[Hyperammonemic encephalopathy after treatment with modified FOLFOX6 regimen for recurrent gastric cancer:a case report].

A 64-year-old female received modified FOLFOX6 therapy with continuous administration of a high concentration of 5-fluorouracil (5-FU) for recurrence of peritoneal dissemination after total gastrectomy. Twenty-nine hours after the administration, there was the sudden onset of altered consciousness and hepatic dysfunction accompanied by hyperammonemia. The consciousness and hepatic function improved the following day after treatment with branched-chain amino acid formulation, lactulose, fresh frozen plasma, and continuous hemodiafiltration. Thus, the diagnosis was 5-FU-induced hyperammonemia. Improvement of dehydration and renal dysfunction would be important for avoiding the risk of developing the side effects. Because recurrent gastric cancer is often a progressive condition, post-treatment might be promptly transferred to the other posterior regimen without 5-FU as required.

Laparoscopic ultrasound guided wedge resection of the stomach: a novel procedure for gastric submucosal tumor.

It is essential for the surgery of gastric submucosal tumors to resect the tumor with a negative margin and minimize the incision of the normal stomach wall. We developed a novel procedure for patients with gastric submucosal tumors using a laparoscopic ultrasound probe as a guide to determine the resection line. Since 2014, we have performed the laparoscopic ultrasound-guided wedge resection of the stomach in seven patients. The tumor was localized, and the property of the tumor was clearly identified using a laparoscopic ultrasound probe. As a result, the ideal incision line was determined without intraoperative endoscopy. The stomach wall was perforated along the marking on the planned incision line and the whole layer is subsequently incised along with the tumor. The surgical margins were negative, and there were no obvious injuries of the pseudocapsule, microscopically, in any case. It is possible that the laparoscopic ultrasound-guided wedge resection of the stomach contributes to a simplification of the surgery of gastric submucosal tumors resulting in reduced medical cost while maintaining curability and functional preservation.

Colonic varices treated with embolization after pancreatoduodenectomy with portal vein resection: a case report.

BACKGROUND: Pancreatoduodenectomy with resection of the portal vein or superior mesenteric vein confluence has been safely performed in patients with pancreatic head cancer associated with infiltration of the portal vein or superior mesenteric vein. In recent years, left-sided portal hypertension, a late postoperative complication, has received focus owing to increased long-term survival with advances in chemotherapy. Left-sided hypertension may sometimes cause fatal gastrointestinal bleeding because of the rupture of gastrointestinal varices. Here, we present a case of colonic varices caused by left-sided portal hypertension after pancreatoduodenectomy with portal vein resection. CASE PRESENTATION: A 69-year-old man diagnosed with pancreatic head cancer was referred to our department for surgery after undergoing chemotherapy with nine courses of gemcitabine and nab-paclitaxel. Computed tomography showed a mass 25 mm in diameter and in contact with the portal vein. He had undergone subtotal stomach-preserving pancreatoduodenectomy with portal vein resection. Four centimeters of the portal vein had been resected, and end-to-end anastomosis was performed without splenic vein reconstruction. We had to completely resect the right colic vein, accessary right colic vein, and middle colic vein due to tumor invasion. The pathological diagnosis was ypT3, ypN1a, ypM0, and ypStageIIB, and he was administered TS-1 as postoperative adjuvant chemotherapy. Seven months after therapeutic radical surgery, he presented with melena with progressive anemia. Computed tomography revealed transverse colonic varices. He was offered interventional radiology. Trans-splenic arterial splenic venography showed that transverse colonic varices had developed as collateral circulation of the splenic vein and inferior mesenteric vein system. An embolic substance was injected into the transverse colonic varices, which halted the progression of the anemia caused by melena. Fifteen months after therapeutic radical surgery, local recurrence of the tumor occurred; he died 28 months after the surgery. CONCLUSIONS: When subtotal stomach-preserving pancreatoduodenectomy with portal vein resection is performed without splenic vein reconstruction, colonic varices may result from left-sided portal hypertension. Interventional radiology is an effective treatment for gastrointestinal bleeding due to colonic varices, but it is important to be observant for colonic necrosis and new varices.

A rare case of localized IgG4-related sclerosing cholecystitis mimicking gallbladder cancer.

Objective: IgG4-related sclerosing cholecystitis is generally associated with IgG4-related sclerosing cholangitis and presents with diffuse, circumferential thickening of the gallbladder wall. We report a rare case of localized IgG4-related sclerosing cholecystitis without IgG4-related sclerosing cholangitis, which was difficult to differentiate from gallbladder cancer preoperatively. Patient: A 56-year-old man with suspected IgG4-related disease or gallbladder cancer was admitted to our ward. The serum IgG4 level was elevated at 721 mg/dL. Computed tomography (CT) demonstrated focal wall thickening of the gallbladder fundus. Drip infusion cholecystocholangiography with CT revealed no dilation, stenosis, or border irregularity of the bile duct. Results: For diagnostic and treatment purposes, cholecystectomy with wedge resection of the gallbladder bed was performed. The pathological diagnosis was IgG4-related sclerosing cholecystitis. Conclusion: It is difficult to differentiate IgG4-related sclerosing cholecystitis from gallbladder cancer in cases involving localized thickening of the gallbladder wall. In similar cases, surgical resection with cancer in mind might be performed based on present clinical knowledge.

Multivalent Mannose-Decorated NIR Nanoprobes for Targeting Pan Lymph Nodes.

Lymphadenectomy is a prerequisite for most malignancies to define the precise staging of cancer, as well as resect the possible metastases completely. While it improves prognosis, lymphadenectomy often causes postoperative edema or bleeding because of unclear surgical margins. In this study, we synthesized near-infrared (NIR) fluorescent nanoprobes with conjugating various mannose moieties on the surface to target macrophages in the lymph node. Armed with these NIR nanoprobes, we demonstrated the feasibility of intraoperative pan lymph nodes (PLN) mapping and real-time optical imaging under the NIR fluorescence imaging system. We found that even single mannose-conjugated ZW800-1 showed specific uptake in lymph nodes within 4 h, and multiple mannose-employed polyrotaxanes highlighted PLN efficiently with low background signals in major organs. This technology can help surgeons perform lymphadenectomy with ease and safety by identifying all regional lymph nodes proficiently after a single intravenous injection of NIR nanoprobes.

Bioimaging of botulinum toxin and hyaluronate hydrogels using zwitterionic near-infrared fluorophores.

BACKGROUND: The injection of botulinum toxin (BTX) to reduce facial wrinkles is one of the most frequently performed plastic surgery procedures. The biocompatible hydrogels are injected with BTX for effective tissue augmentation. However, it is difficult to determine the interval of injection for effective tissue augmentation. METHOD: BTX and hyaluronate (HA) hydrogels were labeled with zwitterionic (ZW) near-infrared (NIR) fluorophores and visualized for 3 weeks after injection to BALB/c nude mice. RESULTS: BTX-ZW conjugates and diaminohexane (DAH)-HA-ZW hydrogels were successfully prepared by the conventional EDC/NHS chemistry. Using the NIR fluorescence imaging, we confirmed that approximately 10% of BTX-ZW conjugates and 50% of DAH-HA-ZW hydrogels remained 3 weeks post-injection. CONCLUSION: This bioimaging technique using invisible NIR fluorescence light can be exploited for various biomedical applications.

Intraoperative Real-Time Assessment of Liver Function with Near-Infrared Fluorescence Imaging.

BACKGROUND: Postoperative liver failure is a serious complication after major hepatectomy, and perioperative prediction of its incidence using current technology is still very difficult. Near-infrared (NIR) fluorescence imaging allows quantitative assessment of the fluorescent signal from indocyanine green (ICG) in regions of interest on the liver surface. This method might offer a new promising modality for evaluating regional liver reserve. However, data are lacking regarding the relationship between liver function and fluorescent signals on the liver surface after intravenous ICG injection. This study was conducted to obtain the data necessary to apply NIR fluorescence imaging as a modality for measuring liver function. MATERIALS AND METHODS: This study included 16 patients who underwent open hepatopancreatobiliary surgery between March 2011 and March 2012. After laparotomy, ICG was injected intravenously at 2.5 mg/L of liver volume, then the fluorescence intensity (FI) and signal-to-background ratio (SBR) in the lateral segment of the liver were assessed for 15 min. Intraoperative blood samples were also obtained to measure the plasma clearance rate of ICG (ICGK). Correlations between ICGK, liver volume, and SBR, as well as between ICGK, liver volume, and rate of change of FI were analyzed. RESULTS: The experimental procedure was performed in all 16 patients. The FI of the liver increased rapidly after ICG injection, then became more gradual, reaching a near-plateau after 15 min. A significant correlation was seen between ICGK and the rate of change of FI up to 15 min (|rS| = 0.5725, p < 0.05). CONCLUSION: This is the first report to show a relationship between liver function and fluorescent signals on the liver surface after intravenous ICG injection. Intraoperative NIR fluorescence imaging with ICG may be useful as a new method for assessing liver function.

Accurate Prediction of Tissue Viability at Postoperative Day 7 Using Only Two Intraoperative Subsecond Near-Infrared Fluorescence Images.

BACKGROUND: The ability to predict the future viability of tissue while still in the operating room and able to intervene would have a major impact on patient outcome. Although several objective methods to evaluate tissue perfusion have been reported, none to date has sufficient accuracy. METHODS: In eight Sprague-Dawley rats, reverse McFarlane dorsal skin flaps were created. Continuous near-infrared fluorescence angiography using indocyanine green was performed immediately after surgery, for a total of 30 minutes. These dynamic measurements were used to quantify indocyanine green biodistribution and clearance, and to develop a simple metric that accurately predicted tissue viability at postoperative day 7. The new metric was compared to previously described metrics. RESULTS: Reproducible patterns of indocyanine green biodistribution and clearance from the flap permitted quantitative metrics to be developed for predicting flap viability at postoperative day 7. Previously described metrics, which set the boundary between healthy and necrotic tissue as either 17 or 25 percent of peak near-infrared fluorescence at 2 minutes after indocyanine green injection, underestimated the area of necrosis by 75 and 48 percent, respectively. Our data suggest that both the shape and area of clinical necrosis occurring at postoperative day 7 can be predicted intraoperatively, with the boundary defined as near-infrared fluorescence intensities of 40 to 55 percent of peak fluorescence measured at 5 minutes. CONCLUSION: Two 750-msec intraoperative near-infrared fluorescence images obtained at time 0 and at 5 minutes after injection of indocyanine green accurately predicted skin flap viability 7 days after surgery.

Intraoperative Near-Infrared Fluorescence Imaging of Thymus in Preclinical Models.

BACKGROUND: There are currently no thymus-specific contrast agents for biomedical imaging. Thus, finding ectopic thymic tissue during certain operations is extremely difficult. The purpose of the present study was to determine if near-infrared (NIR) fluorescence imaging could provide high sensitivity, real-time identification of thymic tissue during the operation. METHODS: After initial in vivo screening of a 315-compound NIR fluorophore library for thymic uptake, methylene blue and five different 700-nm emitting candidate molecules were injected into CD-1 mice for quantitation of the signal-to-background ratio as a function of kinetics and dosing. Results were confirmed in 35-kg Yorkshire pigs. Dual-channel NIR imaging was also performed using a variety of 800-nm emitting NIR fluorophores targeted to various tissues in the mediastinum and neck. RESULTS: The compound Oxazine 170 demonstrated the highest signal-to-background ratio (≥3) for thymic tissue relative to mediastinal fat, heart, lung, muscle, thyroid gland, and parathyroid gland, with peak signal-to-background ratio occurring 4 h after 1 intravenous injection of a human equivalent dose of approximately 7 mg. Simultaneous dual-channel NIR imaging permitted unambiguous identification of the thymus from surrounding tissues, such as endocrine glands and lymph nodes. CONCLUSIONS: In mouse and pig, NIR fluorescence imaging using Oxazine 170 permits high sensitivity, real-time identification of thymic tissue for surgical procedures requiring its resection or avoidance. The performance of Oxazine 170 for imaging human thymic tissue is currently not known.

Renal Clearable Organic Nanocarriers for Bioimaging and Drug Delivery.

Renally cleared zwitterionic nanocarriers (H-Dots) are composed of ε-polylysine backbone for charge variations, near-infrared fluorophores for bioimaging, and ß-cyclodextrins for potential drug delivery. H-Dots show ideal systemic circulation and rapid distribution and excrete from normal tissue/organ via renal excretion after complete targeting to the tumor site without nonspecific uptake by the immune system.

700-nm Zwitterionic Near-Infrared Fluorophores for Dual-Channel Image-Guided Surgery.

PURPOSE: The purpose of this study was to develop a family of 700-nm zwitterionic pentamethine indocyanine near-infrared fluorophores that would permit dual-channel image-guided surgery. PROCEDURES: Three complementary synthetic schemes were used to produce novel zwitterionic chemical structures. Physicochemical, optical, biodistribution, and clearance properties were compared to Cy5.5, a conventional pentamethine indocyanine now used for biomedical imaging. RESULTS: ZW700-1a, ZW700-1b, and ZW700-1c were synthesized, purified, and analyzed extensively in vitro and in vivo. All molecules had extinction coefficients ≥199,000 M(-1) cm(-1), emission ≥660 nm, and stability ≥99 % after 24 h in warm serum. In mice, rats, and pigs, ≥80 % of the injected dose was completely eliminated from the body via renal clearance within 4 h. Either alone or conjugated to a tumor targeting ligand, ZW700-1a permitted dual-channel, high SBR, and simultaneous imaging with 800-nm NIR fluorophores using the FLARE® imaging system. CONCLUSIONS: Novel 700-nm zwitterionic NIR fluorophores enable dual-NIR image-guided surgery.

Cartilage-Specific Near-Infrared Fluorophores for Biomedical Imaging.

A novel class of near-infrared fluorescent contrast agents was developed. These agents target cartilage with high specificity and this property is inherent to the chemical structure of the fluorophore. After a single low-dose intravenous injection and a clearance time of approximately 4 h, these agents bind to all three major types of cartilage (hyaline, elastic, and fibrocartilage) and perform equally well across species. Analysis of the chemical structure similarities revealed a potential pharmacophore for cartilage targeting. Our results lay the foundation for future improvements in tissue engineering, joint surgery, and cartilage-specific drug development.

Sentinel Lymph Node Mapping of Liver.

BACKGROUND: Although the sentinel lymph node (SLN) hypothesis has been applied to many tissues and organs, liver has remained unstudied. Currently, it is unclear whether hepatic SLNs even exist. If so, they could alter the management of intrahepatic cholangiocarcinoma and other hepatic malignancies by minimizing the extent of surgery while still providing precise nodal staging. This study investigated whether invisible yet tissue-penetrating near-infrared (NIR) fluorescent light can provide simultaneous identification of both the SLN and all other regional lymph nodes (RLNs) in the liver. METHODS: In 25 Yorkshire pigs, this study determined whether SLNs exist in liver and compared the effectiveness of two clinically available NIR fluorophores [methylene blue and indocyanine green (ICG)], and two novel NIR fluorophores previously described by our group (ESNF14 and ZW800-3C) for SLN and RLN mapping. RESULTS: In this study, ESNF14 showed the highest signal-to-background ratio and the longest retention time in SLNs without leakage to second-tier lymph nodes. The findings showed that ICG had apparent leakage to second-tier nodes, and ZW800-3C had poor migration after intraparenchymal injection. However, when injected intravenously, ZW800-3C was able to highlight all RLNs in liver during a 4- to 6-h period. Simultaneous dual-channel imaging of SLN (ESNF14) and RLN (ZW800-3C) permitted unambiguous identification and image-guided resection of SLNs and RLNs in liver. CONCLUSION: The NIR imaging technology enables real-time intraoperative identification of SLNs and RLNs in the liver of swine. If these results are confirmed in patients, new strategies for the surgical management of intrahepatic malignancies should be possible.

Structure-inherent targeting of near-infrared fluorophores for parathyroid and thyroid gland imaging.

The typical method for creating targeted contrast agents requires covalent conjugation of separate targeting and fluorophore domains. In this study, we demonstrate that it is possible to create near-infrared (NIR) fluorophores with different tissue specificities driven by their inherent chemical structures. Thus, a single compact molecule performs both targeting and imaging. We use this strategy to solve a major problem in head and neck surgery: the identification and preservation of parathyroid and thyroid glands. We synthesized 700-nm and 800-nm halogenated fluorophores that show high uptake into these glands after a single intravenous (IV) injection of 0.06 mg kg(-1) in a pig. By using a dual-channel NIR imaging system, we observed-in real time and with high sensitivity-the unambiguous distinction of parathyroid and thyroid glands simultaneously in the context of blood and surrounding soft tissue. This novel technology lays a foundation for performing head and neck surgery with increased precision and efficiency along with potentially lower morbidity, and it provides a general strategy for developing targeted NIR fluorophores.

Pancreas-targeted NIR fluorophores for dual-channel image-guided abdominal surgery.

OBJECTIVE: Pancreas-related complications are some of the most serious ones in abdominal surgery. The goal of this study was to develop and validate novel near-infrared (NIR) fluorophores that would enable real-time pancreas imaging to avoid the intraoperative pancreatic injury. DESIGN: After initial screening of a large NIR fluorophore library, the performance of 3 selected pancreas-targeted 700 nm NIR fluorophores, T700-H, T700-F, and MB, were quantified in mice, rats, and pigs. Dose ranging using 25 and 100 nmol, and 2.5 µmol of T700-F, and its imaging kinetics over a 4 h period were tested in each species. Three different 800 nm NIR fluorophores were employed for dual-channel FLARE™ imaging in pigs: 2 µmol of ZW800-1 for vessels and kidney, 1 µmol of ZW800-3C for lymph nodes, and 2 µmol of ESNF31 for adrenal glands. RESULTS: T700-F demonstrated the highest signal to background ratio (SBR), with peak SBR at 4 h postinjection in mice. In pigs, T700-F produced an SBR≥2 against muscle, spleen, and lymph nodes for up to 8 h after a single intravenous injection. The combination of T700-F with each 800 nm NIR fluorophore provided simultaneous dual-channel intraoperative imaging of pancreas with surrounding organs in real time. CONCLUSION: Pancreas-targeted NIR fluorophores combined with the FLARE dual-channel imaging system enable the real-time intraoperative pancreas imaging which helps surgeons perform safer and more curative abdominal surgeries.

Central C-C Bonding Increases Optical and Chemical Stability of NIR Fluorophores.

Functional near-infrared (NIR) fluorophores have played a major role in the recent advances in bioimaging. However, the optical and physicochemical stabilities of NIR fluorophores in the biological and physiological environment are still a challenge. Especially, the ether linkage on the meso carbon of heptamethine core is fragile when exposed to serum proteins or other amine-rich biomolecules. To solve such a structural limitation, a rigid carbon-carbon bond was installed onto the framework of ether-linked NIR fluorophores through the Suzuki coupling. The robust fluorophores replaced as ZW800-1C and ZW800-3C displayed enhanced optical and chemical stability in various solvents and a 100% warm serum environment (> 99%, 24 h). The biodistribution and clearance of C-C coupled ZW800 compounds were almost identical to the previously developed oxygen-substituted ZW800 compounds. When conjugated with a small molecule ligand, ZW800-1C maintained the identical stable form in warm serum (>98%, 24 h), while ZW800-1A hydrolyzed quickly after 4 h incubation (34%, 24 h).

Phosphonated near-infrared fluorophores for biomedical imaging of bone.

The conventional method for creating targeted contrast agents is to conjugate separate targeting and fluorophore domains. A new strategy is based on the incorporation of targeting moieties into the non-delocalized structure of pentamethine and heptamethine indocyanines. Using the known affinity of phosphonates for bone minerals in a model system, two families of bifunctional molecules that target bone without requiring a traditional bisphosphonate are synthesized. With peak fluorescence emissions at approximately 700 or 800 nm, these molecules can be used for fluorescence-assisted resection and exploration (FLARE) dual-channel imaging. Longitudinal FLARE studies in mice demonstrate that phosphonated near-infrared fluorophores remain stable in bone for over five weeks, and histological analysis confirms their incorporation into the bone matrix. Taken together, a new strategy for creating ultra-compact, targeted near-infrared fluorophores for various bioimaging applications is described.

Prototype nerve-specific near-infrared fluorophores.

Nerve preservation is an important issue during most surgery because accidental transection or injury results in significant morbidity, including numbness, pain, weakness, or paralysis. Currently, nerves are still identified only by gross appearance and anatomical location during surgery, without intraoperative image guidance. Near-infrared (NIR) fluorescent light, in the wavelength range of 650-900 nm, has the potential to provide high-resolution, high-sensitivity, and real-time avoidance of nerve damage, but only if nerve-specific NIR fluorophores can be developed. In this study, we evaluated a series of Oxazine derivatives to highlight various peripheral nerve structures in small and large animals. Among the targeted fluorophores, Oxazine 4 has peak emission near into the NIR, which provided nerve-targeted signal in the brachial plexus and sciatic nerve for up to 12 h after a single intravenous injection. In addition, recurrent laryngeal nerves were successfully identified and highlighted in real time in swine, which could be preserved during the course of thyroid resection. Although optical properties of these agents are not yet optimal, chemical structure analysis provides a basis for improving these prototype nerve-specific NIR fluorophores even further.

Video-assisted thoracoscopic left lower lobectomy in a patient with lung cancer and a right aortic arch.

A right aortic arch is a rare congenital anomaly, with a reported incidence of around 0.1%. A patient with a right aortic arch underwent video-assisted thoracic surgery left lower lobectomy and mediastinal lymph node dissection for squamous cell carcinoma. There was no aortic arch or descending aorta in the left thoracic cavity, but the esophagus. There was no anomaly in the location or branching of the pulmonary vessels, the bronchi, and the lobulation of the lungs. The vagus nerve was found at the level of the left pulmonary artery. The arterial ligament was found between the left subclavian artery and the left pulmonary artery. The recurrent laryngeal nerve was recurrent around the left subclavian artery. A Kommerell diverticulum was found at the origin of the left subclavian artery. The patient experienced no complications. We conclude that video-assisted thoracoscopic lobectomy with mediastinal dissection is feasible for treating lung cancer with a right aortic arch.