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Treprostinil is a chemically stable analog of prostacyclin, and inhaled treprostinil was developed to deliver the effects directly to the pulmonary vasculature while minimizing systemic side effects. The objective of the study was to evaluate the efficacy on hemodynamics and exercise capacity, safety, and pharmacokinetics (PK) of inhaled treprostinil in Japanese patients with pulmonary arterial hypertension (PAH). Inhaled treprostinil was administered at three breaths (18 μg)/session four times daily, and the dose was gradually increased to a maximum of nine breaths (54 μg)/session. Endpoints included change in pulmonary vascular resistance index (PVRI) as primary, other efficacy parameters, safety, and PK. Seventeen PAH patients, the majority of whom (76.5%) had been receiving both an endothelin receptor antagonist (ERA) and a phosphodiesterase type-5 (PDE5) inhibitor/soluble guanylate cyclase (sGC) stimulator, received inhaled treprostinil. At Week 12, PVRI statistically decreased by -39.4 ± 25.5% (95% confidence interval: -52.6 to -26.3). The most frequently reported adverse events related to treprostinil were headache, cough, throat irritation, and hot flush. Regarding PK, there were no notable differences in the geometric mean C max and AUC last between Japanese and non-Japanese patients. Treatment with inhaled treprostinil using the dosing regimen approved in the United States resulted in significant improvement in hemodynamics, exercise capacity, and symptoms with a favorable tolerability and safety profile in Japanese patients. Inhaled treprostinil could be a valuable therapeutic option for Japanese patients with PAH, including those receiving a combination therapy with an ERA and a PDE5 inhibitor/sGC stimulator. Trial registration: JAPIC Clinical Trials Information [JapicCTI-194651]., Competing Interests: MK has received grants from Boehringer Ingelheim and Ono Pharmaceutical; royalty from Medical Biological Laboratories; consulting fees from Kissei, Boehringer Ingelheim, and Mochida Pharmaceutical; lecture fees, or speaker fees from Boehringer Ingelheim, Ono Pharmaceutical., AbbVie, Asahi Kasei, Janssen Pharmaceutical, Astellas, Chugai Pharmaceutical, Eisai, Nippon Shinyaku, Mitsubishi‐Tanabe, and Mochida Pharmaceutical; participation on a data safety monitoring board or advisory board at AstraZeneka, Corbus, GlaxoSmithKline, Horizon Therapeutics, and Argenx. KA has received research funds from Mochida Pharmaceutical, Janssen Pharmaceutical, Nippon Shinyaku, Daiichi Sankyo, and Konica Minolta; speaker fees from Mochida Pharmaceutical, Janssen Pharmaceutical, Nippon Shinyaku, Bayer Yakuhin, Daiichi Sankyo, and Otsuka Pharmaceutical; fees for serving on advisory boards from Janssen Pharmaceutical. HK has received speaker fees from Nippon Shinyaku, Janssen Pharmaceutical, Bayer Yakuhin, and Mochida Pharmaceutical; consulting fees from Mochida Pharmaceutical. He belongs to the endowed department by Obama Municipal Hospital. HM has received research funds from Janssen Pharmaceutical, Nippon Shinyaku, and Mochida Pharmaceutical; lecture fees from Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, GlaxoSmithKline, and Mochida Pharmaceutical. SM has received research funds from Fukuda Foundation for Medical Technology. TM has received speaker fees from Mochida Pharmaceutical, Janssen Pharmaceutical, and Bayer Yakuhin. SS has received consulting fees from Mochida Pharmaceutical; lecture fees from Nippon Shinyaku, Bayer Yakuhin, Janssen Pharmaceuticals, Bayer AG, Pfizer, and Mochida Pharmaceutical. YS has received speaker fees from Janssen Pharmaceutical, Viatris, Nippon Shinyaku, and Mochida Pharmaceutical. NT has received lecture fees from Janssen Pharmaceutical, Nippon Shinyaku, Mochida Pharmaceutical, Pfizer, and Bayer Yakuhin. IT has received speaker fees from Mochida Pharmaceuticals. He belongs to the endowed department by Nippon Shinyaku, Boehringer Ingelheim, and Mochida Pharmaceutical. KT and SK are employees of Mochida Pharmaceutical. They have received remuneration and travel fees within the framework of their employment. TO has received lecture fees from GlaxoSmithKline, Janssen Pharmaceutical, Nippon Shinyaku, Pfizer, and Bayer Yakuhin; research grants from Pfizer, and Mochida Pharmaceutical; speaker fees from Mochida Pharmaceutical. He belongs to the endowed department of Janssen Pharmaceuticals., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background: The feasibility and safety of pulmonary vein isolation (PVI) using cryoballoon (CB) for paroxysmal atrial fibrillation (PAF) with minimally interrupted apixaban has not fully explored., Methods: In this multicenter, randomized prospective study, we enrolled patients with PAF undergoing CB or radiofrequency (RF) ablation with interrupted (holding 1 dose) apixaban. The primary composite end point consisted of bleeding events, including pericardial effusion and major bleeding requiring blood transfusion, or thromboembolic events at 4 weeks after ablation; secondary end points included early recurrence of AF and procedural duration., Results: A total of 250 patients underwent PVI (125 assigned to the RF ablation and 125 assigned to the CB ablation). The primary end point occurred in 1 patient in the CB ablation group (0.8%; 90% confidence interval [CI], 0.04 to 3.70) and 3 patients in the RF group (2.4%, P  = .622; risk ratio, 0333; 90% CI, 0.05 to 2.20). All events were pericardial effusion, all of whom recovered after pericardiocentesis. Early recurrence of AF occurred in 4 patients (3.2%) in the RF group and in 6 patients (4.8%) in the CB group ( P  = .749). The procedural duration was shorter in the CB group than that in the RF group (136.5 ± 39.9 vs 179.5 ± 44.8 min, P  < .001)., Conclusion: CB ablation with minimally interrupted apixaban was feasible and safe in patients with PAF undergoing PVI, which was equivalent to RF ablation., Competing Interests: The local institutional review board of Tokyo Medical and Dental University approved the trial on June 23, 2015 (number R2015‐012), and the trial was registered at the UMIN Clinical Trial Registry on September 3, 2015 (number UMIN000018901). Drs. Takahashi and Maeda received an endowment from Medtronic, Boston Scientific, Japan Lifeline, and WIN International. All the other authors report that they have no relationships to disclose that are relevant to the contents of this paper., (© 2020 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Objectives: To examine the influence of hydrostatic pressure on fractional flow reserve (FFR) in vivo., Background: Systematic differences in FFR values have been observed previously in the left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA). It has been suggested that as the hydrostatic pressure variations caused by the height differences between the catheter tip (mean aortic pressure (Pa)) and pressure-wire sensor (mean distal intracoronary pressure (Pd)) are small, intracoronary pressure need not be corrected., Methods: Resting Pd/Pa and FFR values in 23 patients (27 lesions) were measured and compared in supine and prone positions. These values were corrected by hydrostatic pressure influenced by height levels and compared. Height differences between Pa and Pd were calculated using coronary computed tomography angiographies., Results: In LAD, resting Pd/Pa and FFR values were significantly higher in the prone position than in the supine position (0.97 ± 0.05 vs 0.89 ± 0.04, P < 0.001 (resting Pd/Pa); 0.81 ± 0.09 vs 0.72 ± 0.07, P < 0.001 (FFR)). Conversely, in LCX and RCA, these values were significantly lower in the prone position (LCX: 0.93 ± 0.03 vs 0.98 ± 0.03, P < 0.001 (resting Pd/Pa); 0.84 ± 0.05 vs 0.89 ± 0.04, P < 0.001 (FFR); RCA: 0.91 ± 0.04 vs 0.98 ± 0.03, P =0.005 (resting Pd/Pa); 0.78 ± 0.07 vs 0.84 ± 0.07, P =0.019 (FFR)). FFR values corrected by hydrostatic pressure showed good correlations in the supine and prone positions ( R 2  = 0.948 in LAD; R 2  = 0.942 in LCX; R 2  = 0.928 in RCA)., Conclusions: Hydrostatic pressure variations due to height levels influence intracoronary pressure measurements and largely affect resting Pd/Pa and FFR, which might have caused systematic differences in FFR values between the anterior and posterior coronary territories., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Yoshitaka Kawaguchi et al.)

Background: Ventricular fibrillation (VF) in Brugada syndrome (BrS) is known to occur more frequently during nighttime and from spring to early summer. In this study, we investigated whether early repolarization syndrome (ERS) has the same seasonal, weekly, and circadian distribution of VF events as BrS using data from the "J-wave associated with prior cardiac event" (J-PREVENT) registry., Methods: The study included 90 consecutive patients with BrS and 31 patients with ERS during a mean follow-up of 49±37 months. Follow-up data from implantable cardioverter-defibrillators were evaluated in all cases., Results: In patients with ERS, the circadian distribution of VF episodes differed among the four 6-h periods, with a significant peak from midnight to 6:00 am (p<0.01) similar to that observed in BrS patients. However, VF occurred more frequently on weekends in patients with ERS, whereas on weekdays in patients with BrS (p<0.01). The months of peak VF occurrence also differed between the groups, with the frequency of VF episodes at peak between December and March in ERS patients and between March and June in BrS patients. In ERS patients, VF events had an inverse correlation with air temperature (r=-0.726, p<0.01)., Conclusions: ERS and BrS patients show similar nighttime increases in the occurrence of VF, but different seasonal and weekly distributions, suggesting a pathophysiological difference between the two syndromes.

Objective: To clarify the role of pentraxin 3 (PTX3), a multifunctional pattern recognition protein that can suppress fibroblast growth factor 2 (FGF-2), in systemic sclerosis (SSc)-related vasculopathy., Methods: We assessed 171 SSc patients and 19 age- and sex-matched healthy control subjects. Circulating PTX3 and FGF-2 levels were measured by enzyme immunoassay, and CD34+CD133+CD309+ endothelial progenitor cells (EPCs) were counted by flow cytometry. Correlations between PTX3 and FGF-2 and the presence or future development of vascular manifestations, including digital ulcers and pulmonary arterial hypertension (PAH), were identified by univariate and multivariate analysis. The effect of PTX3 on EPC differentiation was evaluated in proangiogenic cultures of mouse bone marrow cells in combination with colony formation assay., Results: Circulating PTX3 and FGF-2 levels were significantly higher in SSc patients than in healthy control subjects. PTX3 was elevated in SSc patients who had digital ulcers or PAH, while FGF-2 was reduced in SSc patients with PAH. Multivariate analysis identified elevated PTX3 as an independent parameter associated with the presence of digital ulcers and PAH, and PTX3 levels were a useful predictor of future occurrences of digital ulcers. Reduced FGF-2 was independently associated with the presence of PAH. EPC counts were significantly lower in patients with digital ulcers or PAH and correlated negatively with circulating PTX3 concentrations. Finally, PTX3 inhibited EPC differentiation in vitro., Conclusion: In SSc patients, exposure to high concentrations of PTX3 may suppress EPC-mediated vasculogenesis and promote vascular manifestations such as digital ulcers and PAH., (Copyright © 2015 by the American College of Rheumatology.)

Objective: The objective of this study was to evaluate the patients' perception of the usefulness of a question prompt sheet (QPS) in facilitating the involvement of advanced cancer patients during consultation., Methods: Advanced cancer patients attending their first consultation after diagnosis were randomly assigned to the intervention group (received QPS and a hospital introduction sheet (HIS)) or the control group (received HIS only). Analysis was conducted on an intention-to-treat basis. The primary outcome measure was patient rating of the usefulness of the material(s) (numerical rating scale of 0-10)., Results: Sixty-three advanced cancer patients (72.4% response rate) were enrolled and analyzed. Nearly three-quarters of patients in both groups read the material(s) before consultation. The rated usefulness of the material(s) for asking questions of physicians was significantly higher in the intervention group than in controls (4.4 ± 3.6 and 2.7 ± 2.8, respectively; p = 0.033). The mean score of the usefulness of the material(s) for understanding the treatment plan tended to be higher in the intervention group than in the controls (4.9 ± 3.6 and 3.3 ± 2.8; p = 0.051). The mean score of willingness to use the material(s) in the future was significantly higher in the intervention group than in the controls (5.3 ± 3.8 and 2.8 ± 2.8; p = 0.006). There were no significant differences between the groups in the average total number of questions asked by patients (median, 1.0; interquartile range in both groups, 2.0)., Conclusions: QPS provided before oncology consultation may be useful for advanced cancer patients, on the other hand, it did not directly promote patient confidence to ask questions., (Copyright © 2011 John Wiley & Sons, Ltd.)

In mast cells, crosslinking the high-affinity IgE receptor (FcɛRI) results in a dynamic reorganization of the actin cytoskeleton that is associated with membrane ruffling. Although the signaling involved in degranulation has been well described, it is less understood in morphological changes. In this study, we investigated the specific role of conventional protein kinase C (cPKC), a crucial signal for degranulation, in antigen-induced membrane ruffling of mast cells. In RBL-2H3 mast cells, antigen induced a long-lasting membrane ruffling, which was blocked with late-added Gö6976, a specific cPKC inhibitor, indicating that sustained activation of cPKC is required for maintaining the reaction. Immunofluorescence staining of endogenous PKCα/β and real-time imaging of transfected green fluorescent protein-tagged PKCα/β demonstrated that in response to antigen both PKCα and PKCβI quickly translocated to the plasma membrane and were colocalized with actin filaments at the ruffling sites. These reactions were blocked by expression of kinase-negative PKCβI, but not kinase-negative PKCα, and by treatment with a specific PKCβ inhibitor, LY333531. The adhesion, spreading and membrane ruffling of mouse bone marrow-derived mast cells (BMMCs), which are mostly nonadhesive, were promoted by both antigen and thymeleatoxin. Treatment with Gö6976 abolished all these reactions. Antigen-mediated migration of BMMC was also sensitive to Gö6076 and LY333531. In addition, BMMC adhesion by and migration toward stem cell factor were shown to be dependent on cPKC. Thus, cPKC, at least PKCβ subtype, may be critical for the dynamic morphological changes that lead to the migration of mast cells.

Background: We tested the hypothesis that in patients with T1 extrahepatic cholangiocarcinoma (EHC), prognosis postresection is significantly different for those with tumors that are limited to the mucosa than for those with tumors that have invaded (but not penetrated) the fibromuscular layer., Methods: A retrospective analysis was conducted of 33 consecutive patients with pathologic T1 (pT1) EHC tumors. According to the depth of invasion, the pT1 tumors were divided into 2 groups: Group 1, tumors that were limited to the mucosa (mucosal tumors); and Group 2, tumors that had invaded (but not penetrated) the fibromuscular layer (fibromuscular layer-invasive tumors). Long-term outcomes after resection were compared between the 2 groups for a median follow-up time of 175 months., Results: Eighteen patients had mucosal tumors and 15 patients had tumors that had invaded the fibromuscular layer. None of the patients with mucosal tumors had lymphovascular invasion, whereas 3 of the patients with fibromuscular layer-invasive tumors had lymphovascular invasion (P = .083). Overall survival after resection was better in Group 1 than in Group 2 (cumulative 10-year survival rate, 100% vs 52%; P = .024). The rate of disease-free survival after resection was higher in Group 1 than in Group 2 (cumulative disease-free 10-year survival rate, 100% vs 56%; P = .022)., Conclusions: The long-term outcome after resection for EHC is significantly better for patients with mucosal tumors than for patients with fibromuscular layer-invasive tumors. This suggests that the depth of tumor invasion affects the postresection prognosis for patients with pT1 EHC.

Background: The examination of pancreatic juice cytology could hypothetically contribute to the establishment of a definite diagnosis of malignant intraductal papillary mucinous neoplasm of the pancreas (IPMN), but to the authors' knowledge, its significance has not been confirmed to date. The current study was conducted to assess the diagnostic value of pancreatic juice cytology in IPMN and to examine the usefulness of peroral pancreatoscopy (POPS) in sampling pancreatic juice., Methods: The study subjects were comprised of 103 patients with IPMN who underwent surgical resection of pancreatic tumors (adenoma in 29 patients, borderline in 17 patients, carcinoma in situ in 25 patients, and invasive carcinoma in 32 patients). Pancreatic juice was collected with a catheter in 71 patients and by POPS in 32 patients. Patients with pancreatic carcinoma (n = 81) and chronic pancreatitis (n = 76) also were investigated., Results: The cytologic diagnosis was found to be of nondiagnostic value in only one patient with an IPMN, whereas it was of no diagnostic value in 14 of the patients with pancreatic carcinoma (17.3%), a difference that was statically significant (P < 0.001). The location of the IPMN (either in the pancreas or the pancreatic ducts) was not found to significantly affect the diagnostic value of the test. The sensitivity for IPMN was 62.2% when pancreatic juice was collected by POPS, and was 38.2% when it was collected using a catheter. In the case of pancreatic carcinoma, the sensitivity of pancreatic juice cytology was found to be 25.4%, which was significantly lower than that for IPMN when the pancreatic juice was collected by POPS (P < 0.001)., Conclusions: Pancreatic juice cytology was found to have better diagnostic value in the patients with IPMNs compared with those with pancreatic carcinoma. POPS was found to be useful for the collection of pancreatic juice., (Copyright 2005 American Cancer Society.)

Background: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a negative regulator of tumor cell growth, and may function as a tumor suppressor. CEACAM1 expression is down-regulated with increasing histologic grade in a number of malignancies. The authors hypothesized that loss of CEACAM1 expression in hepatocellular carcinoma (HCC) cells may function as an adverse prognostic factor., Methods: A retrospective analysis was conducted of 139 consecutive patients who underwent resection for HCC, with a median follow-up period of 83 months. Immunohistochemistry of the resected specimens was conducted using a monoclonal anti-CEACAM1 antibody. CEACAM1 expression in HCC was classified into two categories: diffuse expression, characterized by positive staining throughout the tumor specimen, or loss of expression, in which there were distinct areas of negative staining within the tumor specimen., Results: Of the 139 patients, 113 were classified as having tumors with diffuse expression and 26 had loss-of-expression tumors. Loss of CEACAM1 expression was more frequent in tumor specimens with Edmondson-Steiner Grades III or IV (21 of 32 [66%]) than in tumor specimens with Grades I or II (5 of 107 [5%]; P < 0.001) and was always seen in areas with the highest histologic grade. Loss of CEACAM1 expression was significantly associated with large tumor size, multiplicity of the tumor, portal vein invasion, and satellite nodules and affected survival adversely, according to univariate (P < 0.0001) and multivariate analyses (relative risk, 5.737; P < 0.001)., Conclusions: Loss of CEACAM1 expression reflects aggressive tumor biology and thus indicates a poor prognosis for patients with HCC.

1 To clarify the mechanism of mast cell TNF secretion, especially its release process after being produced, we utilized an antiallergic drug, azelastine (4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)- phthalazinone), which has been reported to inhibit TNF release without affecting its production in ionomycin-stimulated RBL-2H3 cells. 2 Such inhibition was associated with the suppression of an ionomycin-induced increase in membrane-associated PKC activity rather than the suppression of Ca2+ influx, suggesting that PKC might be involved in TNF release process. 3 To see whether conventional PKC family (cPKCs) are involved, we investigated the effects of a selective cPKC inhibitor (Gö6976) and an activator (thymeleatoxin) on TNF release by adding them 1 h after cell stimulation. By this time, TNF mRNA expression had reached its maximum. Gö6976 markedly inhibited TNF release, whereas thymeleatoxin enhanced it, showing a key role of cPKC in TNF post-transcriptional process, possibly its releasing step. 4 To determine which subtype of cPKCs could be affected by azelastine, Western blotting and live imaging by confocal microscopy were conducted to detect the translocation of endogenous cPKC (alpha, betaI and betaII) and transfected GFP-tagged cPKC, respectively. Both methods clearly demonstrated that 1 microM azelastine selectively inhibits ionomycin-triggered translocation of (alpha)PKC without acting on betaI or betaIIPKC. 5 In antigen-stimulated cells, such a low concentration of azelastine did not affect either (alpha)PKC translocation or TNF release, suggesting a functional link between (alpha)PKC and the TNF-releasing step. 6 These results suggest that (alpha)PKC mediates the TNF release process and azelastine inhibits TNF release by selectively interfering with the recruitment of (alpha)PKC in the pathway activated by ionomycin in RBL-2H3 cells.

Background: The current study was performed to clarify whether the presence of residual carcinoma in situ at ductal resection margins differs prognostically from residual invasive ductal lesions in patients undergoing surgical resection for extrahepatic cholangiocarcinoma., Methods: A retrospective analysis of 84 patients with extrahepatic cholangiocarcinoma who underwent surgical resection was conducted. The ductal resection margin status was classified as negative (n = 64 patients), positive with carcinoma in situ (n = 11 patients), or positive with invasive carcinoma (n = 9 patients). The median follow-up period was 105 months., Results: Ductal margin status was found to be a strong independent prognostic factor by both univariate (P = 0.0002) and multivariate (P = 0.0039) analyses. The outcome after surgical resection was comparable between patients with negative ductal margins (median survival time of 45 months; cumulative 10-year survival rate of 40%) and those with positive ductal margins with carcinoma in situ (median survival time of 99 months; cumulative 10-year survival rate of 23%; P = 0.4742). In patients with positive ductal margins, the outcome was found to be significantly better in patients with residual carcinoma in situ than in those with residual invasive carcinoma (median survival time of 21 months; cumulative 5-year survival rate of 0%; P = 0.0003). Of 11 patients with residual carcinoma in situ, 4 died of tumor recurrence and the initial site of the disease recurrence was local. All 9 patients with residual invasive carcinoma died of disease recurrence (local recurrence with or without distant metastases) within 40 months after surgical resection., Conclusions: After surgical resection for extrahepatic cholangiocarcinoma, invasive carcinoma at ductal resection margins appears to have a strong adverse effect on patient survival, whereas residual carcinoma in situ does not.

Background: Adenosquamous/squamous cell carcinoma of the gallbladder generally has been considered a lethal disease. The objective of this study was to clarify the effectiveness of resection for patients with adenosquamous/squamous cell carcinoma of the gallbladder., Methods: Twenty-nine patients who underwent resection for either adenosquamous carcinoma (n = 28 patients) or squamous cell carcinoma (n = 1 patient) were analyzed retrospectively. Sixteen patients underwent radical resection, whereas the other patients underwent primary tumor resection alone. To elucidate the factors that influenced postresectional survival, 10 variables (age, gender, presence or absence of gallstones, size of the primary tumor, lymphatic vessel invasion, blood vessel invasion, perineural invasion, TNM stage, residual tumor status, and type of resection) were examined., Results: Twenty-three patients (79.3%) were categorized with T3 or T4 tumors that invaded adjacent organs. The outcome after undergoing radical resection (cumulative 5-year survival rate, 48.6%) was significantly better compared with the outcome of patients after undergoing primary tumor resection alone (cumulative 3-year survival rate, 7.7%; P = 0.004). The outcome after undergoing resection was better in 14 patients who had no residual tumor (cumulative 5-year survival rate, 62.9%) compared with the outcome in 15 patients who had residual tumor (cumulative 5-year survival rate, 0%; P < 0.001). Univariate analysis revealed that residual tumor status (P < 0.001), type of resection (P = 0.004), patient age (P = 0.012), and blood vessel invasion (P = 0.017) were significant prognostic factors. Residual tumor status (P = 0.026) was the only significant independent prognostic factor., Conclusions: Adenosquamous/squamous cell carcinoma of the gallbladder warrants resection only if potentially curative (R0) resection is feasible., (Copyright 2002 American Cancer Society.)

Background: Hepatic metastases from colorectal carcinoma frequently recur after resection and hepatic micrometastases most likely are important in the development of such recurrences. The objectives of the current study were to assess the feasibility of the immunohistochemical detection of hepatic micrometastases from colorectal carcinoma and to determine their clinical significance., Methods: Fifty-three patients underwent curative hepatic resection for colorectal carcinoma metastases. Multiple tissue sections were cut from the advancing margin of the largest hepatic metastasis in each patient and were stained with an antibody against cytokeratin-20 to detect hepatic micrometastases, which were defined as discrete microscopic cancerous lesions surrounding the dominant metastasis., Results: Normal hepatocytes and intrahepatic bile duct epithelia stained negative for cytokeratin-20 in all patients, whereas the largest hepatic tumors stained positive in 46 patients (86.8%). Among the 46 patients with hepatic tumors that were positive for cytokeratin-20, hepatic micrometastases were found immunohistochemically in 32 patients (69.6%). The presence of hepatic micrometastases was associated with a larger number of macroscopic hepatic metastases (P = 0.047) and patients with hepatic micrometastases were found to demonstrate a higher probability of intrahepatic recurrence (P = 0.003) compared with those patients without hepatic micrometastases. In addition, patients with hepatic micrometastases demonstrated a worse survival (10-year survival rate of 21.9%) compared with those patients without hepatic micrometastases (10-year survival rate of 64.3%) (P = 0.017)., Conclusions: Immunohistochemical detection of hepatic micrometastases is feasible in patients with colorectal carcinoma liver metastases. Hepatic micrometastasis indicates widespread hepatic involvement and thus predicts an increased risk of intrahepatic recurrence after hepatic resection and a poorer patient prognosis., (Copyright 2002 American Cancer Society.)

Background: The objective of this study was to define the sensitivity and clinical implications of the immunohistochemical detection of lymph node micrometastases in patients with gallbladder carcinoma (GBC)., Methods: The authors examined a total of 385 regional lymph nodes taken from 26 consecutive patients with GBC who had undergone a radical resection. Histologic sections of the primary tumor and regional lymph nodes in each case were stained with both hematoxylin and eosin and an antibody against cytokeratins 8 and 18 (CAM5.2). A "micrometastasis" was defined as a metastasis missed on routine histologic examination with hematoxylin and eosin but detected by immunohistochemical examination with CAM5.2. Survival rates were calculated only in patients with Stage II or more advanced stage disease., Results: All primary tumors were positive for CAM5.2. Routine histologic examination revealed 53 positive lymph nodes that were stained consistently with CAM5.2. Another seven lymph nodes had micrometastases. Patients with micrometastases showed a significantly worse survival rate than those without micrometastases (P = 0.037, log rank test). Among patients with no lymph node disease on routine histologic examination, there was a trend toward a worse survival rate in those with lymph node micrometastases (P = 0.10, log rank test). The paraaortic lymph nodes were involved more frequently in patients with lymph node micrometastases than those without (P = 0.009, Fisher exact test)., Conclusions: The immunohistochemical detection of lymph node micrometastases using CAM5.2 is feasible in GBC patients and is useful in predicting survival in patients undergoing radical resection. Lymph node micrometastases may be an indicator of widespread lymph node disease in patients with GBC.

At least three GTP-binding proteins (G-proteins), 28, 25, and 21 kDa, were found in the brain-corpus cardiacum-corpus allatum complex (BR-CC-CA) of the silkworm, Bombyx mori. They bound to GTP and GDP specifically among nucleotides tested, indicating that these proteins are small G-proteins. The 25 kDa G-protein showed a cross-reactivity to anti-rab3A antibody, while it did not cross-react with anti-rhoA, rab3B, and anti-ras antibodies. On the other hand, the 28 and 21 kDa G-proteins showed no cross-reactivity to any of those antibodies tested. Immunoblot analysis using the anti-rab3A antibody demonstrated that the 25 kDa G-protein was detected preferentially in the BR-CC-CA, and to some extent in the suboesophageal ganglion, but not in the salivary gland, fat body, prothoracic gland, and oesophagus. These results suggested that the 25 kDa G-protein was a member of the rab family of G-proteins. Furthermore, 1 mM GTP gamma S capable of activating G-proteins induced BR-CC-CA to release PTTH under the conditions that stimulation of the PTTH release with hetero-trimeric G-protein was suppressed. These results indicated that the small G-proteins may possibly contribute to PTTH release in Bombyx mori.

Background: The objective of this study was to evaluate the efficacy of combined pancreaticoduodenectomy and hepatectomy for the treatment of patients with locally advanced gallbladder carcinoma., Methods: Long term results over 5 years of follow-up were analyzed retrospectively in 17 consecutive patients with gallbladder carcinoma who underwent combined pancreaticoduodenectomy and hepatectomy with radical lymphadenectomy. The indications for pancreaticoduodenectomy were direct invasion of the adjacent organs (stomach, duodenum, or pancreas) and/or the presence of peripancreatic (head only) lymph node metastases. The hepatectomy performed was a nonanatomic resection of the gallbladder bed in 15 patients and an extended right hepatectomy in 2 patients. There was 1 in-hospital death (6%)., Results: Overall, 5 patients (29%) survived 5 years after surgery. Of these patients, four had Stage IVB disease with positive peripancreatic lymph nodes. Eight of the 10 patients who underwent a potentially curative resection survived longer than 3 years, whereas none of the 7 patients with residual tumor survived beyond 15 months. The 5-year survival of 50% (median survival: 58.5 months) in those undergoing a potentially curative resection was significantly better than the 5-year survival of 0% (median survival: 8 months) observed in those patients with residual tumor (P = 0.00086)., Conclusions: Combined pancreaticoduodenectomy and hepatectomy is an efficacious treatment for patients with locally advanced gallbladder carcinoma, but only if a potentially curative resection is feasible. The presence of peripancreatic (head only) lymph node disease is not a contraindication for this procedure.

Background: Lymph node spread is the most common pattern of progression in gallbladder carcinoma (GBC) and is a prognostic factor. The purpose of this study was to determine the prevalence of lymph node metastases in patients with resected advanced GBC, and to evaluate the curative effects of radical surgery for patients with lymph node metastasis., Methods: One hundred and eleven consecutive patients who had undergone radical surgery for GBC were included in this study. The pattern of lymph node metastases was examined histopathologically, using the TNM staging of the American Joint Committee on Cancer., Results: There was no neurovascular invasion or lymph node involvement in 15 patients with pT1 tumors. Sixty of 96 patients with pT2-4 tumors had lymph node metastases. The pericholedochal lymph node was the most common metastatic lymph node, followed by the cystic lymph node. The frequency of metastases in retroportal, posterosuperior pancreaticoduodenal, and interaorticocaval lymph nodes was >15% in all cases. pT3-4 tumors had significantly more lymph node involvement (79%) and significantly higher N2:N1 ratios (2.5) than pT2 tumors (46% and 0.6, respectively). There was no difference in 5-year survival between N0 and N1 groups in pT2-4 tumors (66% in N0 and 53% in N1). Patients with N2 disease had a significantly worse prognosis, but 4 patients survived >5 years., Conclusions: The cystic and pericholedochal lymph nodes are the initial site of spread from GBC. The frequency of lymph node involvement is strongly influenced by the depth of invasion of the primary tumor. GBC limited to such lymph node metastases can be cured by surgery in >50% of such cases.

Background: There is considerable evidence that blood returning from different abdominal organs does not mix completely but maintains streamline flow in the portal vein. This study tested the hypothesis that the location of primary colorectal carcinoma affects the intrahepatic distribution of liver metastases according to streamline flow in the portal vein., Methods: Eighty-five patients with histologically verified liver metastases from colorectal carcinoma underwent potentially curative hepatectomy. Primary tumor location was the right-sided colon in 18 patients and the left-sided colon in 67. The liver was divided into two lobes by Cantlie's line., Results: A total of 195 metastatic deposits were resected: 135 in the right lobe and 60 in the left. In the right-sided colon carcinoma group, 29 deposits were in the right lobe and 3 in the left. In the left-sided colon carcinoma group, 106 deposits were in the right lobe and 57 in the left. The pattern of lobar distribution was significantly different in the two groups (P = 0.003)., Conclusions: Right-sided colon cancers selectively involve the right lobe, while left-sided tumors involve the entire liver, considering the ratio of weights of the right to left lobe is 2:1. This difference suggests that primary tumor location affects the pattern of lobar distribution of colorectal carcinoma liver metastases according to streamline flow in the portal vein.

Background: The optimal hepatic resection margin for gallbladder cancer (GBC) is still debated. To explore this issue, the authors analyzed the mode of hepatic spread of GBC., Methods: Of 85 patients undergoing radical cholecystectomy, 20 had hepatic metastases. The pattern of hepatic metastasis was examined grossly and histologically in specimens., Results: Twelve patients had evidence of microscopic angiolymphatic portal tract invasion, with or without direct liver invasion. Four had direct invasion alone, and three had distant hepatic metastatic nodules. The distance (y axis) between the farthest angiolymphatic lesion and primary tumor (mm) correlated significantly with the gross depth (x axis) of direct invasion (mm): y = 1.3 + 0.33x (r = 0.88, P < 0.01). Three patients with metastatic nodules died of blood-borne disease within a year. Eight of the others obtained either long-term palliation or cure after potentially curative resection. Lymph node metastases were detected in 90% of patients., Conclusions: The extent of microscopic angiolymphatic portal tract invasion correlates well with the gross depth of direct invasion of the liver. This correlation may be useful for estimating adequate hepatectomy margins. A hepatectomy with an adequate margin combined with a radical lymphadenectomy provides benefit for selected patients with hepatic metastases.

Background: Many kinds of human malignant tissue, including hepatocellular carcinoma (HCC), were reported to overexpress transforming growth factor-beta 1 (TGF-beta 1) gene. However, little work has been done on the circulating TGF-beta 1 in patients with malignant tumors., Methods: Plasma TGF-beta 1 levels in patients with HCC (n = 26) were compared with those in patients with chronic hepatitis (CH) (n = 12) and cirrhosis (n = 11) and in normal subjects (n = 20) using an enzyme-linked immunosorbent assay system after acid/ethanol extraction., Results: The patients with HCC had significantly higher plasma TGF-beta 1 levels (19.3 +/- 19.5 ng/ml; mean +/- standard deviation [SD]) than those in normal subjects (1.4 +/- 0.8 ng/ml) and in patients with CH (3.0 +/- 3.1 ng/ml) and cirrhosis (3.7 +/- 2.1 ng/ml) (P < 0.01). Plasma TGF-beta 1 concentrations in the patients with cirrhosis were also significantly higher than those in the normal subjects (P < 0.05). The extracted plasma TGF-beta 1 from the patients with HCC had biologic activity according to a growth inhibitory assay using mink lung epithelial cells. No significant correlation was found between the plasma TGF-beta 1 levels in the patients with HCC and serum alpha-fetoprotein levels. After successful treatment for HCC, the amount of plasma TGF-beta 1 significantly decreased from 22.6 plus or minus 16.7 ng/ml (mean +/- SD) to 10.2 plus or minus 6.5 ng/ml (P < 0.05)., Conclusions: We demonstrated higher levels of plasma TGF-beta 1 in the patients with HCC than those in patients with chronic hepatitis and cirrhosis. Plasma TGF-beta 1 might be a candidate for a novel tumor marker for hepatocellular carcinoma.

Specimens from 3197 consecutive and unselected cholecystectomies performed during a 6-year period were studied. Adenomyomatosis of the gallbladder was defined as a lesion characterized by a thickened wall that consisted of Rokitansky-Aschoff sinuses surrounded by proliferated fibromuscular tissue. Adenomyomatosis was found in 279 specimens and classified as one of three types: segmental, fundal, or diffuse. Segmental adenomyomatosis was found in 188 specimens; gallbladder cancer (GBC) developed in 12 (6.4%) of the patients with segmental type adenomyomatosis. GBC developed in the mucosa of the fundal compartment distal to the annular stricture of the segmental type adenomyomatosis in all 12 of these patients. Conversely, GBC developed in 93 (3.1%) of the other 3009 patients (those with fundal alone, diffuse, or no adenomyomatosis). The prevalence of GBC in patients with segmental adenomyomatosis was significantly (P less than 0.025) higher than that of patients without segmental adenomyomatosis. Clinicians should be aware that segmental adenomyomatosis often coexists with GBC.