Anti-tumor effect of antibody-drug conjugate targeting cell adhesion molecule 1 on GIST cells representing small intestinal GIST.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the alimentary tract. The prognosis depends on the primary site, and small intestinal GISTs have a worse prognosis than gastric GISTs. Molecularly targeted drugs to inhibit tyrosine kinase activity of KIT were used for unresectable or recurrent GISTs. However, secondary resistance to the drugs is often acquired, and treatments based on other mechanisms are needed. Previously, we reported that cell adhesion molecule 1 (CADM1) was highly expressed in most of small intestinal GISTs but not in most of gastric GISTs. In the present study, we examined whether the antibody-drug conjugate (ADC) with anti-CADM1 antibody and monomethyl auristatin E (anti-CAD-ADC) shows anti-tumor effect on CADM1-expressing human GIST cells. The ADC adhibited in this study was previously used for CADM1-expressing human mesothelioma cells and showed anti-tumor effect for them in vitro. GIST-T1 cell line of gastric origin which scarcely expresses CADM1 and GIST-T1 cells transfected with CADM1 cDNA (GIST-T1-CAD cells) which highly expresses CADM1 and represents small intestinal GIST were used. In vitro, anti-CAD-ADC showed remarkable cytotoxic activity on GIST-T1-CAD cells, but control ADC did not. Both anti-CAD-ADC and control ADC did not show anti-tumor effect on original GIST-T1 cells. When GIST-T1-CAD cells were subcutaneously injected to the nude mice, intravenous administration of anti-CAD-ADC showed inhibitory effect for tumor enlargement. Tumor of GIST-T1 cells grew even after anti-CAD-ADC injection. When GIST-T1-CAD cells were injected into peritoneal cavity of the SCID mice, intraperitoneal administration of anti-CAD-ADC showed reduction of the peritoneal tumor. On the other hand, peritoneal tumor grew after control ADC administration. Tissue and organ damage due to administration of anti-CAD-ADC was not apparent by macroscopic and histological examinations in mice. These results indicate that anti-CAD-ADC could have apparent anti-tumor effect on CADM1-expressing human GIST cells both in in vitro and in vivo mouse models.

Left atrial roof region ablation using a visually guided laser balloon.

Balloon-based catheter ablation including visually guided laser balloon (VGLB) has been adopted a first line therapeutic strategy for the patients with atrial fibrillation (AF). Recently, the roof area ablation beyond pulmonary vein (PV) isolation (PVI) using cryoballoon has been described as an effective therapy for the patients with persistent AF. However, the roof area ablation performed with a VGLB remains unknown. In this case, we report the case of roof area ablation for the patient with persistent AF using a VGLB.

Comparison of maximum-sized visually guided laser balloon and cryoballoon ablation.

Balloon ablation therapy has recently been used for atrial fibrillation (AF) ablation. Laser balloons possess the property in which the balloon size can be changed. Standard laser balloon ablation (Standard LBA) was followed by additional ablation using a maximally extended balloon (Extended LBA) and its lesion characteristics were compared to cryoballoon ablation (CBA), another balloon technology. From June 2020 to July 2021, patients with paroxysmal AF who underwent an initial pulmonary vein (PV) isolation were enrolled. Sixty-five patients with paroxysmal AF were included, 32 in the LBA and 33 in the CBA group. To measure the isolated surface area after the ablation procedures, left atrial voltage mapping was performed after Standard LBA, Extended LBA, and CBA. The baseline patient characteristics did not differ between LBA and CBA. Extended LBA could successfully increase the isolated area more than Standard LBA for all four PVs. Compared to CBA, the isolated area of both superior PVs was significantly greater with Extended LBA (left superior PV: 8.5 ± 2.1 vs 7.3 ± 2.4, p = 0.04, right superior PV: 11.4 ± 3.7 vs 8.7 ± 2.7, p < 0.01), and thus the non-isolated posterior wall (PW) was smaller (8.5 ± 3.4 vs 12.4 ± 3.3, p < 0.01). Nevertheless, changes in the cardiac injury markers were significantly lower with LBA than CBA. There was no significant correlation between the cardiac injury level and isolated area in both groups. In conclusion, Extended LBA exhibited a significantly greater isolation of both superior PVs and resulted in a smaller non-isolated PW, but the cardiac injury markers were significantly suppressed as compared to CBA.

[Port Site Recurrence After Laparoscopic Nephrectomy for Renal Cell Carcinoma --Report of Two Cases and Literature review-].

CASE 1: A male in his 60s underwent a right transperitoneal laparoscopic partial nephrectomy procedure for a right renal tumor. Rupture of a renal cyst located close to the tumor occurred intraoperatively. The histopathological diagnosis was clear cell renal cell carcinoma (CCRCC), pT1aN0M0, G2, v0, with negative resection margins. At 84 months after surgery, computed tomography (CT) revealed a 10 mm mass in the rectus abdominis muscle at the camera port site used for the partial nephrectomy. An open lumpectomy was then performed and the histopathological diagnosis was CCRCC. One year later, a 40 mm sized mass was detected in the mesentery of the small intestine by CT, which was removed laparoscopically with part of the mesentery and diagnosed as CCRCC. Since that surgery, the patient has been free from recurrence for 8 years. CASE 2: A male in his 60s underwent a left retroperitoneal laparoscopic nephrectomy procedure for a left renal tumor. The histopathological diagnosis was CCRCC, pT1aN0M0, G1, v0, with negative resection margins. At 31 months after surgery, CT revealed a 32 mm mass in the retroperitoneal cavity at the right hand port site used for the laparoscopic nephrectomy. The mass was removed with part of the twelfth rib and erector spinae muscles in a lump, and the histopathological diagnosis was CCRCC. Since that surgery, the patient has been free from recurrence for 19 months. For the treatment of solitary port site recurrence of renal cell carcinoma after a laparoscopic radical/partial nephrectomy, we recommend surgical resection for a good prognosis.

[A Case of Giant Multilocular Prostatic Cystadenoma Resected by Laparoscopic Pelvic Cystectomy : A Case Report].

A 60-year-old man visited our hospital to treat a large cystic mass in the pelvis which had been found by abdominal ultrasonography in December 201X. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a multilocular cyst with a maximum diameter of about 10 cm. CT-guided drainage and sclerotherapy with minocycline reduced the size of tumor by 40%, but symptoms such as difficulty of defecation and urinary frequency appeared a year and a half later due to re-enlargement of the cysts. Laparoscopic resection of the multilocular cysts was performed, and all cysts were removed almost completely using transrectal ultrasonography. The multilocular cyst was positive for NKX3.1 by immunohistochemical staining, and was diagnosed as a giant multilocular prostatic cystadenoma. After surgery, the symptoms such as difficulty of defecation and urinary frequency were relieved promptly. One year after the surgery, the patient was free from recurrence of the disease.

A case of ectopic pancreas of the stomach accompanied by intraductal papillary mucinous neoplasm with GNAS mutation.

BACKGROUND: Ectopic pancreas is basically a benign disease and is not always necessary to be removed. However, all types of neoplasms occurring in the normal pancreas such as ductal adenocarcinomas and intraductal papillary mucinous neoplasms (IPMNs) may develop even within ectopic pancreas. We recently encountered an extremely rare case of ectopic pancreas in the gastric antrum associated with IPMN possessing a GNAS mutation. CASE PRESENTATION: A 71-year-old Japanese woman complained of epigastric pain. Computed tomography and upper gastrointestinal endoscopy showed an intramural cystic mass in the antrum of the stomach. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy did not give a definitive diagnosis, and the patient underwent resection of the lesion. Histology of the resected specimen showed that the gastric intramural lesion was ectopic pancreas. Moreover, the lesion contained dilated duct components with tubulo-villous epithelial proliferation consistent with pancreatic IPMN. Since the covering epithelial cells had highly atypical nuclei, the lesion was diagnosed as IPMN with high grade dysplasia. Immunohistochemistry showed that the IPMN component showed to be MUC2-, MUC5AC-, and CDX2-positive but MUC1- and MUC6-negative. Mutational analyses using genomic DNA revealed that the IPMN component had a mutation of GNAS at exon 8 (Arg201Cys). CONCLUSION: We finally diagnosed this case as gastric ectopic pancreas accompanied by intestinal type IPMN with high grade dysplasia possessing GNAS mutation. Although there were 17 cases of ectopic pancreas with IPMN including 6 cases of gastric ones reported in the English literature, this is the first case of ectopic pancreas with IPMN which was proved to have GNAS mutation. Intimate preoperative examinations including imaging analyses and EUS-FNA biopsy/cytology are recommended to decide whether the lesion has to be resected or not even if they are not effective for getting the right diagnosis.

[A Case of Pancreatic Adenocarcinoma with Inferior Vena Cava Invasion].

A 66-year-old Japanese woman was admitted to our hospital for jaundice. Abdominal computed tomography(CT) showed dilatation of the intra- and extra-hepatic bile duct, and a hypovascular lesion measuring 30mm in diameter in the head of the pancreas. This tumor was in contact with the(superior mesenteric vein: SMV)and(inferior vena cava: IVC), but there were no obvious signs of invasion. Upper gastrointestinal endoscopy showed obstruction of the duodenum. We chose to perform an upfront surgery, considering the patient's general condition being stable and the difficulties associated with endoscopic biliary drainage. During surgery, stiff attachment between the tumor and IVC was identified and wedge resection of the IVC wall was performed. SMV resection and end-to-end reconstruction were also carried out. Pathological studies of the surgical specimen revealed direct invasion by the pancreatic adenocarcinoma into the adventitia of the IVC. The postoperative course was uneventful, and the patient was discharged from the hospital on the 27th postoperative day; she underwent adjuvant chemotherapy(S-1 100mg/day)and is still alive without tumor recurrence, 21 months after surgery. Cases of resected pancreatic adenocarcinoma directly invading the IVC are rare. In this case, pancreaticoduodenectomy along with wedge resection of the IVC wall could safely be performed, and no complications were observed. There is a need for further accumulation of similar cases.

Expression of programmed death-1 in sentinel lymph nodes of breast cancer.

BACKGROUND AND OBJECTIVES: To explore whether lymphocytes in sentinel lymph nodes (SLNs) are highly exposed to tumor neoantigens and thus express high level of programmed death 1 (PD-1), we examined PD-1 expression in SLNs and non-sentinel regional lymph nodes (non-SLNs) in breast cancer. METHODS: We performed PD-1 immunohistochemistry in two cohorts: 40 metastasis-negative SLNs including 10 patients for each subtype (luminal A-like, luminal B-like, HER2, and triple negative breast cancer [TNBC]); and 25 pairs of metastasis-positive SLNs and non-SLNs (10 luminal A-like, 10 luminal B-like, and 5 TNBC). RESULTS: Among 40 metastasis-negative SLNs, 34 and 6 samples were PD-1 intensity grade 1 (low) and 2 (high), respectively. PD-1 intensity correlated with PD-1-positive lymphocyte numbers (P = 0.005); TNBC had the highest PD-1 lymphocyte numbers among all subtypes. The median PD-1-positive lymphocyte number was higher in SLNs than non-SLNs. In most cases, more lymphocytes in SLNs expressed PD-1 than those in non-SLNs (P < 0.0001). CONCLUSIONS: TNBC had the greatest PD-1 expression among all subtypes, and metastasis-positive SLNs had more PD-1-positive lymphocytes than downstream non-SLNs. These data suggested that lymphocytes in SLNs are activated following exposure to tumor neoantigens and thus tumor specific, and could be utilized as a biomarker platform.

Solid-state structures of peapod bearings composed of finite single-wall carbon nanotube and fullerene molecules.

A supramolecular combination of carbon nanotube and fullerene, so-called a peapod, has attracted much interest, not solely because of its physical properties but also for its unique assembled structures of carbonaceous entities. However, the detailed structural information available was not sufficient for in-depth understanding of its structural chemistry or for exploratory research inspired by novel physical phenomena, mainly because of the severely inhomogeneous nature of currently available carbon nanotubes. We herein report solid-state structures of a molecular peapod. This structure, solved with a belt-persistent finite carbon nanotube molecule at the atomic level by synchrotron X-ray diffraction, revealed the presence of a smooth, inflection-free Hirshfeld surface inside the tube, and the smoothness permitted dynamic motion of the C60 guest molecule even in the solid state. This precise structural information may inspire the molecular design of carbonaceous machines assembled purely through van der Waals contacts between two neutral molecules.

Analysis of the cooperative ATPase cycle of the AAA+ chaperone ClpB from Thermus thermophilus by using ordered heterohexamers with an alternating subunit arrangement.

The ClpB/Hsp104 chaperone solubilizes and reactivates protein aggregates in cooperation with DnaK/Hsp70 and its cofactors. The ClpB/Hsp104 protomer has two AAA+ modules, AAA-1 and AAA-2, and forms a homohexamer. In the hexamer, these modules form a two-tiered ring in which each tier consists of homotypic AAA+ modules. By ATP binding and its hydrolysis at these AAA+ modules, ClpB/Hsp104 exerts the mechanical power required for protein disaggregation. Although ATPase cycle of this chaperone has been studied by several groups, an integrated understanding of this cycle has not been obtained because of the complexity of the mechanism and differences between species. To improve our understanding of the ATPase cycle, we prepared many ordered heterohexamers of ClpB from Thermus thermophilus, in which two subunits having different mutations were cross-linked to each other and arranged alternately and measured their nucleotide binding, ATP hydrolysis, and disaggregation abilities. The results indicated that the ATPase cycle of ClpB proceeded as follows: (i) the 12 AAA+ modules randomly bound ATP, (ii) the binding of four or more ATP to one AAA+ ring was sensed by a conserved Arg residue and converted another AAA+ ring into the ATPase-active form, and (iii) ATP hydrolysis occurred cooperatively in each ring. We also found that cooperative ATP hydrolysis in at least one ring was needed for the disaggregation activity of ClpB.

Vba4p, a vacuolar membrane protein, is involved in the drug resistance and vacuolar morphology of Saccharomyces cerevisiae.

In the vacuolar basic amino acid (VBA) transporter family of Saccharomyces cerevisiae, VBA4 encodes a vacuolar membrane protein with 14 putative transmembrane helices. Transport experiments with isolated vacuolar membrane vesicles and estimation of the amino acid contents in vacuoles showed that Vba4p is not likely involved in the transport of amino acids. We found that the vba4Δ cells, as well as vba1Δ and vba2Δ cells, showed increased susceptibility to several drugs, particularly to azoles. Although disruption of the VBA4 gene did not affect the salt tolerance of the cells, vacuolar fragmentation observed under high salt conditions was less prominent in vba4Δ cells than in wild type, vba1Δ, and vba2Δ cells. Vba4p differs from Vba1p and Vba2p as a vacuolar transporter but is important for the drug resistance and vacuolar morphology of S. cerevisiae.

Risk factors associated with intraoperatively acquired pressure ulcers in the park-bench position: a retrospective study.

Patients undergoing surgery in the park-bench position are at high risk of developing intraoperatively acquired pressure ulcers (IAPUs). The purpose was to examine retrospectively risk factors associated with IAPUs in the park-bench position. This study was conducted at a general hospital during the period of September 2010 to September 2012. Twenty-one potential risk factors were evaluated using data obtained from the hospital database. IAPUs developed in 30 of 277 patients (11%). Perspiration was statistically found to be independently associated with IAPUs [OR 3·09, 95% confidence interval (Cl) 1.07-8·58, P = 0·037]. A length of surgery of more than 6 hours was identified to be likely associated with IAPUs (OR 2·64, 95% Cl 0·84-9·08, P = 0·095) compared with less than 6 hours. Furthermore, there was an interaction between the length of surgery and the core temperature; that is, when the length of surgery was more than 6 hours, a core temperature of more than 38·1°C at the end of surgery had a higher odds ratio (8·45, 95% Cl 3·04-27·46, P < 0·001) than that at a lower core temperature (3·20, 95% Cl 1·23-8·78, P = 0·017). These results suggest that perspiration and core temperature are preventable causative factors of pressure ulcers, even under conditions of prolonged surgery in the park-bench position.

[Intrapulmonary Sewing Needle].

Intrapulmonary aberrant needles are rarely encountered in clinical practice. A 82-year-old woman, though she was asymptomatic, was referred to our department due to an abnormal shadow on a chest X-ray. Chest X-ray and chest computed tomography showed a foreign body suspected to be a sewing needle in the left upper lobe. The needle was successfully removed by video-assisted thoracoscopic surgery.

Absence of primary cilia in cell cycle-arrested human breast cancer cells.

Previous studies using cultured cells showed that primary cilia are present in quiescent cells, but are absent in proliferating cells. We studied here the relationship between the presence or absence of primary cilia and the cell cycle arrest of normal epithelial cells and cancer cells in the human normal breast and breast cancer tissues. In normal breast tissues, although most epithelial cells were nonproliferating as estimated by the immunofluorescence staining of the proliferation marker Ki-67, primary cilia were present only in 20-40% of the epithelial cells. In breast cancer tissues, primary cilia were not observed in any of the breast cancer cells. Furthermore, primary cilia were hardly observed in the nonproliferating cancer cells in the orthotopic and metastatic human breast cancer xenograft tumors in mice. These results indicate that the absence of primary cilia does not necessarily represent the proliferating phases of normal epithelial cells and cancer cells.

Microclimate is an independent risk factor for the development of intraoperatively acquired pressure ulcers in the park-bench position: A prospective observational study.

Preventing pressure ulcers is important in patients undergoing procedures in the park-bench position. We hypothesized that the microclimate around the skin is a significant risk factor for developing pressure ulcers. This research continuously assessed factors of the microclimate in terms of skin temperature and perspiration as well as the interface pressure in order to determine whether the microclimate is an independent risk factor for the development of park-bench position-related pressure ulcers (PBP-PUs). A prospective observational study was conducted among patients undergoing elective surgery in the park-bench position at a general hospital in the metropolitan area of Japan between April and November 2014. Factors of the microclimate, including skin temperature and perspiration, in addition to the interface pressure were continuously measured throughout surgery. Twenty-nine patients were analyzed (mean age 44.4 ± 13.2 years, male 44.8%). Of these 29 patients, seven (24.1%) developed Category I PBP-PUs. The change in skin temperature from baseline to the end of surgery (2.7 ± 0.3 °C vs. 1.9 ± 0.8 °C) and the average peak pressure (119.1 ± 36.8 mmHg vs. 94.5 ± 23.1 mmHg) were significantly higher in the patients with PBP-PUs than in those without PBP-PUs. There were no significant differences in the amount of perspiration between the two groups. A hierarchical logistic regression analysis showed that the change in skin temperature was significantly related to the development of PBP-PUs (unit = 0.1 °C: odds ratio 1.44, 95% confidential interval 1.09-2.33) when adjusted for the average peak pressure and length of surgery. Our results suggest that a change in skin temperature toward a higher value is an independent risk factor for the development of PBP-PUs. Proper intraoperative management of skin temperature may therefore be a promising candidate as a preventive method against PBP-PU development.

A large cavernous malformation of the third ventricle floor: A case report.

Suprasellar and third ventricular region cavernous malformations originating from the floor of the third ventricle are extremely rare. We report a case of third ventricular cavernous malformation arising from the ventricle floor in a 24-year-old woman who presented with short-term memory loss and disorientation. Computed tomography revealed a suprasellar mass with calcification in the posterior chiasmatic region. T2-weighted magnetic resonance imaging revealed a mass with heterogeneous intensity and without hydrocephalus. The mass was slightly enhanced subsequent to gadolinium infusion. Using a basal interhemispheric translamina terminalis approach and a neuroendoscope, we confirmed that the tumor was located at the floor of the third ventricle and removed it. Histopathological examination confirmed the diagnosis of cavernous malformation. The postoperative course was uneventful, but the patient's short-term memory loss persisted. Despite its rarity, cavernous malformation should be suspected when a tumor is detected in the vicinity of the third ventricle floor. It is treatable through surgical resection.

[A case of pancreatic mixed acinar-endocrine carcinoma suggested by preoperative ultrasound-guided fine needle aspiration].

A 73-year-old man visited our hospital for consultation regarding a pancreatic tumor. Abdominal computed tomography, magnetic resonance imaging, and endoscopic ultrasound scan (EUS) revealed tumor 2 cm in diameter located in the pancreatic tail. EUS-guided fine needle aspiration (EUS-FNA) suggested pancreatic mixed acinar-endocrine carcinoma, and he underwent distal pancreatectomy. Few reports exist where preoperative EUS-FNA suggested pancreatic mixed acinar-endocrine carcinoma; thus, we report this case.

Quantitative comparison of the isolation lesions between conventional- and larger-sized visually guided laser balloon ablation.

BACKGROUND: The importance of a wider circumferential isolation of the pulmonary veins (PV), which includes a large portion of the left atrial posterior wall (LAPW), has been suggested in several studies. However, the extended isolation area using a larger inflated visually guided laser balloon (VGLB) ablation remains to be elucidated. METHODS: Seventy-eight patients with atrial fibrillation (AF) who underwent VGLB ablation were enrolled in this prospective study. An electroanatomic map of the left atrium was obtained before and after PV isolation (PVI) using a conventional-sized VGLB. The isolation areas were extended by the largest-sized VGLB ablation and remapped in the same manner. After the ablation, isolation areas were calculated with CARTO-3 system. The one-year atrial arrhythmia (Ata) recurrence was assessed.  RESULTS: The largest-sized VGLB ablation yielded statistically greater areas of isolation in left-sided PV antrum (PVA) (11.5 ± 2.3 cm2 vs. 15.9 ± 3.5 cm2, P < .001) and right-sided PVA (14.2 ± 3.3 cm2 vs. 20.6 ± 4.4 cm2, P < .001) than the conventional-sized VGLB. Further, non-ablated LAPW (12.3 ± 4.4 cm2 vs. 7.8 ± 3.9 cm2, P < .001) was significantly reduced after largest-sized VGLB ablation, compared to the conventional-sized VGLB ablation. The one-year Ata freedom was 83.7% in patients with paroxysmal AF and 96.4% in those with persistent AF. CONCLUSION: The largest-sized VGLB ablation technique can create a significantly wider isolation area of PVA and debulk a large amount of LAPW than the conventional-sized VGLB ablation. The one-year outcome was similarly high in paroxysmal and persistent AF.