Initial clinical outcomes of robotic resection for perihilar cholangiocarcinoma: Is it safe and effective?

BACKGROUND AND OBJECTIVES: We aimed to describe our outcomes of robotic resection for perihilar cholangiocarcinoma, the largest single institutional series in the Western hemisphere to date. METHODS: Between 2016 and 2022, we prospectively followed all patients who underwent robotic resection for perihilar cholangiocarcinoma. RESULTS: In total, 23 patients underwent robotic resection for perihilar cholangiocarcinoma, 18 receiving concomitant hepatectomy. The median age was 73 years. Operative time was 470 min with an estimated blood loss of 150 mL. No intraoperative conversions to open or other intraoperative complications occurred. Median length of stay was 5 days. Four postoperative complications occurred. Three readmissions occurred within 30 days with one 90-day mortality. R0 resection was achieved in 87% of patients and R1 in 13% of patients. At a median follow-up of 27 months, 15 patients were alive without evidence of disease, two patients with local recurrence at 1 year, and six were deceased. CONCLUSIONS: Utilization of the robotic platform for perihilar cholangiocarcinoma is safe and feasible with excellent perioperative outcomes. Further studies are needed to determine the long-term oncological outcomes.

Publication Bias in Upper Gastrointestinal Oncology Clinical Trials.

PURPOSE: Evidence-based medicine requires evaluation of the medical literature to guide clinical reasoning and treatment recommendations. The presence of publication bias towards exclusion of non-statistically significant clinical trials may be leading to an incomplete evaluation of the literature and cause potentially incomplete guidance for patients. We aimed to compare publication rates and impact of publications of positive and negative outcome clinical trials. METHODS: We queried the US National Library of Medicine Clinical Trials database identifying clinical trials with reported results on the topics of pancreatic, liver, and gastric cancer. A "positive" trial was defined as having a statistically significant difference between the treatment arms, while a "negative" did not. Data collected included termination cause, intervention, funding type, publication rates, and journal characteristics. RESULTS: In total, 535 clinical trials were examined, across all pathologies clinical trials with significant findings for the primary outcome were published at a higher rate (99%) compared to those with non-significant findings (77%) (p < 0.01). Significantly, more studies with significant findings reached at least 80% of their estimated enrollment goal versus non-significant studies, 72% and 53% respectively (p < 0.01). Three of four metrics for impact of publication showed no difference between significant and non-significant studies once they reached publication. CONCLUSION: These findings suggest that clinical trials of three of the most common upper gastrointestinal malignancies have a publication bias towards studies with significant primary outcome findings. This study has implications to the way evidence-based medicine is practiced as the medical literature appears to be failing to capture important data for consideration of clinical decision making.

Clinical Outcomes of Robotic Resection for Perihilar Cholangiocarcinoma: A First, Multicenter, Trans-Atlantic, Expert-Center, Collaborative Study.

INTRODUCTION: Perihilar cholangiocarcinoma is a difficult cancer to treat with frequent vascular invasion, local recurrence, and poor survival. Due to the need for biliary anastomosis and potential vascular resection, the standard approach is an open operation. Suboptimal outcomes after laparoscopic resection had been sporadically reported by high-volume centers. In this first, Trans-Atlantic, multicenter study, we report our outcomes of robotic resection for perihilar cholangiocarcinoma. This is the largest study of its kind in the Western hemisphere. METHODS: Between 2016 and 2023, we prospectively followed patients undergoing robotic resection for perihilar cholangiocarcinoma at three, high-volume, robotic, liver-surgery centers. RESULTS: Thirty-eight patients underwent perihilar cholangiocarcinoma utilizing the robotic technique; Klatskin type-3 was the most common. The median age was 72 years, and 82% of the patients underwent preoperative biliary drainage. Median operative time was 481 minutes with a median estimated blood loss of 200 mL. The number of harvested lymph nodes was seven, and 11 (28%) patients yielded positive lymph nodes. Three patients required vascular reconstruction; 18% of patients had >1 biliary anastomosis. R0 resection margins were achieved in 82% of patients. Clavien-Dindo Grade ≥3 complications were seen in 16% of patients. The length of stay was 6 days. Five patients had an unplanned readmission within 30 days. One patient died within 30 days. With a median follow-up of 15 months, 68% of patients are alive without disease, 13% recurred, and 19% died. CONCLUSIONS: Application of the robotic platform for perihilar cholangiocarcinoma is safe and feasible with acceptable short-term clinical and oncological outcomes.

The effect of diabetes on major robotic hepatectomy.

Studies regarding the influence of diabetes on perioperative outcomes after major hepatectomy are conflicting. The objective of this study is to analyze the effects of diabetes on patients undergoing robotic major hepatectomy. With Institutional Review Board (IRB) approval, 94 patients undergoing major hepatectomy were prospectively followed. Demographic data and postoperative outcomes were analyzed and compared between diabetic and non-diabetic patients. Data were presented as median (mean ± SD). Patients were of age 62 (61 ± 13.0) years, BMI of 29 (29 ± 5.9) kg/m2, and ASA class of 3 (3 ± 0.55). The mass size was 5 (5 ± 3.0) cm. Operative duration was 252 (277 ± 106.6) min with estimated blood loss (EBL) was 175 (249 ± 275.9) mL. One operation was converted to 'open' due to bleeding, accounting for one intraoperative complication. Postoperatively, nine patients required ICU admission, with a duration of 1 (4 ± 5.9) day. Seven patients had postoperative complications. Length of stay (LOS) was 4 (4 ± 2.6) days. Fourteen patients were readmitted within 30 days. There were no deaths in-hospital or within 30 days. Of the 94 patients, 22 were diabetic and 72 were nondiabetic. Diabetic patients were older (70 (69 ± 11.3) years versus 58 (58 ± 12.4) years (p = 0.004)). Intraoperatively, operative duration, EBL, and complications were not significantly different. Postoperatively, LOS, ICU admission, ICU duration, complications, in-hospital mortality, readmission in 30 days, and death after 30 days showed no significant difference between diabetics and nondiabetics. In our experience, diabetes has no significant effect on perioperative outcomes after a robotic major hepatectomy.

Robotic Major Hepatectomy: An Institutional Experience and Clinical Outcomes.

INTRODUCTION: Most of the literature has only reported outcomes on robotic minor non-anatomical hepatectomy. This study was undertaken to analyze and examine the safety, feasibly, and perioperative outcomes of robotic major hepatectomy at our institution. METHODS: All patients undergoing robotic major hepatectomy were prospectively followed. Major hepatectomy was defined as a resection of 3 or more segments. Data are expressed as median (mean ± SD). RESULTS: A total of 170 consecutive patients underwent robotic hepatectomies, of which 100 were major resections involving at least 3 segments. The 100 patients were of median 62 (61 ± 13.0) years, and 46% were women. Median BMI was 29 (29 ± 5.9) kg/m2 and median ASA class was 3 (3 ± 0.5). Thirty percent of robotic major hepatectomies were for hepatocellular carcinoma, 28% were for metastatic adenocarcinoma, 9% were for cholangiocarcinoma, and 5% were for metastatic neuroendocrine tumor. Prep time (in the room until incision) was a median 58 min (62 ± 18.4), extraction time (incision until specimen extraction) was 124 min (146 ± 99.5), console time was 198 min (210 ± 123.9), closure time (extraction until dressing placement) was 109 min (131 ± 93.8), operative duration was 246 min (269 ± 123.2), and time under anesthesia was 330 min (353 ± 109.6). Estimated blood loss was 175 ml (249 ± 275.9) and length of stay was 4 days (5 ± 4.3). Seven patients experienced postoperative complications. Thirteen patients were readmitted within 30 days, and one patient died within 30 days. CONCLUSION: Application of the robotic platform to major hepatectomy is safe and feasible. Our early experience shows that this minimally invasive approach results in excellent short-term outcomes.

Translating intracarotid artery transplantation of bone marrow-derived NCS-01 cells for ischemic stroke: Behavioral and histological readouts and mechanistic insights into stem cell therapy.

The present study used in vitro and in vivo stroke models to demonstrate the safety, efficacy, and mechanism of action of adult human bone marrow-derived NCS-01 cells. Coculture with NCS-01 cells protected primary rat cortical cells or human neural progenitor cells from oxygen glucose deprivation. Adult rats that were subjected to middle cerebral artery occlusion, transiently or permanently, and subsequently received intracarotid artery or intravenous transplants of NCS-01 cells displayed dose-dependent improvements in motor and neurological behaviors, and reductions in infarct area and peri-infarct cell loss, much better than intravenous administration. The optimal dose was 7.5 × 106 cells/mL when delivered via the intracarotid artery within 3 days poststroke, although therapeutic effects persisted even when administered at 1 week after stroke. Compared with other mesenchymal stem cells, NCS-01 cells ameliorated both the structural and functional deficits after stroke through a broad therapeutic window. NCS-01 cells secreted therapeutic molecules, such as basic fibroblast growth factor and interleukin-6, but equally importantly we observed for the first time the formation of filopodia by NCS-01 cells under stroke conditions, characterized by cadherin-positive processes extending from the stem cells toward the ischemic cells. Collectively, the present efficacy readouts and the novel filopodia-mediated mechanism of action provide solid lab-to-clinic evidence supporting the use of NCS-01 cells for treatment of stroke in the clinical setting.

Hyperbaric oxygen therapy: A new look on treating stroke and traumatic brain injury.

Although hyperbaric oxygen therapy (HBOT) is common as a treatment for injuries, this study aimed to research the ability of HBOT in preconditioning to diminish any potential damage. The hypothesis stated that HBOT preconditioning alleviated the death of cells in primary rat neuronal cells (PRNCs) by transferring mitochondria from astrocytes. In this experiment, PRNCs were given an HBOT treatment before a tumor necrosis factor-alpha or lipopolysaccharide injury which resembled cell death associated with stroke and traumatic brain injury (TBI). After being examined, the study found more cell viability in the PRNCs that had received HBOT precondition and a mitochondrial transfer. The mitochondrial transfer was visualized by a series of images showing the transfer after the HBOT treatment. This study demonstrated the ability of HBOT preconditioning as a treatment for inflammation in stroke and TBI, with the transfer of mitochondria from astrocytes to PRNCs reducing cell death. Along with discussion of the study, this review also focuses on different stroke treatments in comparison with HBOT.

Prophylactic treatment of hyperbaric oxygen treatment mitigates inflammatory response via mitochondria transfer.

AIMS: Hyperbaric oxygen therapy (HBOT) has been widely used as postinjury treatment; however, we investigate its ability to mitigate potential damage as a preconditioning option. Here, we tested the hypothesis that HBOT preconditioning mitigates cell death in primary rat neuronal cells (PRNCs) through the transfer of mitochondria from astrocytes. METHODS: Primary rat neuronal cells were subjected to a 90-minute HBOT treatment at 2.5 absolute atmospheres prior to either tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) injury to simulate the inflammation-plagued secondary cell death associated with stroke and traumatic brain injury (TBI). After incubation with TNF-alpha or LPS, the cell viability of each group was examined. RESULTS: There was a significant increase of cell viability accompanied by mitochondrial transfer in the injury groups that received HBOT preconditioning compared to the injury alone groups (44 ± 5.2 vs 68 ± 4.48, n = 20, P < 0.05). The transfer of mitochondria directly after HBOT treatment was visualized by capturing images in 5-minute intervals, which revealed that the robust transfer of mitochondria begins soon after HBOT and persisted throughout the treatment. CONCLUSION: This study shows that HBOT preconditioning stands as a robust prophylactic treatment for sequestration of inflammation inherent in stroke and TBI, possibly facilitating the transfer of resilient mitochondria from astrocytes to inflammation-susceptible neuronal cells in mitigating cell death.

Human parthenogenetic neural stem cell grafts promote multiple regenerative processes in a traumatic brain injury model.

International Stem Cell Corporation human parthenogenetic neural stem cells (ISC-hpNSC) have potential therapeutic value for patients suffering from traumatic brain injury (TBI). Here, we demonstrate the behavioral and histological effects of transplanting ISC-hpNSC intracerebrally in an animal model of TBI. Methods: Sprague-Dawley rats underwent a moderate controlled cortical impact TBI surgery. Transplantation occurred at 72 h post-TBI with functional readouts of behavioral and histological deficits conducted during the subsequent 3-month period after TBI. We characterized locomotor, neurological, and cognitive performance at baseline (before TBI), then on days 0, 1, 7, 14, 30, 60, and 90 (locomotor and neurological), and on days 28-30, 58-60, and 88-90 (cognitive) after TBI. Following completion of behavioral testing at 3 months post-TBI, animals were euthanized by transcardial perfusion and brains harvested to histologically characterize the extent of brain damage. Neuronal survival was revealed by Nissl staining, and stem cell engraftment and host tissue repair mechanisms such as the anti-inflammatory response in peri-TBI lesion areas were examined by immunohistochemical analyses. Results: We observed that TBI groups given high and moderate doses of ISC-hpNSC had an improved swing bias on an elevated body swing test for motor function, increased scores on forelimb akinesia and paw grasp neurological tests, and committed significantly fewer errors on a radial arm water maze test for cognition. Furthermore, histological analyses indicated that high and moderate doses of stem cells increased the expression of phenotypic markers related to the neural lineage and myelination and decreased reactive gliosis and inflammation in the brain, increased neuronal survival in the peri-impact area of the cortex, and decreased inflammation in the spleen at 90 days post-TBI. Conclusion: These results provide evidence that high and moderate doses of ISC-hpNSC ameliorate TBI-associated histological alterations and motor, neurological, and cognitive deficits.

Central and Peripheral Secondary Cell Death Processes after Transient Global Ischemia in Nonhuman Primate Cerebellum and Heart.

Cerebral ischemia and its pathological sequelae are responsible for severe neurological deficits generally attributed to the neural death within the infarcted tissue and adjacent regions. Distal brain regions, and even peripheral organs, may be subject to more subtle consequences of the primary ischemic event which can initiate parallel disease processes and promote comorbid symptomology. In order to characterize the susceptibility of cerebellar brain regions and the heart to transient global ischemia (TGI) in nonhuman primates (NHP), brain and heart tissues were harvested 6 months post-TGI injury. Immunostaining analysis with unbiased stereology revealed significant cell death in lobule III and IX of the TGI cerebellum when compared to sham cerebellum, coinciding with an increase in inflammatory and apoptotic markers. Cardiac tissue analysis showed similar increases in inflammatory and apoptotic cells within TGI hearts. A progressive inflammatory response and cell death within the cerebellum and heart of chronic TGI NHPs indicate secondary injury processes manifesting both centrally and peripherally. This understanding of distal disease processes of cerebral ischemia underscores the importance of the chronic aberrant inflammatory response and emphasizes the needs for therapeutic options tailored to target these pathways. Here, we discuss the protocols for characterizing the histopathological effects of transient global ischemia in nonhuman primate cerebellum and heart, with an emphasis on the inflammatory and apoptotic cell death processes.

Histopathological and Behavioral Assessments of Aging Effects on Stem Cell Transplants in an Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) displays cognitive and motor symptoms following the initial injury which can be exacerbated by secondary cell death. Aging contributes significantly to the morbidity of TBI, with higher rates of negative neurological and behaviors outcomes. In the recent study, young and aged animals were injected intravenously with human adipose-derived mesenchymal stem cells (hADSCs) (Tx), conditioned media (CM), or vehicle (unconditioned media) following TBI. The beneficial effects of hADSCs were analyzed using various molecular and behavioral techniques. More specially, DiR-labeled hADSCs were used to observe the biodistribution of the transplanted cells. In addition, a battery of behavior tests was conducted to evaluate the neuromotor function for each treatment group and various regions of the brain were analyzed utilizing Nissl, hematoxylin and eosin (H&E), and human nuclei (HuNu) staining. Finally, flow cytometry was also performed to determine the levels of various proteins in the spleen. Here, we discuss the protocols for characterizing the histopathological and behavioral effects of transplanted stem cells in an animal model of TBI, with an emphasis on the role of aging in the therapeutic outcomes.

May the force be with you: Transfer of healthy mitochondria from stem cells to stroke cells.

Stroke is a major cause of death and disability in the United States and around the world with limited therapeutic option. Here, we discuss the critical role of mitochondria in stem cell-mediated rescue of stroke brain by highlighting the concept that deleting the mitochondria from stem cells abolishes the cells' regenerative potency. The application of innovative approaches entailing generation of mitochondria-voided stem cells as well as pharmacological inhibition of mitochondrial function may elucidate the mechanism underlying transfer of healthy mitochondria to ischemic cells, thereby providing key insights in the pathology and treatment of stroke and other brain disorders plagued with mitochondrial dysfunctions.

Mitochondrial targeting as a novel therapy for stroke.

Stroke is a main cause of mortality and morbidity worldwide. Despite the increasing development of innovative treatments for stroke, most are unsuccessful in clinical trials. In recent years, an encouraging strategy for stroke therapy has been identified in stem cells transplantation. In particular, grafting cells and their secretion products are leading with functional recovery in stroke patients by promoting the growth and function of the neurovascular unit - a communication framework between neurons, their supply microvessels along with glial cells - underlying stroke pathology and recovery. Mitochondrial dysfunction has been recently recognized as a hallmark in ischemia/reperfusion neural damage. Emerging evidence of mitochondria transfer from stem cells to ischemic-injured cells points to transfer of healthy mitochondria as a viable novel therapeutic strategy for ischemic diseases. Hence, a more in-depth understanding of the cellular and molecular mechanisms involved in mitochondrial impairment may lead to new tools for stroke treatment. In this review, we focus on the current evidence of mitochondrial dysfunction in stroke, investigating favorable approaches of healthy mitochondria transfer in ischemic neurons, and exploring the potential of mitochondria-based cellular therapy for clinical applications. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed.

A Dual Role for Hyperbaric Oxygen in Stroke Neuroprotection: Preconditioning of the Brain and Stem Cells.

Stroke continues to be an extremely prevalent disease and poses a great challenge in developing safe and effective therapeutic options. Hyperbaric oxygen therapy (HBOT) has demonstrated significant pre-clinical effectiveness for the treatment of acute ischemic stroke, and limited potential in treating chronic neurological deficits. Reported benefits include reductions in oxidative stress, inflammation, neural apoptosis, and improved physiological metrics such as edema and oxygen perfusion, all of which contribute to improved functional recovery. This pre-clinical evidence has failed to translate into an effective evidence-based therapy, however, due in large part to significant inconsistencies in treatment protocols and design of clinical studies. While the medical community works to standardize clinical protocols in an effort to advance HBOT for acute stroke, pre-clinical investigations continue to probe novel applications of HBOT in an effort to optimize stroke neuroprotection. One such promising strategy is HBOT preconditioning. Based upon the premise of mild oxidative stress priming the brain for tolerating the full-blown oxidative stress inherent in stroke, HBOT preconditioning has displayed extensive efficacy. Here, we first review the pre-clinical and clinical evidence supporting HBOT delivery following ischemic stroke and then discuss the scientific basis for HBOT preconditioning as a neuroprotective strategy. Finally, we propose the innovative concept of stem cell preconditioning, in tandem with brain preconditioning, as a promising regenerative pathway for maximizing the application of HBOT for ischemic stroke treatment.

An update on intracerebral stem cell grafts.

INTRODUCTION: Primary neurological disorders are notoriously debilitating and deadly, and over the past four decades stem cell therapy has emerged as a promising treatment. Translation of stem cell therapies from the bench to the clinic requires a better understanding of delivery protocols, safety profile, and efficacy in each disease. Areas covered: In this review, benefits and risks of intracerebral stem cell transplantation are presented for consideration. Milestone discoveries in stem cell applications are reviewed to examine the efficacy and safety of intracerebral stem cell transplant therapy for disorders of the central nervous system and inform design of translatable protocols for clinically feasible stem cell-based treatments. Expert commentary: Intracerebral administration, compared to peripheral delivery, is more invasive and carries the risk of open brain surgery. However, direct cell implantation bypasses the blood-brain barrier and reduces the first-pass effect, effectively increasing the therapeutic cell deposition at its intended site of action. These benefits must be weighed with the risk of graft-versus-host immune response. Rigorous clinical trials are underway to assess the safety and efficacy of intracerebral transplants, and if successful will lead to widely available stem cell therapies for neurologic diseases in the coming years.