The RECOURSE Study: Long-term Oncologic Outcomes Associated With Robotically Assisted Minimally Invasive Procedures for Endometrial, Cervical, Colorectal, Lung, or Prostate Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: To assess long-term outcomes with robotic versus laparoscopic/thoracoscopic and open surgery for colorectal, urologic, endometrial, cervical, and thoracic cancers. BACKGROUND: Minimally invasive surgery provides perioperative benefits and similar oncological outcomes compared with open surgery. Recent robotic surgery data have questioned long-term benefits. METHODS: A systematic review and meta-analysis of cancer outcomes based on surgical approach was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines using Pubmed, Scopus, and Embase. Hazard ratios for recurrence, disease-free survival (DFS), and overall survival (OS) were extracted/estimated using a hierarchical decision tree and pooled in RevMan 5.4 using inverse-variance fixed-effect (heterogeneity nonsignificant) or random effect models. RESULTS: Of 31,204 references, 199 were included (7 randomized, 23 database, 15 prospective, 154 retrospective studies)-157,876 robotic, 68,007 laparoscopic/thoracoscopic, and 234,649 open cases. Cervical cancer: OS and DFS were similar between robotic and laparoscopic [1.01 (0.56, 1.80), P =0.98] or open [1.18 (0.99, 1.41), P =0.06] surgery; 2 papers reported less recurrence with open surgery [2.30 (1.32, 4.01), P =0.003]. Endometrial cancer: the only significant result favored robotic over open surgery [OS; 0.77 (0.71, 0.83), P <0.001]. Lobectomy: DFS favored robotic over thoracoscopic surgery [0.74 (0.59, 0.93), P =0.009]; OS favored robotic over open surgery [0.93 (0.87, 1.00), P =0.04]. Prostatectomy: recurrence was less with robotic versus laparoscopic surgery [0.77 (0.68, 0.87), P <0.0001]; OS favored robotic over open surgery [0.78 (0.72, 0.85), P <0.0001]. Low-anterior resection: OS significantly favored robotic over laparoscopic [0.76 (0.63, 0.91), P =0.004] and open surgery [0.83 (0.74, 0.93), P =0.001]. CONCLUSIONS: Long-term outcomes were similar for robotic versus laparoscopic/thoracoscopic and open surgery, with no safety signal or indication requiring further research (PROSPERO Reg#CRD42021240519).

A Multidimensional Analysis of Prostate Surgery Costs in the United States: Robotic-Assisted versus Retropubic Radical Prostatectomy.

BACKGROUND: The economic value of robotic-assisted laparoscopic prostatectomy (RALP) in the United States is still not well understood because of limited view analyses. OBJECTIVES: The objective of this study was to examine the costs and benefits of RALP versus retropubic radical prostatectomy from an expanded view, including hospital, payer, and societal perspectives. METHODS: We performed a model-based cost comparison using clinical outcomes obtained from a systematic review of the published literature. Equipment costs were obtained from the manufacturer of the robotic system; other economic model parameters were obtained from government agencies, online resources, commercially available databases, an advisory expert panel, and the literature. Clinical point estimates and care pathways based on National Comprehensive Cancer Network guidelines were used to model costs out to 3 years. Hospital costs and costs incurred for the patients' postdischarge complications, adjuvant and salvage radiation treatment, incontinence and potency treatment, and lost wages during recovery were considered. Robotic system costs were modeled in two ways: as hospital overhead (hospital overhead calculation: RALP-H) and as a function of robotic case volume (robotic amortization calculation: RALP-R). All costs were adjusted to year 2014 US dollars. RESULTS: Because of more favorable clinical outcomes over 3 years, RALP provided hospital ($1094 savings with RALP-H, $341 deficit with RALP-R), payer ($1451), and societal ($1202) economic benefits relative to retropubic radical prostatectomy. CONCLUSIONS: Monte-Carlo probabilistic sensitivity analysis demonstrated a 38% to 99% probability that RALP provides cost savings (depending on the perspective). Higher surgical consumable costs are offset by a decreased hospital stay, lower complication rate, and faster return to work.

Robotic-assisted benign hysterectomy compared with laparoscopic, vaginal, and open surgery: a systematic review and meta-analysis.

The potential benefits and limitations of benign hysterectomy surgical approaches are still debated. We aimed at evaluating any differences with a systematic review and meta-analysis. PubMed, MEDLINE, and EMBASE databases were last searched on 6/2/2021 to identify English randomized controlled trials (RCTs), prospective cohort and retrospective independent database studies published between Jan 1, 2010 and Dec 31, 2020 reporting perioperative outcomes following robotic hysterectomy versus laparoscopic, open, or vaginal approach (PROSPERO #CRD42022352718). Twenty-four articles were included that reported on 110,306 robotic, 262,715 laparoscopic, 189,237 vaginal, and 554,407 open patients. The robotic approach was associated with a shorter hospital stay (p < 0.00001), less blood loss (p = 0.009), and fewer complications (OR: 0.42 [0.27, 0.66], p = 0.0001) when compared to the open approach. The main benefit compared to the laparoscopic and vaginal approaches was a shorter hospital (R/L WMD: - 0.144 [- 0.21, - 0.08], p < 0.0001; R/V WMD: - 0.39 [- 0.70, - 0.08], p = 0.01). Other benefits seen were sensitive to the inclusion of database studies. Study type differences in outcomes, a lack of RCTs for robotic vs. open comparisons, learning curve issues, and limited robotic vs. vaginal publications are limitations. While the robotic approach was mainly comparable to the laparoscopic approach, this meta-analysis confirms the classic benefits of minimally invasive surgery when comparing robotic hysterectomy to open surgery. We also reported the advantages of robotic surgery over vaginal surgery in a patient population with a higher incidence of large uterus and prior surgery.

Methodology to standardize heterogeneous statistical data presentations for combining time-to-event oncologic outcomes.

Survival analysis following oncological treatments require specific analysis techniques to account for data considerations, such as failure to observe the time of event, patient withdrawal, loss to follow-up, and differential follow up. These techniques can include Kaplan-Meier and Cox proportional hazard analyses. However, studies do not always report overall survival (OS), disease-free survival (DFS), or cancer recurrence using hazard ratios, making the synthesis of such oncologic outcomes difficult. We propose a hierarchical utilization of methods to extract or estimate the hazard ratio to standardize time-to-event outcomes so that study inclusion into meta-analyses can be maximized. We also provide proof-of concept results from a statistical analysis that compares OS, DFS, and cancer recurrence for robotic surgery to open and non-robotic minimally invasive surgery. In our example, use of the proposed methodology would allow for the increase in data inclusion from 108 hazard ratios reported to 240 hazard ratios reported or estimated, resulting in an increase of 122%. While there are publications summarizing the motivation for these analyses, and comprehensive papers describing strategies to obtain estimates from published time-dependent analyses, we are not aware of a manuscript that describes a prospective framework for an analysis of this scale focusing on the inclusion of a maximum number of publications reporting on long-term oncologic outcomes incorporating various presentations of statistical data.

A systematic review of robotic versus open and video assisted thoracoscopic surgery (VATS) approaches for thymectomy.

BACKGROUND: Median sternotomy has been the most commonly used approach for thymectomy to date. Recent advances in video-assisted thoracoscopic surgery (VATS) and robotic access with CO2 insufflation techniques have allowed more minimally invasive approaches. However, prior reviews have not compared robotic to both open and VATS thymectomy. METHODS: A systematic review was conducted in accordance with the PRISMA guidelines using PubMed, Embase and Scopus databases. Original research articles comparing robotic to VATS or to open thymectomy for myasthenia gravis, anterior mediastinal masses, or thymomas were included. Meta-analyses were performed for mortality, operative time, blood loss, transfusions, length of stay, conversion to open, intraoperative and postoperative complication rates, and positive/negative margin rates. RESULTS: Robotic thymectomy is a valid alternative to the open approach; advantages include: reduced blood loss [weighted mean difference (WMD): -173.03, 95% confidence interval (95% CI): -305.90, -40.17, P=0.01], fewer postoperative complications (odds ratio: 0.37, 95% CI: 0.22, 0.60, P<0.00001), a shorter hospital stay (WMD: -2.78, 95% CI: -3.22, -2.33, P<0.00001), and a lower positive margin rate (relative difference: -0.04, 95% CI: -0.07, -0.01, P=0.01), with comparable operative times (WMD: 6.73, 95% CI: -21.20, 34.66, P=0.64). Robotic thymectomy was comparable with the VATS approach; both have the advantage of avoiding median sternotomy. CONCLUSIONS: While randomized controlled studies are required to make definitive conclusions, current data suggests that robotic thymectomy is superior to open surgery and comparable to a VATS approach. Long-term follow-up is required to further delineate oncological outcomes.

A systematic review and meta-analysis of robotic versus open and video-assisted thoracoscopic surgery approaches for lobectomy.

OBJECTIVES: A number of meta-analytical and database studies have sought to compare open, video-assisted thoracoscopic surgery (VATS) and robotic operative approaches to lobectomy, often with conflicting results. Our objective was to perform a comprehensive review of these meta-analytical and database studies published to date. METHODS: A systematic review was conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines using the PubMed and Scopus databases. Primary outcome was short-term mortality, and secondary outcomes were operative time, blood loss or transfusion rate, hospital stay, conversions, lymph node yield and complications. Meta-analyses of the primary and secondary outcomes were performed. RESULTS: Robotic lobectomy is a valid alternative to the VATS approach and is superior to the open approach with respect to complications [OR 0.67, 95% CI 0.58-0.76, P < 0.00001] and duration of hospital stay (WMD -1.4, 95% CI -1.96-0.85, P < 0.00001). It is inferior to both VATS and open with respect to operative duration (robotic vs. VATS; WMD 4.98, 95% CI 2.61-7.36, P < 0.001, robotic vs. open WMD 65.56, 95% CI 53.66-77.46, P < 0.00001). Robotic approach is superior with respect to 30-day mortality compared to VATS (OR 0.61, 95% CI 0.45-0.83, P = 0.001 and open approaches (OR 0.53, 95% CI 0.33-0.85, P = 0.008). CONCLUSIONS: This is the largest published systematic review and meta-analysis to date qualifying the robotic lobectomy as a reasonable alternative to VATS and open surgery. Short-term survival is superior in the robotic cohorts. No definitive conclusions on long-term outcomes can be drawn until a randomized controlled trial comparing approaches is conducted.

A role for the prefrontal cortex in recall of recent and remote memories.

Declarative memories are thought to be initially stored in the hippocampus, and then transferred to the neocortex. This is a key feature of the standard model of consolidation and is supported by studies reporting a requirement for activity within the neocortex for recall of remote, but not recent, hippocampal-dependent memories. New evidence from our and other laboratories, however, suggests that, for trace fear conditioning, memories are stored in the rodent medial prefrontal cortex and in the hippocampus from the time of training. Consistent with this, we show that activity in the medial prefrontal cortex is necessary for retrieval of recent and remote memories, suggesting that information stored in this neocortical structure from the time of training is necessary for memory recall.

Plasticity in the entorhinal cortex suppresses memory for contextual fear.

Several studies have delineated a role for the hippocampus in fear conditioning. However, in this task, the role of the entorhinal cortex (EC), the main input-output structure for the hippocampus, is uncertain. The extracellular signal-regulated kinase (ERK) cascade has been shown to be a molecular correlate for long-term memory, and its activity is required for various types of memory storage, including fear memory. In this study, we show that ERK activity in the EC increased 90 min after fear conditioning. Post-training intra-EC infusion of ERK cascade inhibitors (PD098059, UO126) at 40 min, but not at 10 min, resulted in increased freezing to the context, but not to the tone, during a 48 hr retention test. Interestingly, both PD098059- and UO126-infused animals also demonstrated anticipatory freezing in the context, freezing maximally at the time the shock was given during training. This anticipatory behavior was also seen in naive animals receiving additional training. Together, these results suggest that ERK-mediated plasticity in the EC normally suppresses context-specific fear memory, especially the temporal nature of the freezing response, and that blocking this plasticity mimics the effects of additional training.

Nonredundant roles for hippocampal and entorhinal cortical plasticity in spatial memory storage.

Recently, it has been demonstrated that targeted blockade of the extracellular signal-regulated kinase (ERK) cascade in either the entorhinal cortex (EC) or hippocampus (HIP) results in spatial memory deficits. However, it is unclear if ERK-mediated plasticity in these structures has redundant functions or unique roles. In this report, we contrast the role of long-term plasticity in these two structures with side-by-side comparisons of the effects of PD098059 infusion following water maze training. Analysis of performance during the long-term retention test indicates a role for plasticity in the EC in storing broad location information. In contrast, blocking plasticity in the HIP resulted in deficits in indices of precise location information and goal-directed navigational error. To distinguish between a navigational and location deficit, a "two-room" experimental design was employed. Training in the first room allowed animals to consolidate information regarding navigational strategies prior to training and drug infusion in the second room. Hippocampal-PD098059-infused animals demonstrated behavior suggestive of an expanded representation of the platform location and, thus, a loss of precise location information, suggesting that plasticity in these structures is involved in nonredundant, but complementary, processes necessary for spatial memory.

Comparative analysis of vaginal versus robotic-assisted hysterectomy for benign indications.

We aimed to compare perioperative outcomes of robotic-assisted hysterectomy versus vaginal hysterectomy in patients with benign gynecologic conditions, using a retrospective chart review of 240 consecutive benign hysterectomies from May 2008 to April of 2010 performed by a single surgical team at the Eisenhower Medical Center. The analysis included an equal number of cases in each group: 120 robotic-assisted total laparoscopic hysterectomies and 120 total vaginal hysterectomies. Consecutive cases met the inclusion criteria of benign disease. There were no statistically significant differences related to age, body mass index, history of prior abdominal surgery, or uterine weight. Operative times in the robotic group were significantly longer by an average of 59 min (p < 0.001). Patients with robotic-assisted hysterectomy had clinically equivalent estimated blood loss (55.5 ml vs. 84.7 ml, p < 0.001) and the intraoperative complication rates were 1.7% vaginal versus 0% robotic (p = 0.156). There was one conversion in the vaginal group due to pelvic adhesions and no conversions in the robotic group. Length of hospital stay was 1 day for both groups. The perioperative complication rates were equivalent between groups (6.7 vs. 11.7%, p = 0.180), but there were more major complications in the vaginal group (0 vs. 3.3%, p = 0.044). We conclude that, in a comparable group of patients, robotic-assisted hysterectomy takes longer to complete but results in fewer major complications.

Single-site robotic cholecystectomy: efficiency and cost analysis.

BACKGROUND: Single-incision surgery has gained in popularity, and the recent development of specialized robotic and laparoscopic instruments may remove some of the ergonomic and technical difficulties associated with this approach. However, questions of cost and efficiency remain. METHODS: We prospectively collected perioperative outcome and efficiency (operative time, case volume) data for our single-site robotic cholecystectomy cases and retrospectively reviewed data for our single-incision laparoscopic cholecystectomy cases. RESULTS: There were no differences in patient characteristics or perioperative outcomes between the robotic (n = 20) and laparoscopic (n = 10) groups; operative times were equivalent (84.6 vs 85.5 min; p = 0.8737) and blood loss and complications were minimal. There was a higher robotic case volume, with an average of two robotic cases (range 1-4)/day vs one/day for laparoscopic cases (range 1-1; p = 0.0306). Streamlined instrument costs were essentially equivalent. CONCLUSIONS: Robotic single-site cholecystectomy is a safe, cost-effective alternative to single-incision laparoscopic cholecystectomy in a robot-existing model.

Positive surgical margin and perioperative complication rates of primary surgical treatments for prostate cancer: a systematic review and meta-analysis comparing retropubic, laparoscopic, and robotic prostatectomy.

CONTEXT: Radical prostatectomy (RP) approaches have rarely been compared adequately with regard to margin and perioperative complication rates. OBJECTIVE: Review the literature from 2002 to 2010 and compare margin and perioperative complication rates for open retropubic RP (ORP), laparoscopic RP (LRP), and robot-assisted LRP (RALP). EVIDENCE ACQUISITION: Summary data were abstracted from 400 original research articles representing 167,184 ORP, 57,303 LRP, and 62,389 RALP patients (total: 286,876). Articles were found through PubMed and Scopus searches and met a priori inclusion criteria (eg, surgery after 1990, reporting margin rates and/or perioperative complications, study size>25 cases). The primary outcomes were positive surgical margin (PSM) rates, as well as total intra- and perioperative complication rates. Secondary outcomes included blood loss, transfusions, conversions, length of hospital stay, and rates for specific individual complications. Weighted averages were compared for each outcome using propensity adjustment. EVIDENCE SYNTHESIS: After propensity adjustment, the LRP group had higher positive surgical margin rates than the RALP group but similar rates to the ORP group. LRP and RALP showed significantly lower blood loss and transfusions, and a shorter length of hospital stay than the ORP group. Total perioperative complication rates were higher for ORP and LRP than for RALP. Total intraoperative complication rates were low for all modalities but lowest for RALP. Rates for readmission, reoperation, nerve, ureteral, and rectal injury, deep vein thrombosis, pneumonia, hematoma, lymphocele, anastomotic leak, fistula, and wound infection showed significant differences between groups, generally favoring RALP. The lack of randomized controlled trials, use of margin status as an indicator of oncologic control, and inability to perform cost comparisons are limitations of this study. CONCLUSIONS: This meta-analysis demonstrates that RALP is at least equivalent to ORP or LRP in terms of margin rates and suggests that RALP provides certain advantages, especially regarding decreased adverse events.

Mid-term biochemical recurrence-free outcomes following robotic versus laparoscopic radical prostatectomy.

We compared 5-year biochemical recurrence (BCR)-free rates for robotic-assisted laparoscopic prostatectomy (RALP) and laparoscopic radical prostatectomy (LRP). Three hundred and twelve consecutive patients who underwent RALP from 2003 to 2008 were compared to 97 consecutive LRP patients from 1999 to 2004. All laparoscopic surgeries were performed by one surgeon and robotic surgeries were performed by this surgeon or a laparoscopically naïve surgeon. Both groups were evaluated for perioperative outcome, pathologic status, and mid-term oncologic outcomes (5-year BCR-free rates at prostate-specific antigen [PSA] cutoffs of <0.4, <0.2, or <0.1 ng/ml). Baseline characteristics were equivalent except for age (61.9 years vs. 65.1 years, P < 0.0001). RALP operating time was shorter (215.5 min vs. 305.3, P < 0.0001), and resulted in fewer complications (3.8% vs. 10.3%, P = 0.0214) and blood transfusions (2.9% vs. 13.4%, P = 0.0003). Positive surgical margins were equivalent (pT2 20.9% vs. 28.8%, P = 0.1818). Overall 5-year BCR-free rates were comparable for RALP (97.6, 93.4, and 85.1%) and LRP (97.7, 89.7, and 79.7%) at PSA cutoff levels of <0.4, <0.2, and <0.1 ng/ml, respectively. There was a significant difference in BCR-free rates between the RALP and LRP groups for patients with organ-confined (pT2) disease at 0.2 ng/ml (96.4% vs. 88.7%, P = 0.0373) and 0.1 ng/ml (91.0% vs. 83.0%, P = 0.0470). We report lower morbidity, comparable pathologic outcome and improved mid-term oncologic results in patients with organ-confined disease after RALP in comparison to LRP.

Extracellular signal-regulated kinase activity in the entorhinal cortex is necessary for long-term spatial memory.

Lesion studies have provided evidence that the entorhinal cortex (EC) participates in spatial memory. However, the molecular cascades that underlie memory-associated changes in the EC and its specific role in spatial memory, however, have not been clearly delineated. Recently, it has been shown that activation of extracellular signal-regulated kinase (Erk, a mitogen-activated protein kinase family member) in the dorsal hippocampus is necessary for spatial memory. To examine whether similar mechanisms are used for spatial memory storage in the EC, Erk activity was inhibited after training in the Morris water maze. Bilateral infusion of the mitogen-activated protein kinase kinase inhibitor PD098059 into the EC immediately after training resulted in a memory deficit observed during a retention test performed 48 h later. This deficit was abolished with pretraining in a different water maze in which animals were able to learn the general task requirements and the appropriate search strategies. The absence of a deficit indicates that Erk activity in the EC may be involved in storing the task requirements or the search strategies. The findings presented in this article are consistent with the idea that the EC is involved in spatial memory and indicate that Erk activity is necessary for memory consolidation in this structure.

A unified theory for systems and cellular memory consolidation.

The time-limited role of the hippocampus for explicit memory storage has been referred to as systems consolidation where learning-related changes occur first in the hippocampus followed by the gradual development of a more distributed memory trace in the neocortex. Recent experiments are beginning to show that learning induces plasticity-related molecular changes in the neocortex as well as in the hippocampus and with a similar time course. Present memory consolidation theories do not account for these findings. In this report, we present a theory (the C theory) that incorporates these new findings, provides an explanation for the length of time for hippocampal dependency, and that can account for the apparent longer consolidation periods in species with larger brains. This theory proposes that a process of cellular consolidation occurs in the hippocampus and in areas of the neocortex during and shortly after learning resulting in long-term memory storage in both areas. For a limited time, the hippocampus is necessary for memory retrieval, a process involving the coordinated reactivation of these areas. This reactivation is later mediated by longer extrahippocampal connectivity between areas. The delay in hippocampal-independent memory retrieval is the time it takes for gene products in these longer extrahippocampal projections to be transported from the soma to tagged synapses by slow axonal transport. This cellular transport event defines the period of hippocampal dependency and, thus, the duration of memory consolidation. The theoretical description for memory consolidation presented in this review provides alternative explanations for several experimental observations and presents a unification of the concepts of systems and cellular memory consolidation.