Evaluation of new motorized articulating laparoscopic instruments by laparoscopic novices using a standardized laparoscopic skills curriculum.

BACKGROUND: Motorized articulating laparoscopic instruments (ALI) offer more degrees of freedom than conventional laparoscopic instruments (CLI). However, a difficult learning curve and complex instrument handling are still a problem of ALI. We compared the performance of new prototypes of motorized ALI with CLI in a series of standardized laparoscopic tasks performed by laparoscopic novices. Further, usability of the new ALI was assessed. METHODS: A randomized cross-over study with 50 laparoscopic novices who either started with CLI and then changed to ALI (CA) or vice versa (AC) was conducted. All participants performed the European training in basic laparoscopic urological skills (E-BLUS) with each instrument in given order. Time and errors were measured for each exercise. Instrument usability was assessed. RESULTS: Overall, using CLI was significantly faster (CLI 4:27 min vs. ALI 4:50 min; p-value 0.005) and associated with fewer exercise failures in needle guidance (CLI 0 vs. ALI 12; p-value 0.0005) than ALI. Median amount of errors was similar for both instruments. Instrument sequence did not matter, as CA and AC showed comparable completion times. Regarding the learning effect, participants were significantly faster in the second attempt of exercises than in the first. In the needle guidance task, participants using CLI last demonstrated a significant speed improvement, whereas ALI were significantly slower in the second run. Regarding usability, CLI were preferred over ALI due to lighter weight and easier handling. Nevertheless, participants valued ALI's additional degrees of freedom. CONCLUSION: Using new motorized ALI in the E-BLUS examination by laparoscopic novices led to a worse performance compared to CLI. An explanation could be that participants felt overwhelmed by ALI and that ALI have an own distinct learning curve. As participants valued ALI's additional degrees of freedom, however, a future application of ALI could be for training purposes, ideally in combination with CLI.

Retzius-sparing robot-assisted laparoscopic radical prostatectomy: functional and early oncologic results in aggressive and locally advanced prostate cancer.

BACKGROUND: Retzius-sparing robot-assisted laparoscopic radical prostatectomy (rsRARP) allows entire prostatectomy procedure via the pouch of Douglas. In low- and intermediate-risk prostate cancer (PCa) there is level 1 evidence that the Retzius-sparing approach impacts early continence recovery. Since specific data on aggressive and locally advanced cancer is lacking and avoiding rsRARP is presently suggested, we investigated urinary and sexual recovery, perioperative complications and early oncologic outcomes after rsRARP in this particular cohort. METHODS: Prospectively collected data of 50 consecutive men (median age 66 years) with high-risk PCa who underwent rsRARP in a single institution was analysed retrospectively. The follow-up for all patients was 12 months after surgery. RESULTS: 3 vs. 12 months after surgery, 82% vs. 98% of men used no pad or one safety pad and 50% vs. 72% used no pad. 89% of patients did not observe a decline of continence if postoperative radiotherapy was carried out. Considering the 17 preoperatively potent patients who underwent bi- or unilateral nerve-sparing surgery, 41% reported their first sexual intercourse within 1 year after rsRARP. 84% of patients had ≥pT3a disease and 42% positive surgical margins. A lymphadenectomy was done in 94% of patients with a median lymph node removal of 15 and lymph node metastasis in 13%. 34% underwent adjuvant radiotherapy and 22% adjuvant androgen deprivation therapy (ADT). 1-year recurrence-free survival was 96%, including 25% of patients on adjuvant or salvage ADT. CONCLUSIONS: RsRARP in high-risk PCa is feasible and results in excellent continence rates, even after postoperative radiotherapy. The potency rates are promising but need further clarification in larger cohorts. Reliable oncologic outcomes require longterm follow-up and are awaited.

Catching moving targets: cancer stem cell hierarchies, therapy-resistance & considerations for clinical intervention.

It is widely believed that targeting the tumour-initiating cancer stem cell (CSC) component of malignancy has great therapeutic potential, particularly in therapy-resistant disease. However, despite concerted efforts, CSC-targeting strategies have not been efficiently translated to the clinic. This is partly due to our incomplete understanding of the mechanisms underlying CSC therapy-resistance. In particular, the relationship between therapy-resistance and the organisation of CSCs as Stem-Progenitor-Differentiated cell hierarchies has not been widely studied. In this review we argue that modern clinical strategies should appreciate that the CSC hierarchy is a dynamic target that contains sensitive and resistant components and expresses a collection of therapy-resisting mechanisms. We propose that the CSC hierarchy at primary presentation changes in response to clinical intervention, resulting in a recurrent malignancy that should be targeted differently. As such, addressing the hierarchical organisation of CSCs into our bench-side theory should expedite translation of CSC-targeting to bed-side practice. In conclusion, we discuss strategies through which we can catch these moving clinical targets to specifically compromise therapy-resistant disease.

TOP: Prospective Evaluation of a Volume Based, Computer Assisted Method for Transperineal Optimized Prostate Biopsy.

OBJECTIVE: This study is a prospective evaluation of a volume-based, computer-assisted method for transperineal optimized prostate (TOP) biopsy. The TOP algorithm automates core planning for systematic prostate biopsies using the 3-dimensional organ contour and an alterable volume for tumors to be excluded. SUBJECTS AND METHODS: MRI-transrectal ultrasound fusion biopsy with MRI-targeted biopsies (TBs) and systematic-TOP biopsies were performed on 172 men between October 2013 and March 2014. Systematic biopsies were placed according to TOP for detection of tumor volumes >0.5 mL with a minimum of 80% organ coverage in prostates up to 50 mL (70% in larger organs). RESULTS: Median 24 TOP cores and 3 MRI-TBs have been placed. Prostate cancer (PCa) was detected in 112 of 172 (65%) of men; TOP detected 109 (97%) and TB 62 (55%). Significant cancer (Gleason score ≥7) was detected in 75 (44%) of men and of these TOP detected 73 of 75 (97%) and TB 51 of 75 (68%). Overall, systematic-TOP sampling significantly outperformed TB for the detection of both, all PCa as well as significant PCa (p < 0.0001, p = 0.0005). CONCLUSION: The TOP method is innovative by integrating the individual prostate volume and PCa volume detection thresholds. In the present cohort, it diagnosed more significant tumors than TB alone. However, at the same time, more low-risk tumors are detected.

Developing ovarian cancer stem cell models: laying the pipeline from discovery to clinical intervention.

Despite decades of research, ovarian cancer is still associated with unacceptably high mortality rates, which must be addressed by novel therapeutic approaches. One avenue through which this may be achieved is targeting of tumor-initiating 'Cancer Stem Cells' (CSCs). CSCs are sufficient to generate primary and recurrent disease through extensive rounds of asymmetric division, which maintain the CSC pool while producing the tissues that form the bulk of the tumor. CSCs thrive in the harsh tumor niche, are generally refractory to therapeutic intervention and closely-linked to the Epithelial-Mesenchymal Transition process, which facilitates invasion and metastasis. While it is well-accepted that CSC-targeting must be assessed as a novel therapeutic avenue, few ovarian CSC models have been developed due to perceived and actual difficulties associated with the process of 'CSC Discovery'. In this article we review contemporary approaches to CSC Discovery and argue that this process should start with an understanding of the specific challenges associated with clinical intervention, laying the pipeline backwards towards CSC Discovery. Such an approach would expedite the bridging of the gap between laboratory isolation and clinical targeting of ovarian CSCs.

A Platform and Multisided Market for Translational, Software-Defined Medical Procedures in the Operating Room (OP 4.1): Proof-of-Concept Study.

BACKGROUND: Although digital and data-based technologies are widespread in various industries in the context of Industry 4.0, the use of smart connected devices in health care is still in its infancy. Innovative solutions for the medical environment are affected by difficult access to medical device data and high barriers to market entry because of proprietary systems. OBJECTIVE: In the proof-of-concept project OP 4.1, we show the business viability of connecting and augmenting medical devices and data through software add-ons by giving companies a technical and commercial platform for the development, implementation, distribution, and billing of innovative software solutions. METHODS: The creation of a central platform prototype requires the collaboration of several independent market contenders, including medical users, software developers, medical device manufacturers, and platform providers. A dedicated consortium of clinical and scientific partners as well as industry partners was set up. RESULTS: We demonstrate the successful development of the prototype of a user-centric, open, and extensible platform for the intelligent support of processes starting with the operating room. By connecting heterogeneous data sources and medical devices from different manufacturers and making them accessible for software developers and medical users, the cloud-based platform OP 4.1 enables the augmentation of medical devices and procedures through software-based solutions. The platform also allows for the demand-oriented billing of apps and medical devices, thus permitting software-based solutions to fast-track their economic development and become commercially successful. CONCLUSIONS: The technology and business platform OP 4.1 creates a multisided market for the successful development, implementation, distribution, and billing of new software solutions in the operating room and in the health care sector in general. Consequently, software-based medical innovation can be translated into clinical routine quickly, efficiently, and cost-effectively, optimizing the treatment of patients through smartly assisted procedures.

Mutations in TP53 or DNA damage repair genes define poor prognostic subgroups in primary prostate cancer.

BACKGROUND: Mutations in DNA damage repair genes, in particular genes involved in homology-directed repair, define a subgroup of men with prostate cancer with a more unfavorable prognosis but a therapeutic vulnerability to PARP inhibition. In current practice, mutational testing of prostate cancer patients is commonly done late i.e., when the tumor is castration resistant. In addition, most sequencing panels do not include TP53, one of the most crucial tumor suppressor genes in human cancer. In this proof-of-concept study, we sought to extend the clinical use of these molecular markers by exploring the early prognostic impact of mutations in TP53 and DNA damage repair genes in men with primary, nonmetastatic prostate cancer undergoing radical prostatectomy (RPX). METHODS: Tumor specimens from a cohort of 68 RPX patients with intermediate (n = 11, 16.2%) or high-risk (n = 57, 83.8%) disease were analyzed by targeted next generation sequencing using a 37 DNA damage repair and checkpoint gene panel including TP53. Sequencing results were correlated to clinicopathologic variables as well as PSA persistence or time to PSA failure. In addition, the distribution of TP53 and DNA damage repair gene mutations was analyzed in three large publicly available datasets (TCGA, MSKCC and SU2C). RESULTS: Of 68 primary prostate cancers analyzed, 23 (33.8%) were found to harbor a mutation in either TP53 (n = 12, 17.6%) or a DNA damage repair gene (n = 11, 16.2%). The vast majority of these mutations (22 of 23, 95.7%) were detected in primary tumors from patients with high-risk features. These mutations were mutually exclusive in our cohort and additional data mining suggests an enrichment of DNA damage repair gene mutations in TP53 wild-type tumors. Mutations in either TP53 or a DNA damage repair gene were associated with a significantly worse prognosis after RPX. Importantly, the presence of TP53/DNA damage repair gene mutations was an independent risk factor for PSA failure or PSA persistence in multivariate Cox regression models. CONCLUSION: TP53 or DNA damage repair gene mutations are frequently detected in primary prostate cancer with high-risk features and define a subgroup of patients with an increased risk for PSA failure or persistence after RPX. The significant adverse impact of these alterations on patient prognosis may be exploited to identify men with prostate cancer who may benefit from a more intensified treatment.

Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial.

PURPOSE: Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months). PATIENTS AND METHODS: Patients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan-Meier methods. RESULTS: The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61-0.96]. Kaplan-Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug-drug interactions were observed between ribociclib and either NSAI. CONCLUSIONS: Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2- ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).

MicroRNA expression profiling and biomarker validation in treatment-naïve and drug resistant non-small cell lung cancer.

BACKGROUND: In the absence of targetable mutations or immune checkpoints, cisplatin-doublet chemotherapy remains the standard of care in non-small cell lung cancer (NSCLC). Drug resistance has however become a significant clinical challenge. Exploring a role for small non-coding microRNAs (miRNA) as biomarker candidates in cisplatin resistant (CisR) lung cancer is lacking and warrants further investigation. METHODS: miRNA expression profiling was assessed in a panel of cisplatin sensitive and resistant NSCLC cell lines and validated by qPCR. Modulation of altered miRNAs was studied using antagomiRs and pre-miRs while functional assays were used to assess cisplatin response. The translational relevance of these miRNAs as potential biomarkers was assessed in serum and matched normal and tumour lung tissues from chemo-naïve NSCLC patients, in addition to xenograft formalin-fixed paraffin-embedded (FFPE) tumours derived from cisplatin sensitive and resistant cell lines. RESULTS: Differential expression of a 5-miR signature (miR-30a-3p, miR-30b-5p, miR-30c-5p, miR-34a-5p, miR-4286) demonstrated their ability to distinguish between normal and tumour lung tissue and between NSCLC histologies. In squamous cell carcinoma (SqCC), tissue miRNA expression was associated with poor survival. miR-4286 showed promise as a blood-based diagnostic biomarker that could distinguish between adenocarcinoma and SqCC histologies. In a xenograft model of cisplatin resistance, using 7-9 week old female NOD/SCID mice (NOD.CB17-Prkdcscid/NCrCrl), a 5-miRNA panel showed altered expression between sensitive and resistant tumours. CONCLUSIONS: This study identified a panel of miRNAs which may have diagnostic and prognostic potential as novel biomarkers in lung cancer and furthermore, may have a predictive role in monitoring the emergence of resistance to cisplatin.

Standardized Magnetic Resonance Imaging Reporting Using the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation Criteria and Magnetic Resonance Imaging/Transrectal Ultrasound Fusion with Transperineal Saturation Biopsy to Select Men on Active Surveillance.

BACKGROUND: Contemporary selection criteria for men with prostate cancer (PC) suitable for active surveillance (AS) are unsatisfactory, leading to high disqualification rates based on tumor misclassification. Conventional biopsy protocols are based on standard 12-core transrectal ultrasound (TRUS) biopsy. OBJECTIVE: To assess the value of magnetic resonance imaging (MRI)/TRUS fusion biopsy over 4-yr follow-up in men on AS for low-risk PC. DESIGN, SETTING, AND PARTICIPANTS: Between 2010 and 2018, a total of 273 men were included. Of them, 157 men with initial 12-core TRUS biopsy and 116 with initial MRI/TRUS fusion biopsy were followed by systematic and targeted transperineal MRI/TRUS fusion biopsies based on Prostate Cancer Research International Active Surveillance criteria. MRI from follow-up MRI/TRUS fusion biopsy was assessed using the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) scoring system. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: AS-disqualification rates for patients on AS initially diagnosed by either 12-core TRUS biopsy or by MRI/TRUS fusion biopsy were compared using Kaplan-Meier estimates, log-rank tests, and regression analyses. We also analyzed the influence of negative primary MRI and PRECISE scoring to predict AS disqualification using Kaplan-Meier estimates, log-rank tests, and receiver operating characteristic (ROC) curve analysis. RESULTS AND LIMITATIONS: Of men diagnosed by 12-core TRUS biopsy, 59% were disqualified from AS based on the results of subsequent MRI/TRUS fusion biopsy. In the initial MRI fusion biopsy cohort, upgrading occurred significantly less frequently (19%, p<0.001). ROC curve analyses demonstrated good discrimination for the PRECISE score with an area under the curve of 0.83. No men with a PRECISE score of 1 or 2 (demonstrating absence or downgrading of lesions in follow-up MRI) were disqualified from AS. In our cohort, a negative baseline MRI scan was not a predictor of nondisqualification from AS. Limitations include transperineal approach and extended systematic biopsies used with MRI/TRUS fusion biopsy, which may not be representative of other centers. CONCLUSIONS: MRI/TRUS fusion biopsies allow a reliable risk classification for patients who are candidates for AS. The application of the PRECISE scoring system demonstrated good discrimination. PATIENT SUMMARY: In this study, we investigated the value of multiparametric magnetic resonance imaging (MRI) and MRI/transrectal ultrasound (TRUS) fusion biopsies for the assessment of active surveillance (AS) reliability using the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation criteria. Standard TRUS biopsies lead to significant underestimation of prostate cancer. In contrast, MRI/TRUS fusion biopsies allowed for a more reliable risk classification. For appropriate inclusion into AS, men should receive either an initial or a confirmatory MRI/TRUS fusion biopsy.