical administration of gemcitabine and docetaxel (Gem/Doce) as a first-line treatment for BCG-naïve patients with high-risk NMIBC (HR NMIBC). From October 2019 until April 2022, we enrolled 52 patients and followed the treatment protocol set forth by the University of Iowa. Follow-up assessments were conducted every 3 months. In this cohort, 25 (48.1%) patients were diagnosed with high-grade T1 (T1HG) bladder cancer, 10 (19.2%) patients had carcinoma in situ (CIS), and 17 (32.7%) patients had a combination of T1HG+CIS. The median time to first recurrence in the T1HG, CIS, and T1HG+CIS groups was 11, 10.5, and 8.8 months, respectively. The recurrence-free survival was 98.1%, 94.2%, and 80.8% at 6, 9, and 12 months, respectively. The rate of progression-free survival was 100%, 98.1%, and 92.3% at 6, 9, and 12 months, respectively. We demonstrated the safety and efficacy of Gem/Doce therapy in BCG-naïve patients with HR NMIBC during a one-year follow-up. Further research with extended follow-ups, as well as direct comparisons of Gem/Doce with other anticancer agents, is essential.

Biosensors for Cancer Biomarkers Based on Mesoporous Silica Nanoparticles.

Mesoporous silica nanoparticles (MSNs) exhibit highly beneficial characteristics for devising efficient biosensors for different analytes. Their unique properties, such as capabilities for stable covalent binding to recognition groups (e.g., antibodies or aptamers) and sensing surfaces, open a plethora of opportunities for biosensor construction. In addition, their structured porosity offers capabilities for entrapping signaling molecules (dyes or electroactive species), which could be released efficiently in response to a desired analyte for effective optical or electrochemical detection. This work offers an overview of recent research studies (in the last five years) that contain MSNs in their optical and electrochemical sensing platforms for the detection of cancer biomarkers, classified by cancer type. In addition, this study provides an overview of cancer biomarkers, as well as electrochemical and optical detection methods in general.

Comparative Study of Field-Effect Transistors Based on Graphene Oxide and CVD Graphene in Highly Sensitive NT-proBNP Aptasensors.

Graphene-based materials are actively being investigated as sensing elements for the detection of different analytes. Both graphene grown by chemical vapor deposition (CVD) and graphene oxide (GO) produced by the modified Hummers' method are actively used in the development of biosensors. The production costs of CVD graphene- and GO-based sensors are similar; however, the question remains regarding the most efficient graphene-based material for the construction of point-of-care diagnostic devices. To this end, in this work, we compare CVD graphene aptasensors with the aptasensors based on reduced GO (rGO) for their capabilities in the detection of NT-proBNP, which serves as the gold standard biomarker for heart failure. Both types of aptasensors were developed using commercial gold interdigitated electrodes (IDEs) with either CVD graphene or GO formed on top as a channel of liquid-gated field-effect transistor (FET), yielding GFET and rGO-FET sensors, respectively. The functional properties of the two types of aptasensors were compared. Both demonstrate good dynamic range from 10 fg/mL to 100 pg/mL. The limit of detection for NT-proBNP in artificial saliva was 100 fg/mL and 1 pg/mL for rGO-FET- and GFET-based aptasensors, respectively. While CVD GFET demonstrates less variations in parameters, higher sensitivity was demonstrated by the rGO-FET due to its higher roughness and larger bandgap. The demonstrated low cost and scalability of technology for both types of graphene-based aptasensors may be applicable for the development of different graphene-based biosensors for rapid, stable, on-site, and highly sensitive detection of diverse biochemical markers.

Direct electrochemical reduction of graphene oxide thin film for aptamer-based selective and highly sensitive detection of matrix metalloproteinase 2.

Simple and low-cost biosensing solutions are suitable for point-of-care applications aiming to overcome the gap between scientific concepts and technological production. To compete with sensitivity and selectivity of golden standards, such as liquid chromatography, the functionalization of biosensors is continuously optimized to enhance the signal and improve their performance, often leading to complex chemical assay development. In this research, the efforts are made on optimizing the methodology for electrochemical reduction of graphene oxide to produce thin film-modified gold electrodes. Under the employed specific conditions, 20 cycles of cyclic voltammetry (CV) are shown to be optimal for superior electrical activation of graphene oxide into electrochemically reduced graphene oxide (ERGO). This platform is further used to develop a matrix metalloproteinase 2 (MMP-2) biosensor, where specific anti-MMP2 aptamers are utilized as a biorecognition element. MMP-2 is a protein which is typically overexpressed in tumor tissues, with important roles in tumor invasion, metastasis as well as in tumor angiogenesis. Based on impedimetric measurements, we were able to detect as low as 3.32 pg mL-1 of MMP-2 in PBS with a dynamic range of 10 pg mL-1 - 10 ng mL-1. Further experiments with real blood samples revealed a promising potential of the developed sensor for direct measurement of MMP-2 in complex media. High specificity of detection is demonstrated - even to the closely related enzyme MMP-9. Finally, the potential of reuse was demonstrated by signal restoration after experimental detection of MMP-2.

Senhance robotic radical prostatectomy: A single-centre, 3-year experience.

BACKGROUND: Senhance Surgical System is a novel robotic platform used in University Hospital Centre Zagreb since February 2019. In this study, we present our 3-year experience with this platform. PATIENTS AND METHODS: Data were prospectively collected for 200 patients who underwent extraperitoneal robotic radical prostatectomy (RRP) from May 2019 to March 2022. RESULTS: The median age of the patients was 65 years, and the prostate-specific antigen was 6.9 ng/mL. Clinically, most of the patients had T1c stage. The estimated blood loss was 250 mL, and there were 6 conversions to laparoscopic and 2 to open prostatectomy. There were 15 early postoperative complications, 11 Clavien-Dindo classification grade I, 3 grade II and 1 grade IV. Functional outcomes in the first 150 patients: 140 patients (93.3%) had good urinary control. Thirteen patients underwent additional oncological treatment. CONCLUSION: RRP performed with the Senhance robotic platform is a feasible and safe procedure with good initial results.

TRENDS IN SURGICAL MANAGEMENT OF RENAL NEOPLASMS: SINGLE CENTER RESULTS IN THE LAST DECADE.

The majority of renal neoplasms can be treated surgically using open or minimally-invasive approach. Nephron-sparing surgery should be used when possible, regardless to the operative approach. In this retrospective study, we analyzed surgical trends of operative treatment of renal neoplasms in the period from February 2011 until December 2020. There were a total of 1031 procedures, 703 (68.2%) radical nephrectomies (RN) and 328 (31.8%) partial nephrectomies (PN). Laparoscopic approach was used in 211 (20.5%) (111 PN and 100 RN), while open approach was used in 820 (79.5%) (328 PN and 703 RN) cases. There were 12 procedures performed with the use of cardiopulmonary bypass and hypothermic arrest. The median operative time was 161 minutes for open RN and 158 for open PN, 160 for laparoscopic RN, and 162 for laparoscopic PN. The most common pathology was clear cell carcinoma in 693 (67.3%), papillary carcinoma in 115 (11.2%), chromophobe carcinoma in 67 (6.5%), oncocytoma in 46 (4.5%), and angiomyolipoma in 33 (3.2%) patients. Pathologically, pT1 stage was diagnosed in 56.9%, pT2 in 5.8%, pT3 in 22.4% and pT4 in 1.2% of patients. Regional lymphadenectomy was performed in 354 (34.3%) patients, among which lymph nodes were positive in 40 (11.3%) cases. Surgical margins were positive in 27 cases when PN was performed (8.2%). In conclusion, there was an ongoing raising trend in the number of procedures in general, and also in minimally invasive and nephron-sparing surgery in our study.

SHORT-TERM OUTCOMES OF PERCUTANEOUS RADIOFREQUENCY AND MICROWAVE ABLATION IN THE TREATMENT OF SMALL RENAL MASSES.

Although the gold standard in the management of kidney tumors is surgical treatment, thermal ablation methods are a viable therapeutic option for patients with small (<4 cm) renal masses who are poor surgical candidates. The aim of this study was to compare the technical success, primary efficacy and complication rate of percutaneous radiofrequency and microwave ablation in the treatment of small renal masses. A retrospective analysis of consecutive patients with small renal masses treated with radiofrequency or microwave ablation between December 2017 and January 2022 was conducted. Response to the ablative therapy was assessed on contrast-enhanced computed tomography examination after 3 months. Ablations of 44 kidney lesions were performed in 43 patients. Sixteen lesions were treated with radiofrequency and 28 with microwave ablation. Both methods were associated with high technical success (100%). Primary efficacy rates of radiofrequency and microwave ablation were 81.3% and 89.3%, respectively. Ablation-related complications were noted only in the patients treated with microwave ablation (18.5%), all of them being low grade (Clavien-Dindo 1 and 2). Radiofrequency and microwave ablation exhibited comparable efficacy in the treatment of small renal masses. Microwave ablation was associated with a comparatively higher number of complications.

LAPAROSCOPIC ADRENAL-SPARING SURGERY CASE SERIES: PARTIAL ADRENALECTOMY AND CYST RESECTION.

The aim is to present our case series documenting indications, laparoscopic technique, surgical and endocrinologic outcomes of laparoscopic partial adrenalectomy. In the period from April 2011 until October 2021, we performed 39 procedures. The patients were divided into three groups: unilateral adrenal gland tumor with a normal contralateral gland (group 1), tumor of the solitary adrenal gland (group 2), and adrenal cysts (group 3). There were 20 patients in group 1, 6 patients in group 2, and 13 patients in group 3. The most common histology in group 1 was adenoma (40%), all tumors in group 2 were renal cell carcinoma metastases, and all cysts in group 3 were benign. There were no major complications (Clavien Dindo grade ≥2) in the whole cohort. All patients in groups 1 and 3 had favorable endocrinologic outcomes, and 50% of group 2 patients required lifelong hydrocortisone replacement therapy. The procedure is safe and feasible with favorable outcomes in the hands of a high volume adrenal surgeon.

One-Step Photochemical Immobilization of Aptamer on Graphene for Label-Free Detection of NT-proBNP.

A novel photochemical technological route for one-step functionalization of a graphene surface with an azide-modified DNA aptamer for biomarkers is developed. The methodology is demonstrated for the functionalization of a DNA aptamer for an N-terminal B-type natriuretic peptide (NT-proBNP) heart failure biomarker on the surface of a graphene channel within a system based on a liquid-gated graphene field effect transistor (GFET). The limit of detection (LOD) of the aptamer-functionalized sensor is 0.01 pg/mL with short response time (75 s) for clinically relevant concentrations of the cardiac biomarker, which could be of relevance for point-of-care (POC) applications. The novel methodology could be applicable for the development of different graphene-based biosensors for fast, stable, real-time, and highly sensitive detection of disease markers.

Subtyping primary aldosteronism by inconclusive adrenal vein sampling: A derivation and validation study in a tertiary centre.

OBJECTIVE: Indices based on aldosterone/cortisol (A/C) concentration in the successfully cannulated adrenal vein (AV) and in the inferior vena cava (IVC) (AV/IVC) appear to be possible markers to verify the subtype of primary aldosteronism (PA) in the case of inconclusive results of adrenal vein sampling (AVS). The variability of results in previous studies encouraged us to calculate AV/IVC and adrenal A/C cutoff values that could predict the aetiology of PA. METHODS: This retrospective study included 96 patients who underwent AVS due to PA between 2015 and 2020. The derivation cohort ultimately consisted of 60 patients with bilaterally successful AVS and a clear diagnosis of unilateral or bilateral disease. Receiver operating characteristic analysis was used to find the optimal A/C and AV/IVC cutoff values predicting the subtype of PA. The validation cohort consisted of 11 patients with either unsuccessful cannulation or a borderline lateralization index (LI), those patients underwent adrenalectomy because their indices were suggestive of unilateral disease based on the derivation cohort data. RESULTS: The cutoff values of A/C ≤ 0.63 or AV/IVC ≤ 0.37 identified unaffected glands with a sensitivity of 91.2% and 97.1%, respectively, and a specificity of 90.7% and 88.4%, respectively. Unilateral ipsilateral gland involvement was characterized by A/C ≥ 3.5 or AV/IVC ≥ 3.4 with a corresponding specificity of 100%. All patients in the validation cohort achieved biochemical remission postoperatively. CONCLUSIONS: A/C and AV/IVC cutoff values could be a useful tool to determine the subtype of PA in patients with unilateral successful AVS as well as in patients with a borderline LI.

Senhance robot-assisted adrenalectomy: a case series.

We present a case series of 12 consecutive robot-assisted adrenalectomies performed from May 2019 to March 2020 by a single surgeon experienced in laparoscopy using the novel Senhance robotic system. Eleven patients had primary aldosteronism due to an adrenal adenoma, diagnosed by means of endocrinological and radiological evaluation, and 1 had a benign adrenal cyst. The robotic adrenalectomy technique is described in detail. The mean procedure time was 165.1 minutes, with robotic docking time of 11.6 minutes and console time of 98.6 minutes. The mean estimated blood loss was 47 mL, and hospital stay duration was 4.5 days. There was 1 Clavien Dindo IIIB complication and 1 patient underwent conversion to laparoscopy. All patients with adenoma had complete biochemical remission after surgery. In conclusion, the Senhance robotic system is a safe and feasible platform for benign adrenal surgery in high-volume centers.

Correction to: Letter to the editor on "Initial experience of laparoscopic radical nephrectomy using the Senhance® robotic system for renal cell carcinoma".

[This corrects the article DOI: 10.1007/s13691-021-00494-y.].

The Effect of Surgeon Expertise on the Outcome of Patients with Adrenocortical Carcinoma.

Complete surgical removal of adrenocortical carcinoma (ACC) represents the only chance of long-term cure. In this study, we compared the long-term outcomes of ACC patients depending on whether they had adrenal surgery performed in a high-volume (HVC) or in a low-volume (LVC) center. This retrospective study included 49 patients from the Croatian ACC Registry with the European Network for the Study of Adrenal Tumors (ENSAT) stage I-III ACC, of which 35 underwent surgery in a HVC whereas 14 of them were operated in one of the LVCs. Patients operated in the LVCs had a significantly higher rate of ACC recurrence (57.1% vs. 22.9%; p = 0.02). Accordingly, RFS was significantly longer in patients operated on in HVC (p = 0.04). The difference in RFS remained significant after controlling for age, gender, tumor size, Ki-67 index, Weiss score, and type of surgery (HR 4.55; 95% CI 1.16-17.88; p = 0.03). In addition, there is a tendency towards longer DSS in patients in the HVC group compared to those in the LVC group (p = 0.05). These results point to the centralization of adrenal surgery as a key prerequisite for improving the outcomes of ACC patients.

ANESTHESIA FOR ROBOT-ASSISTED RADICAL PROSTATECTOMY - A CHALLENGE FOR ANAESTHESIOLOGIST.

Mininimally invasive surgery has become one of the most popular ones over the last few decades due to many benefits. The advantages are minimal surgical incision, reduced blood loss, reduced postoperative pain, faster postoperative recovery, shorter hospital stay, lower morbidity and better outcomes compared to open surgery. The most common robotic procedures in urology are radical prostatectomies. In UHC Zagreb, since November 2019 until now, there have been more than 180 robotic assisted radical prostatectomies (RALP) using Senhance robotic system performed. As a procedure with many possible complications, it represents a challenge for anaesthesiologist. Some of the problems the anaesthesiologists have to face are related to limited patient access, possible difficulties connected with positioning, pneumoperitoneum, subcutaneous emphysema, possible airway oedema. Pneumoperitoneum has impact on almost every system: cardiovascular, renal, respiratory, gastrointestinal and other. Detailed understanding of physiological changes of RALP, with intraoperative impact on nearly every body system is ultimate. Careful preoperative evaluation and intraoperative conduction minimize the risk of complications, and help patients to reach full recovery in a very short time. Excellent outcomes are the result of individualized approach to the patient and good communication between team members.

SENHANCE ROBOTIC RADICAL PROSTATECTOMY.

Since its introduction 20 years ago, robotic radical prostatectomy has become a standard of care in the treatment of localized prostate cancer in many Centers. Until recently, they have all been performed by the only available robotic platform. Senhance is a novel robotic platform that was approved for clinical use. The term Senhance was used to systematically search PubMed and Scopus databases for relevant articles that were afterward filtered for appropriate designs and data reports. There were two reports that met all of the criteria and were included in the review. Both studies were designed as prospective case series with a total of 234 patients where the data including operative data and oncological outcomes were reported. The average operative time ranged between 180 and 195 min, with estimated blood loss between 250 and 300 mL. There was 3 Clavien - Dindo grade III, and 1 Clavien - DIndo grade IV complication reported. One of the studies compared it with laparoscopy, but no significant difference in operative time and blood loss was found. Both studies concluded that the Senhance is a feasible and safe robotic platform for radical prostatectomy.

Comparison of extraperitoneal laparoscopic and extraperitoneal Senhance radical prostatectomy.

BACKGROUND: Senhance is novel robotic platform which can be used to perform radical prostatectomy (RP). We compare our results of robotic RP to similar patients operated with laparoscopic technique. PATIENTS AND METHODS: A prospective study of 61 patients operated laparoscopically and 107 patients operated using the Senhance robotic system. We have analysed operative and postoperative results in both groups. RESULTS: There was no difference in the operative time, estimated blood loss, positive surgical margins, length of hospitalisation and catheterisation. There were 4 (6.5%) Clavien-Dindo grade I complications, and 5 (8.1%) late complications in laparoscopy. There were 6 (5.6%) Clavien-Dindo grade I, 3 (2.8%) grade II, 1 (0.9%) grade IV complications and 2 (1.9%) late complications in robotic group. CONCLUSION: Senhance robot-assisted RP is safe, feasible and offers good and comparable functional and oncological outcomes to laparoscopy. The transition to robotic surgery with a relatively fast learning curve can be done effectively for surgeons with previous laparoscopic experience.

Advanced mesoporous silica nanocarriers in cancer theranostics and gene editing applications.

Targeted nanomaterials for cancer theranostics have been the subject of an expanding volume of research studies in recent years. Mesoporous silica nanoparticles (MSNs) are particularly attractive for such applications due to possibilities to synthesize nanoparticles (NPs) of different morphologies, pore diameters and pore arrangements, large surface areas and various options for surface functionalization. Functionalization of MSNs with different organic and inorganic molecules, polymers, surface-attachment of other NPs, loading and entrapping cargo molecules with on-desire release capabilities, lead to seemingly endless prospects for designing advanced nanoconstructs exerting multiple functions, such as simultaneous cancer-targeting, imaging and therapy. Describing composition and multifunctional capabilities of these advanced nanoassemblies for targeted therapy (passive, ligand-functionalized MSNs, stimuli-responsive therapy), including one or more modalities for imaging of tumors, is the subject of this review article, along with an overview of developments within a novel and attractive research trend, comprising the use of MSNs for CRISPR/Cas9 systems delivery and gene editing in cancer. Such advanced nanconstructs exhibit high potential for applications in image-guided therapies and the development of personalized cancer treatment.

pH-Responsive Release of Ruthenium Metallotherapeutics from Mesoporous Silica-Based Nanocarriers.

Ruthenium complexes are attracting interest in cancer treatment due to their potent cytotoxic activity. However, as their high toxicity may also affect healthy tissues, efficient and selective drug delivery systems to tumour tissues are needed. Our study focuses on the construction of such drug delivery systems for the delivery of cytotoxic Ru(II) complexes upon exposure to a weakly acidic environment of tumours. As nanocarriers, mesoporous silica nanoparticles (MSN) are utilized, whose surface is functionalized with two types of ligands, (2-thienylmethyl)hydrazine hydrochloride (H1) and (5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)hydrazine (H2), which were attached to MSN through a pH-responsive hydrazone linkage. Further coordination to ruthenium(II) center yielded two types of nanomaterials MSN-H1[Ru] and MSN-H2[Ru]. Spectrophotometric measurements of the drug release kinetics at different pH (5.0, 6.0 and 7.4) confirm the enhanced release of Ru(II) complexes at lower pH values, which is further supported by inductively coupled plasma optical emission spectrometry (ICP-OES) measurements. Furthermore, the cytotoxicity effect of the released metallotherapeutics is evaluated in vitro on metastatic B16F1 melanoma cells and enhanced cancer cell-killing efficacy is demonstrated upon exposure of the nanomaterials to weakly acidic conditions. The obtained results showcase the promising capabilities of the designed MSN nanocarriers for the pH-responsive delivery of metallotherapeutics and targeted treatment of cancer.

Cultivating Multidisciplinarity: Manufacturing and Sensing Challenges in Cultured Meat Production.

Meat cultivation via cellular agriculture holds great promise as a method for future food production. In theory, it is an ideal way of meat production, humane to the animals and sustainable for the environment, while keeping the same taste and nutritional values as traditional meat and having additional benefits such as controlled fat content and absence of antibiotics and hormones used in the traditional meat industry. However, in practice, there is still a number of challenges, such as those associated with the upscale of cultured meat (CM). CM food safety monitoring is a necessary factor when envisioning both the regulatory compliance and consumer acceptance. To achieve this, a multidisciplinary approach is necessary. This includes extensive development of the sensitive and specific analytical devices i.e., sensors to enable reliable food safety monitoring throughout the whole future food supply chain. In addition, advanced monitoring options can help in the further optimization of the meat cultivation which may reduce the currently still high costs of production. This review presents an overview of the sensor monitoring options for the most relevant parameters of importance for meat cultivation. Examples of the various types of sensors that can potentially be used in CM production are provided and the options for their integration into bioreactors, as well as suggestions on further improvements and more advanced integration approaches. In favor of the multidisciplinary approach, we also include an overview of the bioreactor types, scaffolding options as well as imaging techniques relevant for CM research. Furthermore, we briefly present the current status of the CM research and related regulation, societal aspects and challenges to its upscaling and commercialization.