Field experiment of a telesurgery system using a surgical robot with haptic feedback.

PURPOSE: To verify the usefulness of haptic feedback in telesurgery and improve the safety of telerobotic surgery. METHODS: The surgeon's console was installed at two sites (Fukuoka and Beppu; 140 km apart), and the patient cart was installed in Fukuoka. During the experiment, the surgeon was blinded to the haptic feedback levels and asked to grasp the intestinal tract in an animal model. The surgeon then performed the tasks at each location. RESULTS: No marked differences in task accuracy or average grasping force were observed between the surgeon locations. However, the average task completion time was significantly longer, and the system usability scale (SUS) was significantly lower rating for remote operations than for local ones. No marked differences in task accuracy or task completion time were observed between the haptic feedback levels. However, with haptic feedback, the organ was grasped with a significantly weaker force than that without it. Furthermore, with haptic feedback, experienced surgeons in robotic surgery tended to perform an equivalent task with weaker grasping forces than inexperienced surgeons. CONCLUSION: The haptic feedback function is a tool that allows the surgeon to perform surgery with an appropriate grasping force, both on site and remotely. Improved safety is necessary in telesurgery; haptic feedback will thus be an essential technology in robotic telesurgery going forward.

Telesurgery and telesurgical support using a double-surgeon cockpit system allowing manipulation from two locations.

BACKGROUND: Although several studies on telesurgery have been reported globally, a clinically applicable technique has not yet been developed. As part of a telesurgical study series conducted by the Japan Surgical Society, this study describes the first application of a double-surgeon cockpit system to telesurgery. METHODS: Surgeon cockpits were installed at a local site and a remote site 140 km away. Three healthy pigs weighing between 26 and 29 kg were selected for surgery. Non-specialized surgeons performed emergency hemostasis, cholecystectomy, and renal vein ligation with remote assistance using the double-surgeon cockpits and specialized surgeons performed actual telesurgery. Additionally, the impact of adding internet protocol security (IPsec) encryption to the internet protocol-virtual private network (IP-VPN) line on communication was evaluated to address clinical security concerns. RESULTS: The average time required for remote emergency hemostasis with the double-surgeon cockpit system was 10.64 s. A non-specialized surgeon could safely perform cholecystectomy or renal vein ligation with remote assistance. Global Evaluative Assessment of Robotic Skills and System Usability Scale scores were higher for telesurgical support-assisted surgery by a non-specialized surgeon using the double-surgeon cockpits than for telesurgery performed by a specialized surgeon without the double-cockpit system. Adding IPsec encryption to the IP-VPN did not have a significant impact on communication. CONCLUSION: Telesurgical support through our double-surgeon cockpit system is feasible as first step toward clinical telesurgery.

Tele-assessment of bandwidth limitation for remote robotics surgery.

PURPOSE: We investigated the communication bandwidth (CB) limitation for remote robotics surgery (RRS) using hinotori™ (Medicaroid, Kobe, Japan). METHODS: The operating rooms of the Hokkaido University Hospital and Kyushu University Hospital were connected using the Science Information NETwork (SINET). The minimum required CB for the RRS was verified by decreasing the CB from 500 to 100 Mbps. Ten surgeons were tested on a task (intracorporeal suturing) at different levels of video compression (VC) (VC1: 120 Mbps, VC2: 40 Mbps, VC3: 20 Mbps) with the minimum required CB, and assessed based on the task completion time, Global Evaluative Assessment of Robotic Skills (GEARS), and System and Piper Fatigue Scale-12 (PFS-12). RESULTS: Packet loss was observed at 3-7% and image degradation was observed at 145 Mbps CB. The task performance with VC1 was significantly worse than that with VC2 and VC3 according to the task completion time (VC1 vs VC2, P = 0.032; VC1 vs. VC3, P = 0.032), GEARS (VC1 vs VC2; P = 0.029, VC1 vs VC3; P = 0.031), and PFS-12 (VC1 vs. VC2; P = 0.032, VC1 vs. VC3; P = 0.032) with 145 Mbps. CONCLUSION: Our findings provide evidence that RRS using hinotori™ requires a CB ≥ 150 Mbps. We also found that when there is insufficient CB, RRS can be continued by compressing the image.

Potential risk of residual cancer cells in the surgical treatment of initially unresectable pancreatic carcinoma after chemoradiotherapy.

BACKGROUND: With development of chemoradiotherapy for pancreatic carcinoma, borderline resectable or initially unresectable cases sometimes become operable after long-term intensive chemoradiotherapy. However, there is no established strategy for adjuvant surgery with respect to whether the surgical resection should be extensive or downsized accordingly with diminished disease areas following response to chemoradiotherapy. METHODS: The clinical and pathological aspects of 18 patients with initially unresectable pancreatic cancer who underwent adjuvant surgery after chemo(radio)therapy in our department from 2007 were evaluated. RESULTS: Overall survival from initial treatment was much better for patients with R0 resection than for patients with R1/2 resection. In two of three patients who had complete improvement of plexus (PL) invasion after chemo(radio)therapy, there had still remained pathological plexus invasion. It was shown that tumors did not shrink continuously from the tumor front, but parts remained discontinuously at the distal portion in the process of tumor regression by chemo(radio)therapy. CONCLUSIONS: In adjuvant surgery for patients with locally advanced pancreatic cancer, the potential risk of residual cancer in the regression area following chemoradiotherapy should be considered. Achieving R0 resection will lead to an improved prognosis, and it is necessary to consider how well the extent of resection is after a favorable response to chemoradiotherapy.

Tele-robotic distal gastrectomy with lymph node dissection on a cadaver.

The purpose of this study is to evaluate the performance of tele-robotic distal gastrectomy (tele-RDG) with lymph node dissection (LND) using a novel Japanese-made surgical robot hinotori™ (Medicaroid, Kobe, Japan) in a cadaver with a presumptive gastric cancer. The Cadaveric Anatomy and Surgical Training Laboratory (CAST-Lab.) at Hokkaido University and Kushiro City General Hospital (KCGH) are connected by a guaranteed type line (1 Gbps), and the distance between the two facilities is 250 km. A patient cart was installed at CAST-Lab, and a surgeon cockpit was installed at KCGH. Tele-RDG with D2 LND was performed on an adult human cadaver. In all surgical processes, the communication environment was stable without image degradation, and the mean round trip time was 40 milliseconds (36.5-55 milliseconds). For tele-RDG with D2 LND, the operation time was 199 minutes without any technical problems. Tele-RDG using hinotori™ was feasible and similar to local robotic RDG.

Group analysis and classification of working memory task conditions using electroencephalogram cortical currents during an n-back task.

Electroencephalographic studies of working memory have demonstrated cortical activity and oscillatory representations without clarifying how the stored information is retained in the brain. To address this gap, we measured scalp electroencephalography data, while participants performed a modified n-back working memory task. We calculated the current intensities from the estimated cortical currents by introducing a statistical map generated using Neurosynth as prior information. Group analysis of the cortical current level revealed that the current amplitudes and power spectra were significantly different between the modified n-back and delayed match-to-sample conditions. Additionally, we classified information on the working memory task conditions using the amplitudes and power spectra of the currents during the encoding and retention periods. Our results indicate that the representation of executive control over memory retention may be mediated through both persistent neural activity and oscillatory representations in the beta and gamma bands over multiple cortical regions that contribute to visual working memory functions.

Dedifferentiated liposarcoma primary to the chest wall with spontaneous shrinking: report of a case.

An 80-year-old man presented to our emergency department complaining of a mass on the right side of his chest and pain in the right flank of his back. A chest computed tomography (CT) scan showed a relatively heterogenous oval-shaped tumor measuring 7.5 × 6.0 cm eroded to the 8th rib, with slightly dense fluid accumulation inside and calcification of the tumor wall. A 1-month follow-up CT scan showed spontaneous shrinkage of the tumor. The tumor was completely excised from the thoracic wall and the wall was reconstructed with a polytetrafluoroethylene mesh. Pathological examination showed coagulation necrosis in the chest wall tumor, but immunohistochemical staining revealed murine double minute 2- and Cyclin-dependent kinase 4-positive cells with irregular nuclear size and bizarre morphology. Therefore, dedifferentiated liposarcoma (DDLPS) was the final pathological diagnosis. Remarkable infiltration of CD8+ lymphocytes into the tumor was observed, along with a 90% positive ratio for programmed cell death-ligand 1. The patient has been followed-up for 1 year without any recurrence, despite not receiving any additional treatment. Liposarcoma is one of the most common types of soft tissue sarcomas; however, spontaneous regression of primary DDLPS arising from the chest wall is extremely rare. Herein, we report a case of DDLPS primary to the chest wall with spontaneous regression, probably due to a spontaneously induced T cell response.

Technical evaluation of robotic tele-cholecystectomy: a randomized single-blind controlled pilot study.

Although robotic telesurgery is growing in popularity, the benefits of telesurgery compared to local surgery are unclear. This study aimed to evaluate the performance of robotic tele-cholecystectomy with a commercial line using the Saroa™ (Riverfield, Inc., Tokyo, Japan) system. The operation rooms of the Hokkaido University Hospital and Kushiro City General Hospital were connected using a best effort-type line (1 Gbps), with a distance of 250 km between the two hospitals. In this experimental single-blind randomized crossover trial, eight expert robotic surgeons performed robotic cholecystectomy in an artificial organ model using the Saroa™ system and were randomized to begin with either local surgery or telesurgery. All surgeons were assessed on task completion time, total path length of the right- and left- hand forceps and camera, Global Evaluative Assessment of Robotic Skills (GEARS), Global Operative Assessment of Laparoscopic Skills (GOALS), and System and Piper Fatigue Scale-12 (PFS-12). In all experiments, the communication environment was stable and the mean communication delay was 8 ms (3-31 ms). All tele-cholecystectomies were performed safely. There was no significant difference in completion time (P = 0.495), score of GEARS (P = 0.258), GOALS (P = 0.180), or PFS-12 (P = 0.528) between local surgery and telesurgery. The total path of the forceps tended to be longer in tele-cholecystectomy, particularly with significantly longer left-hand forceps total path length (P = 0.041). Robotic tele-cholecystectomy using a commercial line can be performed safely as same as local robotic surgery, but the total path of the left-hand forceps was prolonged in robotic tele-cholecystectomy due to overshoot. Therefore, a solution for overshooting will be required in the future.

Laparoscopic cholecystectomy after transcatheter arterial embolisation for haemobilia due to a pseudoaneurysm in the gallbladder: A case report.

Pseudoaneurysms of the cystic artery are a rare but significant complication of acute cholecystitis. Laparoscopic cholecystectomy may be a safe alternative to open cholecystectomy in such cases. We report the case of a female patient in her seventies, who presented with anaemia, jaundice, and hepatic dysfunction during hospitalisation for right knee pyogenic arthritis. The patient had no pain in the right upper quadrant. Her serum haemoglobin level was 6.5 g/dL, and upper gastrointestinal endoscopy revealed no abnormalities. Six days later, jaundice worsened, and endoscopic retrograde cholangiopancreatography revealed bloody bile. An endoscopic biliary drainage tube was inserted at the discretion of the gastroenterology department. Contrast-enhanced computed tomography revealed a haematoma in the gallbladder and a pseudoaneurysm in the lateral wall of the gallbladder. On the same day, the endoscopic biliary drainage tube was replaced with an endoscopic nasobiliary drainage tube, which indicated the degree of haemorrhage and enabled lavage of the lumen in cases of obstruction. The next day, angiography revealed a pseudoaneurysm of the deep branch of the cystic artery and coil embolisation was performed at the periphery of the cystic artery. Uninterrupted laparoscopic cholecystectomy was performed. Although laparoscopic cholecystectomy is difficult when bleeding is uncontrolled, it was safely performed following haemostasis using transcatheter arterial embolisation. Laparoscopic cholecystectomy is feasible in haemodynamically stable patients with cystic artery pseudoaneurysms after transcatheter arterial embolisation.

Identification of antibody against wingless­type MMTV integration site family member 7B as a biliary cancer tumor marker.

Biliary cancer has a poor prognosis due to a lack of specific biomarkers and difficulty in diagnosis. The present study aimed to identify serum tumor markers for the diagnosis of biliary cancer via serological identification of antigens by recombinant cDNA expression cloning. Wingless­type MMTV integration site family, member 7 (WNT7B) was identified as a target antigen, suggesting the presence of serum antibodies against this antigen. Deletion mutants were then prepared to evaluate the response to serum antibodies. When serum antibody levels against WNT7B deletion mutants (WNT7B-92­2, -92­260, 2-260 and 184-260) were examined using amplified luminescence proximity homogeneous assay­linked immunosorbent assay, the levels of the antibody against WNT7B with amino acids 184­260 were higher in patients with biliary cancer than in healthy donors. Therefore, the region covering residues 184­260 of WNT7B was decomposed to generate seven peptides, and the levels of antibodies against these peptides were measured. Among them, the levels of antibodies against WNT7B234­253 and WNT7B244­260 were higher in patients with biliary cancers than in healthy donors (WNT7B234­253, P=0.0009; WNT7B244­260, P=0.0005). The levels of the antibody against the former were specifically high in patients with biliary cancer but not in those with esophageal, gastric, colorectal, pancreatic, or breast cancer. Furthermore, analysis by the cutoff value of WNT7B234­253 defined by ROC showed a high sensitivity of 70% in patients with biliary cancer. Therefore, the serum levels of the antibody against WNT7B234­253 may be useful as a marker for biliary cancer diagnosis.

[A case of sigmoid colon cancer with temporary dysarthria associated with irinotecan].

A40 -year-old woman visited our hospital with adenocaricinoma of the sigmoid colon with multiple liver metastases and ovarian metastasis. Because of a stenosis of the primary tumor, she underwent a colostomy before chemotherapy. 5-fluorouracil and irinotecan and leucovorin(FOLFIRI)was selected as first-line chemotherapy. At the start of chemotherapy, just after the end of irinotecan and leucovorin administration, the patient developed dysarthria. There were no neurological abnormalities or hematological abnormalities. The treatment was temporarily discontinued, and the dysarthria completely disappeared within 90 minutes. 5-fluorouracil was administered after the disappearance of dysarthria. Within 60 minutes of the administration of irinotecan and leucovorin at the second chemotherapy treatment, the patient developed dysarthria again. The patient had no neurological or hematological abnormalities. Magnetic resonance imaging(MRI)showed no abnormalities. The treatment was stopped and dysarthria disappeared within 60 minutes as it did the first time. At each time, no treatment for dysarthria was performed. This patient refused to continue irinotecan because of dysarthria. Therefore, chemotherapy without irinotecan was continued for the third time onward. In the previous literature, 8 cases of dysarthria caused by irinotecan were reported as a rare toxicity. In all cases, dysarthria was temporary and reversible. Because the mechanism of dysarthria is unclear, specific treatment and precaution for dysarthria is not recommended. Since dysarthria is reversible, however, irinotecan might be continued until progression.

Characteristics of Visual Saliency Caused by Character Feature for Reconstruction of Saliency Map Model.

Visual saliency maps have been developed to estimate the bottom-up visual attention of humans. A conventional saliency map represents a bottom-up visual attention using image features such as the intensity, orientation, and color. However, it is difficult to estimate the visual attention using a conventional saliency map in the case of a top-down visual attention. In this study, we investigate the visual saliency for characters by applying still images including both characters and symbols. The experimental results indicate that characters have specific visual saliency independent of the type of language.

[A case of sigmoid colon cancer with lymphangitis carcinomatosa successfully treated with chemotherapies including molecular targeting drugs].

A 51-year-old man was referred to our hospital with adenocarcinoma of sigmoid colon with multiple lymph node metastasis. At the time of admission, he had dyspnea, and computed tomography (CT) showed typical signs of lymphangitis carcinomatosa of the lung. Combination of mFOLFOX6 and bevacizumab was started. After start of the therapy, CT revealed an improvement in lymphangitis carcinomatosa. 8 months later, the tumor assessment became progressive disease. FOLFIRI was started as the second-line chemotherapy, but the patient did not respond. Then, dyspnea emerged again, and CT indicated the lymphangitis carcinomatosa had become worse. So as the third-line chemotherapy, combination of irinotecan and cetuximab was started. Dyspnea immediately disappeared, and CT showed an improvement of lymphangitis carcinomatosa. In the previous literature, malignant tumor cases which accompany lymphangitis carcinomatosa might always have a poor course. Our case dramatically responded to the chemotherapy including molecular targeting drug and showed a long survival. So we conclude that aggressive chemotherapy including a molecular targeting drug may be recommended in a case of colorectal cancer which accompanies lymphangitis carcinomatosa of the lung.

Therapeutic activity of retroviral replicating vector-mediated prodrug activator gene therapy for pancreatic cancer.

Toca 511, a retroviral replicating vector (RRV) encoding the yeast cytosine deaminase (yCD) prodrug activator gene, which mediates conversion of the prodrug 5-fluorocytosine (5-FC) to the anticancer drug 5-fluorouracil (5-FU), is currently being evaluated in Phase II/III clinical trials for glioma, and showing highly promising evidence of therapeutic activity. Here we evaluated RRV-mediated prodrug activator gene therapy as a new therapeutic approach for pancreatic ductal adenocarcinoma (PDAC). RRV spread rapidly and conferred significant cytotoxicity with prodrug in a panel of PDAC cells. Efficient intratumoral replication and complete inhibition of tumor growth upon 5-FC administration were observed in both immunodeficient and immunocompetent subcutaneous PDAC models. Biodistribution of RRV was highly restricted in normal tissues, especially in immunocompetent hosts. Tumor growth inhibition by Toca 511 followed by 5-FC was also confirmed in the orthotopic PDAC model. This study provides the first proof-of-concept for application of Toca 511 and Toca FC (extended release 5-FC) to the treatment of human PDAC, and provided support for inclusion of PDAC in a Phase I study evaluating Toca 511 in various systemic malignancies, (NCT02576665), which has recently been initiated.

Identification of novel serum autoantibodies against EID3 in non-functional pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (pNETs) are relatively rare heterogenous tumors, comprising only 1-2% of all pancreatic neoplasms. The majority of pNETs are non-functional tumors (NF-pNETs) that do not produce hormones, and as such, do not cause any hormone-related symptoms. As a result, these tumors are often diagnosed at an advanced stage because patients do not present with specific symptoms. Although tumor markers are used to help diagnosis and predict some types of cancers, chromogranin A, a widely used tumor marker of pNETs, has significant limitations. To identify novel NF-pNET-associated antigens, we performed serological identification of antigens by recombinant cDNA expression cloning (SEREX) and identified five tumor antigens (phosphatase and tensin homolog, EP300-interacting inhibitor of differentiation 3 [EID3], EH domain-containing protein 1, galactoside-binding soluble 9, and BRCA1-associated protein). Further analysis using the AlphaLISA® immunoassay to compare serum antibody levels revealed that antibody levels against the EID3 antigen was significantly higher in the patient group than in the healthy donor group (n = 25, both groups). In addition, higher serum anti-EID3 antibody levels in NF-pNET patients correlated with shorter disease-free survival. The AUC calculated by ROC analysis was 0.784 with moderate diagnostic accuracy. In conclusion, serum anti-EID3 antibody levels may be useful as a tumor marker for prediction of tumor recurrence in NF-pNETs.

Molecular targeting of cell-permeable peptide inhibits pancreatic ductal adenocarcinoma cell proliferation.

BACKGROUND: Chromosome 16 open reading frame 74 (C16orf74) is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and is involved in cancer cell proliferation and invasion through binding to calcineurin (CN). Therefore, C16orf74 is a good target for the development of a PDAC treatment. A cell-permeable dominant-negative (DN) peptide that can inhibit the C16orf74/CN interaction was designed to examine whether this peptide can inhibit PDAC cell proliferation in vitro and in vivo. METHOD: TheDN-C16orf74 peptide, which corresponds to the portion of C16orf74 that interacts with CN, was synthesized, and we assessed its anti-tumor activity in proliferation assays with human PDAC cells and the underlying molecular signaling pathway. Using an orthotopic xenograft model of PDAC, we treated mice intraperitoneally with phosphate-buffered saline (PBS), control peptide, or DN-C16orf74 and analyzed the tumor-suppressive effects. RESULT: DN-C16orf74 inhibited the binding of C16orf74 to CN in an immunoprecipitation assay. DN-C16orf74 suppressed PDAC cell proliferation, and the level of suppression depended on the expression levels of C16orf74 in vitro. DN-C16orf74 also exhibited anti-tumor effects in orthotopic xenograft model. Furthermore, the tumor-suppressive effect was associated with inhibition of the phosphorylation of Akt and mTOR. CONCLUSION: The cell-permeable peptide DN-C16orf74 has a strong anti-tumor effect against PDAC in vitro and in vivo.

Inhibition of Eph receptor A4 by 2,5-dimethylpyrrolyl benzoic acid suppresses human pancreatic cancer growing orthotopically in nude mice.

Ephrin receptor A4 (EphA4) is overexpressed in human pancreatic adenocarcinoma (PDAC) and activate cell growth. Recent studies have identified small molecules that block EphA4. In this study, we investigated the correlation between EphA4 expression and the prognosis of patients with PDAC. We also examined the cytostatic efficacy of 2,5-dimethylpyrrolyl benzoic acid (compound 1), a small molecule that blocks EphA4, in PDAC cells. Overall survival of patients with EphA4 positivity was significantly shorter than that of patients with EphA4 negativity (P = 0.029). In addition, multivariate analysis revealed that EphA4 expression was an independent prognostic factor in PDAC patients (P = 0.039). Compound 1 showed a cytostatic efficacy in PDAC cells expressing EphA4 in vitro and in vivo. Our study indicated that compound 1 suppressed both EphA4 and Akt phosphorylations, and induced apoptosis in PDAC cells expressing EphA4. In conclusion, compound 1 has a high potential as a therapeutic agent for patients with PDAC.

Chemotherapy-Derived Inflammatory Responses Accelerate the Formation of Immunosuppressive Myeloid Cells in the Tissue Microenvironment of Human Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic malignancies. PDAC builds a tumor microenvironment that plays critical roles in tumor progression and metastasis. However, the relationship between chemotherapy and modulation of PDAC-induced tumor microenvironment remains poorly understood. In this study, we report a role of chemotherapy-derived inflammatory response in the enrichment of PDAC microenvironment with immunosuppressive myeloid cells. Granulocyte macrophage colony-stimulating factor (GM-CSF) is a major cytokine associated with oncogenic KRAS in PDAC cells. GM-CSF production was significantly enhanced in various PDAC cell lines or PDAC tumor tissues from patients after treatment with chemotherapy, which induced the differentiation of monocytes into myeloid-derived suppressor cells (MDSC). Furthermore, blockade of GM-CSF with monoclonal antibodies helped to restore T-cell proliferation when cocultured with monocytes stimulated with tumor supernatants. GM-CSF expression was also observed in primary tumors and correlated with poor prognosis in PDAC patients. Together, these results describe a role of GM-CSF in the modification of chemotherapy-treated PDAC microenvironment and suggest that the targeting of GM-CSF may benefit PDAC patients' refractory to current anticancer regimens by defeating MDSC-mediated immune escape.